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Why is metabolism of ethanol catabolism? Could it be also detoxification?

Why is metabolism of ethanol catabolism? Could it be also detoxification?



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Detoxification is the physiological or medicinal removal of toxic substances from a living organism, including the human body, which is mainly carried out by the liver. Additionally, it can refer to the period of withdrawal during which an organism returns to homeostasis after long-term use of an addictive substance. (Source: https://en.wikipedia.org/wiki/Detoxification)

  • Ethanol is metabolised in liver with ADH, which oxidises ethanol to acetaldehyde. The latter is a toxic substance and can cause tissue damage, therfore, it must be further oxidised by ALDH to form a non-toxic product, acetate.

  • Ethanol can be an addictive substance.

Why is ethanol metabolism catagorized as catabolism? Could it also be detoxification (according to the assumptions above)? Why not?

Is ethanol metabolism a catabolic metabolic pathway because it provides NADH and acetate (which can be activated to acetyl-CoA) for anabolic reactions? Or is there another reason?


These are somewhat loosely defined terms, but I would say catabolism is any metabolic process that extracts energy from a substrate. Ethanol conversion to acetate (via alcohol dehydrogenase; see this schematic) is an oxidative pathway which extracts energy in the form of NADH, so yes, it is a catabolic pathway.

I guess you can also call this process detoxification, since it removes a (mildly) toxic metabolite. Anyway, I think the "classification" of a pathway is less important than understanding the actual biochemistry.


The Detox Scam: How to spot it, and how to avoid it

New Year, New You, right? 2014 is the year you’re finally going to get serious about your health. You’re winding down from a week (or more) of celebrations and parties. You’re pretty much recovered from New Year’s Eve by now. It’s time to make some resolutions. Conveniently, there is no shortage of solutions being advertised to absolve you of your sins while overhauling your body and soul for 2014: What you need to do is “detox”. You’ll see the detox kits at your local Whole Foods (or even your local pharmacy). Books, boxes or bottles, with some combination of “detox”, “cleanse” or “flush” in the product name. Supplements, tea, homeopathy, coffee enemas, ear candles, and footbaths all promise detoxification. The advertising suggests you’ll gain a renewed body and better health – it’s only seven days and $49.95 away. Or try to cleanse yourself with food alone: Dr. Oz is hyping his Holiday Detox plan. Bon Appetit is featuring their 2014 Food Lover’s Cleanse. Or what about that old standby, the “Master Cleanse”? It’s the New Year – wouldn’t a purification from your sins of 2013 be a good idea to start the year? After all, the local naturopath offers complete detoxification protocols, including vitamin drips and chelation. There must be something to it, right?

Wrong. “Detox” is a case of a legitimate medical term being turned into a marketing strategy – all designed to treat a nonexistent condition. In the setting of real medicine, detoxification means treatments for dangerous levels of drugs, alcohol, or poisons, like heavy metals. Detoxification treatments are medical procedures that are not casually selected from a menu of alternative health treatments, or pulled off the shelf in the pharmacy. Real detoxification is provided in hospitals when there are life-threatening circumstances. But then there are the “toxins” that alternative health providers claim to eliminate. This form of detoxification is simply the co-opting of a real term to give legitimacy to useless products and services, while confusing consumers into thinking they’re science-based. Evaluating any detox is simple: We need to understand the science of toxins, the nature of toxicity, and how detox rituals, kits, and programs claim to remove toxins. With this framework, it’s a simple matter to spot the pseudoscience and be a smarter consumer.

Premise one: Our bodies are accumulating toxins

There’s a reason we fall for the marketing of detoxification – we seem hardwired to believe we need it, perhaps related to our susceptibility to ideas of sympathetic magic. Purification rituals date back to the earliest reaches of recorded history. The idea that we’re somehow poisoning ourselves and we need to atone for our sins seems to be a part of human nature, which may explain why it’s still a part of most of the world’s religions. It’s not miasmas or perhaps sin that we’re as worried about today, however. As our knowledge of biology grew, these fears manifested as “autointoxication.” Clean out the bowels, went the theory, and you could cure any illness. Science led us to discard autointoxication by the 1900’s as we gained a better understanding of anatomy, physiology, and the true cause of disease. Despite the science, however, the idea persists among alternative practitioners. Today’s version of autointoxication argues that some combination of food additives, gluten, salt, meat, fluoride, prescription drugs, smog, vaccine ingredients, GMOs, and perhaps last night’s bottle of wine are causing a buildup of “toxins” in the body. But what is the actual “toxin” causing harm? It’s nothing more than a meaningless term that sounds scientific enough to be plausible. A uniform feature of detox treatments is the failure to name the specific toxins that these rituals and kits will remove. For example Renew Life promises you:

CleanseSMART is a 2 part, 30 day, advanced herbal cleansing program. It is formulated to stimulate the detoxification process of the body’s 7 channels of elimination: the liver, lungs, colon, kidneys, blood, skin, and lymphatic system. In today’s toxic world, cleansing and detoxification is a necessity. Toxins enter our body daily through the air we breathe, the food we eat, and the water we drink. Over time, these toxins build up and slowly start to affect our health in a negative way.

Through cleansing and detoxification, you enable your body to better process this toxic load. Reducing the toxic load in your body decreases the risk of developing chronic health problems, improves overall health and immune response, and can increase energy levels. CleanseSMART works to cleanse and detoxify the entire body, but with focus on the body’s two main detoxification pathways – the liver and the colon. CleanseSMART is essential for helping eliminate constipation and improving bowel health.

Note the vague language. Toxins are alluded to – but not named. It sounds somewhat plausible, but is non-specific. Note that even if you’re well (and presumably toxin free?) a detox is still recommended.

The colon remains ground zero for detox advocates. They argue that some sort of toxic sludge (sometimes called a mucoid plaque) is accumulating in the colon, making it a breeding ground for parasites, Candida (yeast) and other nastiness. Fortunately, science tells us otherwise: mucoid plaques and toxic sludge simply do not exist. It’s a made-up idea to sell detoxification treatments. Ask any gastroenterologist (who look inside colons for a living) if they’ve ever seen one. There isn’t a single case that’s been documented in the medical literature. Not one.

Premise two: Illness is the result of toxins

Marketing materials for detox treatments typically describe an array of symptoms and diseases linked to toxin buildup: A few that are general enough to apply to anyone (e.g., headache, fatigue, insomnia, hunger) with a few specifics to frighten you (cancer, etc.) Which toxins cause which disease is missing, and how the toxins cause the symptoms is never actually explained. Here again we see the contrast with real science. To establish that even a single chemical can cause disease requires a significant amount of research (i.e., the entire field of epidemiology). Despite the variety of toxins that are claimed to be causing your illness, marketing claims for detox treatments will uniformly fail to link specific toxins to specific symptoms or illnesses.

The reality is that our bodies are constantly being exposed to a huge variety of natural and synthetic chemicals. The presence of any chemical in the body, (natural or synthetic) does not mean that it is doing harm. Many naturally-derived substances can be exceptionally toxic, and consequently the human body has evolved a remarkable system of defenses and mechanisms to defend against, and remove unwanted substances. The skin, kidneys, lymphatic system, our gastrointestinal system, and most importantly, the liver make up our astoundingly complex and sophisticated intrinsic detoxification system. Importantly, the dose makes the poison – even water can be toxic (dilutional hyponatremia) when consumed in excessive amounts.

Advocates for detox typically describe the liver and kidney as acting like filters, where toxins are physically captured and retained. It’s argued that these organs to be cleaned out periodically, like you’d rinse out a sponge, or change the air filter in your car. But the reality is the kidney and liver don’t work this way. The liver performs a series of chemical reactions to convert toxic substances into ones that can be eliminated in bile, or the kidneys. The liver is self-cleansing – toxins don’t accumulate in it, and unless you have documented liver disease, it generally functions without any problem. The kidney excretes waste products into the urine – otherwise the substance stays in the blood. To argue that either organ need a “cleanse” is to demonstrate a profound ignorance of human physiology, metabolism, and toxicology.

Premise three: Detox treatments remove toxins

A search of the medical literature for clinical studies of detox kits provides the following result:

There is no credible evidence to demonstrate that detox kits do anything at all. They have not been shown to remove remove “toxins” or offer any health benefits. The same can be said for quackery like coffee enemas – there is no credible evidence to support claims that coffee enemas help the body to “detoxify” compounds, or help the liver function more effectively. Vitamin injections are another treatment that fail to offer meaningful benefits to consumers, and have no beneficial effect on the ability of your liver or kidneys to work effectively. Chelation injections are touted as a cure-all for all kinds of illnesses, but unlike real chelation that’s administered in hospitals for real cases of poisoning, naturopath chelation is not science-based and doesn’t seem to do much of anything.

Can Detoxing be harmful?

If they provide no benefit, is there the potential for detox treatments to harm?

When it comes to simple dietary changes, there’s little evidence of harm. Eating more quinoa and kale, and less processed and refined foods is reasonable dietary advice for everyone. Homeopathic “detox” is also likely safe – with no active ingredients, homeopathy is an elaborate placebo system. As you get into more unorthodox detox treatments that actually contain active ingredients, it’s clear that some approaches are demonstrably risky. Coffee enemas are considered unsafe and should be avoided. Harms such as septicemia (bacteria in the bloodstream), rectal perforation, and electrolyte abnormalities have been reported. Even deaths. Vitamin injections don’t seem as risky, as long as you trust the sterile technique of your alternative provider. However, given some naturopaths seem to be willing to inject products intended for oral use, you might want to think carefully about taking a vitamin injection or chelation treatment, especially when there’s no reasonable expectation of any benefit.

What about the detox kits? Contents vary, but typically contain two categories of ingredients:

  1. A liver “booster” – typically milk thistle (Silibum marianum). If the liver can’t be wrung out and rejuvenated, can it be boosted to do a better job? Milk thistle is the most popular product purported to “boost” the liver’s effectiveness. There are no published studies that demonstrate milk thistle has a detoxifying effect on the liver. Milk thistle has been studied in patients with alcoholic liver disease, and in patients with hepatitis B or C, and it has not been found to exhibit any meaningful effects. There is no evidence to suggest that consuming milk thistle will cleanse you of unnamed “toxins”.
  2. A laxative – Typically magnesium hydroxide, senna, rhubarb, cascara, etc. Laxatives are the ingredients in detox kits that give you the effect you can see (and feel). However, these ingredients can cause dehydration and electrolyte imbalances if not used carefully. Regular use of stimulant laxatives, like senna and cascara, are ill-advised for most healthy adults due to the risk of dependence and electrolyte depletion. They’re among the most potent laxatives, usually used for short periods to alleviate significant constipation or to clear out your bowels before a medical procedure. With regular use, your bowel can grow accustomed to the effects of laxatives which may result in constipation once you stop using them. It’s a perfect case of the treatment causing the illness: After the detox, you get could conceivably become constipated: Time for another detox!

Side effects can continue once a detox ends. Some people experience post-detox effects like nausea and diarrhea. Advocate call these “cleansing reactions” and will assure you it’s “toxins leaving the body”. A more plausible, science-based explanation is that this is a consequence of restarting the digestion process after a period of catharsis, where, depending on the extent and duration of fasting, little to no digestion occurred, and the normal gastrointestinal flora may have been severely disrupted. It’s the same effect seen in hospitalized patients who have difficulty initially digesting food after being fed intravenously. The detox ingredients, and resulting catharsis, may irritate the colon to such an extent that it may take time to return to normal.

Immediate weight loss is not uncommon after a detox, especially one that involves a laxative. Unfortunately this is usually due to losses in water and possibly muscle tissue, depending on the how disruptive the detox was to normal body function Regardless of the weight loss, the body will move back to its pre-detox weight over time if diet and activity levels remain the same.

Conclusion

Any product or service with the words “detox” or “cleanse” in the name is only truly effective at cleansing your wallet of cash. Alternative medicine’s ideas of detoxification and cleansing have no basis in reality. There’s no published evidence to suggest that detox treatments, kits or rituals have any effect on our body’s ability to eliminate waste products effectively. They do have the ability to harm however – not only direct effects, like coffee enemas and purgatives, but the broader distraction away from the reality of how the body actually works and what we need to do to keep it healthy. “Detox” focuses attention on irrelevant issues, and gives consumers the impression that they can undo lifestyle decisions with quick fixes. Improved health isn’t found in a box of herbs, a bottle of homeopathy, or a bag of coffee pushed into your rectum. The lifestyle implications of a poor diet, lack of exercise, smoking, lack of sleep, and alcohol or drug use cannot simply be flushed or purged away. Our kidneys and liver don’t need a detox treatment. If anyone suggests a detox or cleanse to you, you’d do well to ignore the suggestion, and question any other health advice they may offer.


The Truth About How Your Metabolism Changes As You Age

No matter what your metabolism is like in your teens and 20s, you’ve probably been told that it’s all just downhill once you hit 30. “Wait until you hit 30,” or “You won’t be able to eat like that once you hit 30,” are commonly dispensed tidbits of “advice” from our elders. This makes it seem like an internal switch is flipped once we hit the big 3-0, and our bodies just stop knowing how to use energy efficiently. While there is truth to the notion that many people’s metabolisms slow down with age, it’s not as simple as pinpointing one specific birthday upon which everything changes.

“It is an actual fact that metabolism changes over time,” Kristen F. Gradney, R.D., director of nutrition and metabolic services at Our Lady of the Lake Regional Medical Center and spokesperson for the Academy of Nutrition and Dietetics, tells SELF. But, rest assured, you’re not going to just wake up one morning with a drastically slower metabolism. “It happens more progressively over time,” she says. That’s because it’s preempted by hormonal shifts that happen slowly as we go through life—not overnight.

And while we can’t avoid these natural changes that come with age, we can do some things to push them off a bit. Here, experts explain what’s actually happening when your metabolism slows down, and what lifestyle habits you can adopt to resist it for longer.

Even when we’re just sitting around doing nothing, our bodies need energy for basic things like breathing, adjusting hormones, and repairing cells. The amount of calories we burn at rest is called our basal metabolic rate. You can use an online calculator to find yours, or get it measured in a doctor’s office. While the calories you burn each day can vary drastically depending on how active you are, your BMR stays pretty consistent. It’s regulated by hormones. Everyone’s is different, depending on things like genetics, age, gender, and body composition. As we age, “there are actual real hormonal changes that take place in our body that then affect the way we store fat and lose fat,” Gradney explains. “Our metabolic rate actually decreases because of these differences in hormones.”

The epic slowdown usually happens later than we think. Gradney says, “Menopause is more the indicator of when it happens, which is around 50 on average.” While multiple hormones are important for regulating metabolism, the decrease in estrogen around menopause makes a big impact.

The pituitary gland’s production of growth hormone also slows more noticeably as we age, according to Harvard Health. Growth hormone stimulates cell growth, and is especially important as we’re young and, yes, growing. But throughout our entire lives, the hormone is used to build muscle mass, boost protein production, and effectively utilize fat. As growth hormone decreases, your body can't make or maintain muscle as well, and it can impact how efficiently your body breaks down calories, Jackie Baumrind, M.S., C.D.N., a dietician at Selvera Wellness, tells SELF.

Shifts in other hormones and other age-related changes like cell damage and inflammation, can further lead to sarcopenia, or age-related muscle loss. Muscle fibers may break down faster and be built back up more slowly. “Muscle mass is more metabolically active than fat mass,” Baumrind says, which means that it demands more energy from our bodies to maintain itself. Less muscle mass means our bodies will burn fewer calories at rest.

Gradney says your metabolism may start to decline very slowly in your 30s and 40s, but lifestyle changes during this time (that you may not even know you’re making) are usually more responsible for weight gain. “Most people at 20 are a lot more active than when at 30,” says Gradney. “Evaluate what your level of physical activity has been over time and maintain that,” she suggests. If your lifestyle has changed—maybe you just had a baby (which comes with its own set of hormonal changes) or got a big promotion and are working more hours—that may mean getting creative and sneaky about fitting in activity. Same thing goes for healthy eating.

Your genetics matter, of course, but the way you take care of yourself also makes a difference. “If you have good genes but don’t exercise or eat right, there’s still the risk that you could see that decline earlier,” says Gradney. “The best thing to do is to remain physically active, maintain muscle mass, and have a good diet. If you do those things, that progressive decline will be slower.” If genetics are on your side and you make the effort to maintain healthy habits over the years, she says you can stave off big metabolism changes until you approach your 60s or for some, even early 70s. Thirty shmirty.


Aberrant Metabolism in Hepatocellular Carcinoma Provides Diagnostic and Therapeutic Opportunities

Hepatocellular carcinoma (HCC) accounts for over 80% of liver cancer cases and is highly malignant, recurrent, drug-resistant, and often diagnosed in the advanced stage. It is clear that early diagnosis and a better understanding of molecular mechanisms contributing to HCC progression is clinically urgent. Metabolic alterations clearly characterize HCC tumors. Numerous clinical parameters currently used to assess liver functions reflect changes in both enzyme activity and metabolites. Indeed, differences in glucose and acetate utilization are used as a valid clinical tool for stratifying patients with HCC. Moreover, increased serum lactate can distinguish HCC from normal subjects, and serum lactate dehydrogenase is used as a prognostic indicator for HCC patients under therapy. Currently, the emerging field of metabolomics that allows metabolite analysis in biological fluids is a powerful method for discovering new biomarkers. Several metabolic targets have been identified by metabolomics approaches, and these could be used as biomarkers in HCC. Moreover, the integration of different omics approaches could provide useful information on the metabolic pathways at the systems level. In this review, we provided an overview of the metabolic characteristics of HCC considering also the reciprocal influences between the metabolism of cancer cells and their microenvironment. Moreover, we also highlighted the interaction between hepatic metabolite production and their serum revelations through metabolomics researches.

1. Introduction

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. It represents the fifth most common cancer worldwide and the second most frequent cause of cancer-related deaths [1]. HCC occurs most often in people with chronic liver diseases related to viral (chronic hepatitis B and C), toxic (alcohol and aflatoxin), metabolic (diabetes, hemochromatosis, and nonalcoholic fatty liver disease), and immune (autoimmune hepatitis and primary biliary) factors [1].

Effective management of HCC depends on early diagnosis and proper monitoring of the patients’ response to therapy through the identification of pathways and mechanisms that are modulated during the process of tumorigenesis. In this context, the interest towards the concept of tumor metabolism is growing for several reasons: (i) metabolic alteration is a recognized hallmark of cancer, (ii) oncogenes drive alterations in cancer metabolism, (iii) metabolites can regulate gene and protein expressions, and (iv) metabolic proteins and/or metabolites represent diagnostic and prognostic biomarkers [2–6].

Metabolic alterations constitute a selective advantage for tumor growth, proliferation, and survival as they provide support to the crucial needs of cancer cells, such as increased energy production, macromolecular biosynthesis, and maintenance of redox balance. Although this is a common feature for all tumor types, it is still not completely clear how the tumor metabolic demand can really influence the metabolic profile and homeostasis of other tissues. Can they act as tumor bystanders or do they have an active role in supporting tumor growth? In this scenario, the liver represents a perfect metabolic model that governs body energy metabolism through the physiological regulation of different metabolites including sugars, lipids, and amino acids [7]. How can HCC metabolic alterations support tumor growth and influence systemic metabolism?

In this review, we take a detailed look at the alterations in intracellular and extracellular metabolites and metabolic pathways that are associated with HCC and describe the functional contribution on cancer progression and metabolic reprogramming of tumor microenvironment including immune cells. The analysis of circulating metabolites by metabolomics may provide us with novel data about this systemic crosstalk.

2. Reprogramming of Glucose Metabolism: Increased Uptake of Glucose and Lactate Production

In physiological conditions, the liver produces, stores, and releases glucose depending on the body’s need for this substrate. After a meal, blood glucose enters the hepatocytes via the plasma membrane glucose transporter (GLUT). Human GLUT protein family includes fourteen members which exhibit different substrate specificities and tissue expression [8]. Once inside the cell, glucose is first converted, by glycolysis, into pyruvate and then completely oxidized into the mitochondrial matrix by the tricarboxylic acid (TCA) cycle and the oxidative phosphorylation. Alternatively, it can be channelled in the fatty acid synthesis pathway through the de novo lipogenesis (DNL). Glucose-6-phosphate dehydrogenase, the rate-limiting enzyme of the pentose phosphate pathway, is used in the liver to generate reduced nicotinamide adenine dinucleotide phosphate (NADPH) that is required for lipogenesis and biosynthesis of other bioactive molecules. In pathological conditions, glucose energy metabolism is altered. Important changes have been observed not only in the expression of specific transporters and enzyme isoforms but also in the flux of metabolites.

HCC tumors display a high level of glucose metabolism [9] (Figure 1). This enhanced metabolic demand is important for metabolic imaging and well supported by the ability of 18F-fludeoxyglucose (18F-FDG) positron emission tomography (PET) to correlate with unfavorable histopathologic features [10] and with the proliferative activity of tumor [11]. Moreover, high glucose levels as observed in patients with diabetes can accelerate tumorigenesis in HCC cells by generating advanced glycation end-products and O-GlcNAcylation of the Yes-associated protein (YAP) and c-Jun [12, 13].

The common feature of these alterations is an increased glucose uptake and production of lactate even in the presence of oxygen and fully functioning mitochondria (Warburg effect) [2, 3], but it is not correlated with enhanced gluconeogenesis as the expression of phosphoenolpyruvate carboxykinases 1 and 2 and fructose 1,6-bisphosphatase 1 (FBP1), has been reported to be downregulated in HCC [14]. Overall, this metabolic reprogramming promotes growth, survival, proliferation, and long-term maintenance [15]. To respond to this metabolic requirement, HCC tumors enhance glucose uptake [16] by upregulating GLUT1 and GLUT2 isoforms [17–19]. siRNA-mediated abrogation of GLUT1 expression inhibits proliferative and migratory potential of HCC cells [20], while GLUT2 overexpression was correlated to a worse prognosis [21, 22].

Once inside the cell, glucose is converted in glucose-6-phosphate (G6P) by the hexokinase (HK), which is the first enzyme of the glycolytic pathway. Five major hexokinase isoforms are expressed in mammalian tissues and denoted as HK1, HK2, HK3, HK4, and the isoform hexokinase domain containing 1 (HKDC1). HCC tumors express high levels of the HK2 isoform, and its expression is correlated with the pathological stage of the tumor [23, 24]. In HCC, HK2 knockdown inhibited the flux of glucose to pyruvate and lactate, increased oxidative phosphorylation, and sensitized to metformin [24]. Moreover, HK2 silencing also synergized with sorafenib to inhibit tumor growth in mice [24]. Interestingly, a new member of the HK family the isoform HKDC1 was upregulated in HCC tissues compared with the adjacent normal tissues. HCC patients with high expression levels of HKDC1 had poor overall survival. Silencing HKDC1 suppressed HCC cell proliferation and migration in vitro, probably by the repression of the Wnt/β-catenin pathway [25].

The transition to glucose metabolism involves alterations in different glycolytic enzymes. A well-characterized example is the decreased expression of FBP1 [26]. FBP1 downregulation by promoter methylation and copy-number loss contributed to HCC progression by altering glucose metabolism [26]. An increased expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) [27, 28] and pyruvate kinases 2 (PKM2) [9, 29, 30] was also described. The altered expression of these enzymes supports the flux of glucose in the glycolytic pathway leading to the generation of pyruvate that may be either used to generate lactate or be directed towards the TCA cycle. The high glutamine utilization and the high levels of lactate observed in HCC tissues are both in accordance with the first hypothesis, suggesting an increased TCA carbon anaplerosis in HCC cells [24, 31]. Glutamine represents the most abundant amino acid in blood and tissues and represents the major hepatic gluconeogenic substrate. A metabolic shift towards glutamine regulates tumor growth in HCC [14]. Hepatoma cells have an accelerated metabolism and net glutamine consumption, with potential implication at the systemic level [32].

Glutamine is metabolized in several distinct pathways. By glutaminolysis, glutamine can be converted to α-ketoglutarate to replenish TCA cycle thus supporting energy production and providing intermediates for other biosynthetic pathways. By reductive carboxylation, glutamine moves in reverse of the TCA cycle from α-ketoglutarate to citrate to sustain lipid synthesis. So far, conflicting data have been reported on the role of glutamine in HCC. In fact, a study demonstrated that glutamine is metabolized mainly via glutaminolysis and not via reductive carboxylation to be converted into lactate [24]. Another study did not support this hypothesis as the great majority of enzymes involved in the conversion of glutamine to α-ketoglutarate were significantly downregulated in HCC compared to the normal liver [14]. This highlights the heterogeneous behaviour of this pathway that might be influenced by specific conditions of the microenvironment or its correlation to specific genetic alterations. For instance, glutamine metabolism in HCC varied in relation to the initiating lesion. Mouse liver tumors induced by MYC overexpression significantly increased both glucose and glutamine catabolism, whereas MET-induced liver tumors used glucose to produce glutamine [33].

The metabolic reaction that generates lactate from pyruvate is catalysed by lactate dehydrogenase (LDH). In humans, five active LDH isoenzymes are present and each of which is a tetrameric enzyme composed of two major subunits, M and H (formally A and B), encoded by Ldh-A and Ldh-B, respectively. The M subunit is predominantly found in the skeletal muscle, whereas the H subunit in the heart. LDHA and LDHB are upregulated in human cancers and associated with aggressive tumor outcomes [34–36].

In human HCC, LDHA expression was upregulated as a consequence of the downregulation of the microRNA-383 [37]. LDHA knockdown induced apoptosis and cell growth arrest in HCC cells and suppressed metastasis in a xenograft mouse model [38]. Serum LDH has been used as a prognostic indicator for patients with HCC treated with sorafenib, undergoing transcatheter arterial chemoembolization (TACE), or curative resection [39–42].

Lactate, the product of LDH activity, is exported in the extracellular milieu by monocarboxylate transporters (MCT). In HCC samples, an overexpression of MCT4 has been reported [43] and was also associated with Ki-67 expression [44]. Basigin, a transmembrane glycoprotein also called CD147, was found to be involved in the reprogramming of glucose metabolism in HCC cells. In particular, CD147 promoted glycolysis and facilitated the cell surface expression of MCT1 and lactate export [45]. Interestingly, blocking CD147 and/or MCT1 was reported to suppress HCC proliferation [45].

At a metabolic level, a high level of lactate with a low level of glucose was detected by nuclear magnetic resonance analysis in HCC samples [46]. This confirms the glycolytic shift toward lactate and provides a correlation between enzymatic alterations and metabolite expression [46]. The increased lactate concentration observed in the serum of HCC patients, compared to normal subjects, seems to be a consequence of this metabolic change [47]. However, the role of this secreted lactate still remains largely unclear. Nevertheless, increased lactate production was observed in patients with steatosis and steatohepatitis (NASH) compared to normal patients suggesting that the shift toward and anaerobic glucose metabolism can be involved in the first steps of liver carcinogenesis [48].

3. Altered Anabolic and Catabolic Lipid Pathways in HCC

The liver plays a key role in the metabolism of lipids and lipoproteins, and the anomalies in these metabolic pathways underlie HCC pathogenesis as demonstrated by increased risks observed in patients with obesity [49], diabetes [50], and hepatic steatosis [51]. After a carbohydrate reach meal, fatty acids can be synthetized from glycolytic pyruvate by DNL. Thus, entering the mitochondria, pyruvate is converted into acetyl-CoA by the pyruvate dehydrogenase enzyme. In the mitochondrial matrix, acetyl-CoA condensates with oxaloacetate to form citrate which, in conditions of high energetic charge, is conveyed to the cytoplasm throughout the citrate carrier for lipid synthesis. Key enzymes of cytosolic DNL are acetyl-CoA carboxylase (ACC), which catalyses the ATP-dependent carboxylation of acetyl-CoA to malonyl-CoA, and the multifunctional enzyme fatty acid synthase (FASN), which utilizes malonyl-CoA for synthesizing palmitoyl-CoA [52]. DNL also needs reducing power in the form of NADPH + H + , which is mainly generated through the glucose metabolism in the pentose phosphate pathway and in the malic enzyme reaction. DNL alterations were observed in HCC samples [53] and in other liver diseases, including nonalcoholic fatty liver disease (NAFLD) [54]. A combinatorial network-based analysis revealed that many enzymes involved in DNL, as well as enzymes related to NADPH production, such as glucose-6-phosphate dehydrogenase and malic enzyme, were upregulated in HCC with respect to the noncancerous liver samples [14].

During cancer progression, an overexpression of FASN is important for promoting tumor cell survival and proliferation [54], and it was also associated with poor patient prognosis [55]. In line with what observed in other types of tumors, recent studies described a functional association among lipogenesis, FASN, sterol regulatory element-binding protein-1 (SREBP-1), a transcription factor regulating FASN expression, and HCC [56–64]. The therapeutic effects of targeting FASN were investigated in several works. For instance, HCC induced by AKT/c-Met was fully inhibited in FASN knockout mice [65].

Alternative carbon sources can support the generation of acetyl-CoA required for DNL. This can derive from exogenous acetate, which is transported into cells by members of the MCT family and then converted to acetyl-CoA by acetyl-CoA synthase enzymes (mitochondrial ACSS1 and ACSS3 or cytosolic ACSS2) to fuel fatty acid synthesis (Figure 1). Mitochondrial ACSS1 expression, but not ACSS2 or ACSS3 ones, is significantly upregulated in HCC compared to noncancerous liver and associated with increased tumor growth and malignancy under hypoxic conditions [14].

Tumors can be addicted or independent from DNL by the activation of complementary pathways. In fact, both de novo synthetized and exogenous fatty acids can support the growth of HCC tumors [66]. The studies performed on animal models demonstrated that the inhibition of lipogenesis via genetic deletion of ACC genes increased susceptibility to tumorigenesis in mice treated with the hepatocellular carcinogen diethylnitrosamine, demonstrating that lipogenesis is essential for liver tumorigenesis [67].

The liver is able to take up nonesterified fatty acids from the blood, in proportion to their concentration, either via specific transporters (fatty acid transport protein (FATP) or fatty acid translocase/CD36) or by diffusion. The activation of the CD36 pathway has been associated with tumor aggressiveness by the induction of the epithelial-mesenchymal transition (EMT) program [68], which is a process that contributes to cancer progression [69, 70]. This is mediated through the involvement of specific pathways. The analysis of the Cancer Genome Atlas (TGCA) dataset revealed a significant association between CD36 and EMT markers, potentially by the activation of Wnt and TGF-β signaling pathways [71].

The liver is able to oxidize fatty acids by both mitochondrial and peroxisomal β-oxidation. The entry of fatty acids into the mitochondria is regulated by the activity of the enzyme carnitine palmitoyltransferase-I (CPT-I) [72], which catalyses the synthesis of acylcarnitines from very long acyl-CoA and carnitine, thus allowing the entry of polar fatty acids in the mitochondrial matrix. In a rat model of NASH, a decreased mitochondrial CPT-I activity [73] and dysfunction of both complex I and II of the mitochondrial respiratory chain [74] have been demonstrated. Moreover, deregulation of mitochondrial β-oxidation with downregulation of many enzymes involved in fatty acid oxidation has been reported in HCC patients [14]. Accordingly, the urinary level of short- and medium-chain acylcarnitines was found to be different in HCC vs. cirrhosis, and butyrylcarnitine (carnitine C4:0) was defined as a potential marker for distinguishing between HCC and cirrhosis [75]. All together, these data indicate that mitochondrial alterations can represent an early determinant in HCC.

The liver represents also a major site of synthesis and metabolism of endogenous cholesterol. The pool of cholesterol is tightly regulated, and it reflects the input of cholesterol from the diet, its biosynthesis, the secretion and uptake of cholesterol from plasma lipoproteins, the conversion of cholesterol into bile, and the reuptake of biliary cholesterol and bile acids from the intestine to the liver. The rate-limiting enzyme in the cholesterol synthesis is the 3-hydroxy-3-methylglutaryl-CoA reductase, which catalyses the synthesis of mevalonate.

There is increasing evidence that the mevalonate pathway is implicated in the pathogenesis of HCC [76, 77]. To this respect, clinical studies demonstrated that statins, widely used to reduce cholesterol levels, were able to reduce the risk of HCC [78] and showed antiproliferative effects in vitro on HepG2 cells and in vivo on rats with HCC [79]. Data from a meta-analysis report that the use of statins could significantly cut the risk of liver cancer and that fluvastatin is the most effective drug for reducing HCC risk compared to other statin interventions [80].

Cholesterol is also used in the liver for the synthesis of bile acids, which are hydroxylated steroids that, once secreted in the intestine, provide for solubilisation of dietary cholesterol, lipids, fat-soluble vitamins, and other essential nutrients, thus promoting their delivery to the liver. Primary bile acids, such as cholic acid and chenodeoxycholic acid, are synthesized in hepatocytes and can be conjugated to glycine or taurine [81]. Cholic acid conjugated to glycine, in the form of glycocholic acid, represents a secondary bile acid that is synthesized by microbiota in the small intestine [81]. It has been reported that intrahepatic bile acid may have a stimulatory effect of hepatic tumorigenesis [82] and abnormal bile acid metabolism has been correlated with HCC [83–86]. The hepatic deregulation of bile acid metabolism can result in increased serum level of glycolic acid, as reported by Guo and collaborators [87].

Modification in the activity of enzymes related to phospholipid remodelling has been reported in a rat model of cirrhosis [88]. Moreover, an altered lipid metabolism, including phospholipids, fatty acids, and bile metabolites, was observed in serum samples from HCC patients [89, 90]. In particular, higher phosphatidylcholines (PC) concentrations were observed in HCC patients at early and late stage compared to cirrhotic and control subjects, indicating a disturbance of the phospholipid catabolism [85]. This result significantly correlated with higher levels of PC observed at tissue level [91].

4. Alterations in Amino Acid and Protein Metabolism Underlying HCC

The liver carries out many functions in protein metabolism. A broad spectrum of proteins responsible for the maintenance of hemostasis, oncotic pressure, hormone, lipid transport, and acute phase reactions are synthetized in the liver. Among these proteins, albumin is synthesized almost exclusively by the liver, and alone, it accounts for 40% of hepatic protein synthesis. Moreover, the liver is also able to synthetize thyroid-binding globulin, VLDL apoB 100, and complement.

A very recent work reports that patients with lower serum albumin levels have significantly larger maximum tumor diameters, greater prevalence of portal vein thrombosis, increased tumor multifocality, and higher α-fetoprotein levels with respect to patients with higher albumin levels. These data indicate that decreased serum albumin correlates with increased parameters of HCC aggressiveness, therefore, having a role in HCC aggressiveness [92].

In the liver, the synthetized nonessential amino acids (AA) play a pivotal role in the maintenance of diverse homeostatic functions such as gluconeogenesis. Both synthetized amino acids and those derived from the diet are utilized either for protein synthesis or catabolized (except branched chain amino acids) by transamination or oxidative deamination reactions. These processes produce keto acids that can be oxidized to produce energy in the form of ATP. Several enzymes used in these pathways (for example, alanine transaminase and aspartate transaminase) are commonly assayed in serum to assess liver damage. Moreover, the oxidative deamination of amino acids produces ammonium ions, a toxic product whose detoxification can either occur in extrahepatic tissues, throughout the synthesis of glutamine when combined with glutamate, or in the liver, to make urea which is then transported to the kidneys where it can be directly excreted in urine.

An increased AA metabolism is generally observed in human tumors, in line with the role of AA and enzymes responsible for their production in cancer initiation and progression [93–96]. The shift toward an increased amino acid production is considered as a consequence of the described altered glucose metabolism. In the condition of increased consumption of glucose by aerobic glycolysis, amino acids can be used as glucose precursors or activators of glycolytic enzymes [97].

An altered AA metabolism characterizes HCC compared to other liver diseases. For instance, serum levels of alanine, serine, glycine, cysteine, aspartic acid, lysine, methionine, tyrosine, phenylalanine, tryptophan, and glutamic acid were dramatically increased in HCC compared with healthy subjects, together with a lower ratio of branched-chain amino acids (valine, leucine, and isoleucine) to aromatic amino acids (tyrosine, phenylalanine, and tryptophan) [98, 99].

Furthermore, AA bioavailability not only contributes to anabolic and catabolic pathways but it is also essential during HCC pathogenesis by supporting cellular hypoxic responses [100].

5. Oxidative Metabolism Imbalance in HCC

Oxidative stress occurs when reactive oxygen species (ROS) production overwhelms the normal antioxidant capacity of cells [101]. ROS are short-lived and very reactive molecules that rapidly react with cellular biomolecules yielding oxidatively modified products that eventually lead to cell injury and death. Due to the high instability of ROS, they cannot be easily detected, and protein carbonyls, 8-hydroxydeoxyguanosine, and 4-hydroxynonenal (which are oxidatively modified products of proteins, DNA, and lipids, respectively) have been widely used as markers for oxidative stress [102].

Accumulating evidence suggests that many types of cancer cells have increased levels of oxidative stress and ROS production with respect to normal cells [103]. As a consequence of this, redox homeostasis is finely regulated in cancer cells with an underappreciated role in the control of cell signaling and metabolism. For instance, ROS-mediated inhibition of PKM2 allows cancer cells to sustain antioxidant responses by diverting glucose flux into the pentose phosphate pathway and increasing the production of reducing equivalents for ROS detoxification [104]. Understanding the mechanisms at the basis of ROS homeostasis might have therapeutic implications.

Oxidative damage is considered a key pathway in HCC progression and increases patient vulnerability for HCC recurrence [105]. Oxidative stress closely correlates with HCV- and NASH-related HCC, but relatively weakly with HBV-related HCC [106]. Moreover, it has been reported that NASH-related HCC patients had a diminished serum antioxidative function compared with nonalcoholic fatty liver disease patients [107].

Glutathione is a nonenzymatic tripeptide that plays a central role in the cellular antioxidant defense system, and it represents the most abundant antioxidant in hepatocytes. Glutathione is synthesized intracellularly from cysteine, glycine, and glutamate, and it is abundantly found in the cytosol and mitochondria and in a smaller percentage in the endoplasmic reticulum [108]. During glutathione antioxidant function, the reduced form of glutathione (GSH) is oxidized to the glutathione disulfide dimer (GSSG). The regeneration of the reduced form requires the enzymatic action of glutathione reductase and reducing equivalents in the form of NADPH + H + . A significant increase in all amino acids related to the GSH synthesis, including 5-oxoproline, was observed in the serum of HCC patients, and an increase of G6P that represents an important source of NADPH for the generation of GSH has been also reported [109]. Moreover, signs of DNA and lipid oxidative damages were found in HCC. Indeed, an increased level of 8-hydroxydeoxyguanosine was found in chronic hepatitis, corresponding to an increased risk of HCC [110, 111]. In addition, a mass spectrometry study highlighted an increased level of 4-hydroxynonenal in human tissues of HCC compared to peripheral noncancerous tissues [112].

The GSH:GSSG ratio is considered an important indicator of the redox balance in cells, with a higher ratio representing low oxidative stress [107]. Upon depletion of GSH, ROS induce oxidative stress which causes liver damage, and reduced GSH levels have been reported in various liver diseases [113]. By-products of GSH synthesis are represented by γ-glutamyl peptides that are biosynthesized through a reaction of ligation of glutamate with various amino acids and amines by the action of γ-glutamylcysteine synthetase. Serum level of γ-glutamyl peptides, measured by capillary chromatography-MS/MS, was increased in patients with virus-related HCC [114, 115], and it was considered a reliable potential biomarker for this pathology [115]. The 2-hydroxybutyric acid is another compound considered in relation to GSH metabolism. It is primarily produced in mammalian hepatic tissues, which catabolize threonine or synthesize glutathione. Under conditions of intense oxidative stress, hepatic glutathione synthesis is increased, and there is a high demand for cysteine. In such cases, homocysteine is diverted from the transmethylation pathway and instead it is used to produce cystathionine, which is then cleaved into cysteine and finally incorporated into glutathione. 2-Hydroxybutyric acid is then produced from reduction of α-ketobutyrate, which is released as a by-product of the cystathionine conversion to cysteine. An increased serum concentration of 2-hydroxybutyric acid as well as of xanthine, an intermediate in the purine degradation process producing H2O2, and several γ-glutamyl peptides, were found in HCC with respect to control subjects [116, 117].

6. Metabolic Reprogramming of HCC Microenvironment

HCC microenvironment consists of stromal cells, hepatic stellate cells, and endothelial and immune cells. The crosstalk between tumor cells and their surrounding microenvironment is required for sustaining HCC development by promoting angiogenesis, EMT, or by modulating the polarization of immune cells. Tumor-associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC) are the major components of tumor-infiltrate and are abundant in HCC microenvironment (Figure 2) [118–120]. Metabolites released from tumor cells can have an impact on immune cells.

Inflammatory stimuli promote the switching of macrophages towards an M1-like phenotype characterized by the production of inflammatory cytokines. On the contrary, anti-inflammatory stimuli induce these cells to acquire an M2-like phenotype with immunosuppressive functions [121]. Thus, during chronic inflammation, macrophages predispose a given tissue to tumor initiation by releasing themselves factors that promote neoplastic transformation. In the successive phases of inflammation, the macrophage phenotype shifts more toward one that is immunosuppressive and supports tumor growth, angiogenesis, and metastasis [122]. In this respect, both epidemiological and clinical studies have demonstrated that various chronic inflammatory diseases can predispose to increased risk of cancer at the same site of inflammation, and HCC is a clear example of inflammation-related cancer.

TAM originate from circulating monocytic precursors, and they are recruited to tumor cells by tumor-derived signals. It has been reported that, in the early phase of the tumor, TAM acquire an inflammatory phenotype and shift their metabolism toward an anaerobic glycolytic pathway [122, 123]. This allows polarized macrophages to rapidly fuel themselves with energy and to cope with hypoxic tissue microenvironment. The interplay between M2-like TAM and cancer is complex, and it is involved in each step of HCC development. It has been demonstrated that this TAM subset promotes migration and EMT. It also induces cancer stem cell-like properties and drug resistance in human HCC, thus highlighting the importance of targeting the immune microenvironment as a mechanism to inhibit HCC recurrence and metastasis (Figure 2) [124]. Moreover, it has been shown that an increase in the M2-macrophage population is associated with poor prognosis in HCC [125]. TAM can use metabolites released from cancer cells to modulate their polarization status. This is supported by the findings that demonstrated that tumor-released lactate is utilized by TAM to increase the expression of vascular endothelial growth factor and to induce an M2-like status [126]. Lactate can also have effects on other cell types by increasing the number of MDSC, thus inhibiting NK cell function (Figure 2) [127]. The immunosuppressive functions of MDSC can also be regulated by other metabolites, including fatty acids. In MDSC, increased fatty acid uptake and fatty acid oxidation are induced by a STAT3/STAT5-mediated pathway leading to an increased expression of CD36. Accumulation of lipids increases the oxidative metabolism of MDSC and activates their immunosuppressive mechanisms [128].

7. Concluding Remarks and Perspectives

Global changes in metabolic pathways were identified across different tumor types [129, 130]. The picture that emerged for the comparison between tumors and normal tissue revealed common demands in biochemical pathways associated with biomass production, such as glycolysis, pentose phosphate pathway, purine, and pyrimidine biosynthesis, irrespective of the cell of origin. This cancer tissue-specific metabolic signature is well defined in HCC, where the high glucose demand supports PPP pathway, lactate production by anaerobic glycolysis, and fatty acid production by FASN. Glucose utilization is regulated at multiple levels, including the transcriptional regulation of metabolic enzymes and transporters whose expression is altered in HCC tissues, and consistent with the identification of mitochondrial DNA alterations which was associated with a reduced oxidative phosphorylation and enhanced glycolysis [131].

HCC cells also rely on other carbon substrates to support anaplerotic pathways. A role for glutamine and acetate in sustaining HCC bioenergetics has been proposed. Alternative anaplerotic pathways exist that rely on the transformation of pyruvate to oxaloacetate by pyruvate carboxylase to support the growth of HCC cells in glutamine-free conditions [132]. The dependence of HCC cells from lipid uptake should be also considered, suggesting the existence of a metabolic flexibility and of a possible cross-talk between metabolic pathways that might result by changes imposed by the tumor microenvironment or by the activation of specific signaling pathways. HCC cells can, for instance, modulate fatty acids uptake by the upregulation of CD36 and caveolin 1 that is mediated by the activation of Wnt and TGF-β pathways.

More unique metabolic features were also defined by TGCA studies where significant alterations by mutation or downregulation by hypermethylation in albumin, apolipoprotein B, and carbamoyl phosphate synthase I metabolic genes were observed in HCC [71].

Overall, this metabolic program seems to be essential for HCC biology to sustain tumor growth and progression, and targeting of these pathways might have significant clinical implications. For instance, clinical effects of dexamethasone are explicated in vivo by restoring gluconeogenesis [133], inhibition of proline production and targeting of transketolase significantly enhances the cytotoxic effect of sorafenib in vivo [134], and insights into nucleotide and lipid metabolism of HCC may provide novel clinical opportunities [135].

However, the design of therapeutic metabolic targeted strategies should be carefully evaluated taking into account tumor heterogeneity and tumor interaction with the microenvironment. Several approaches were applied to address these complexities, including computational, proteomics, and metabolomics. Specifically, these methods tried to move forward the analysis of a single metabolite to obtain not a static snapshot of tumor biology but a more dynamic picture of metabolic changes in cancer. In this context, the field has expanded to bypass some classical limitations as the small number of samples to be analyzed and the number of analytes to be revealed. By the integration of different omics approaches, genome-scale metabolic models (GEMM) provided a way to study metabolic pathways at systems level [136] and to predict the action of a pathway inhibition at multiple layers of biological complexity. A personalized GEMM has been realized for NAFLD patients [137, 138] and HCC patients [14, 139] to characterize a specific disease-related metabolic phenotype. Moreover, the detailed analysis of a specific metabolic status provides the opportunity to study network perturbations after drug treatment. GEMM built from six HCC patients has been used to predict the action of antimetabolites on cancer growth. The model identified 147 antimetabolites that can inhibit growth in any of the studied HCC tumors, and a smaller group of antimetabolites that were predicted to be effective in only some of the HCC patients, showing a more personalized mechanism of action [139]. Moreover, GEMM has become an informative approach to elucidate tumor heterogeneity at the metabolic level [14].

Although most studies were centered on tumor tissue, metabolomics analyses at the blood level showed to be promising in predicting metabolic alterations at the tissue level. Solid results were obtained with some metabolites, such as lactate and AA, and their altered expression in serum clearly mirrors a metabolic alteration of tumor tissue. The same is probably true for other metabolites such as fatty acids but not yet clarified.

Conflicts of Interest

The authors declare that there is no conflict of interest regarding the publication of this paper.

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Copyright

Copyright © 2018 Serena De Matteis et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Glycolysis

The Embden–Meyerhof–Parnas Pathway

Glycolysis can be broadly defined as an energy-yielding pathway that results in the cleavage of a hexose (glucose) to a triose (pyruvate). Although the term is often taken to be synonymous with the Embden–Meyerhof–Parnas (EMP) pathway, other glycolytic pathways exist, among them the Entner–Doudoroff pathway that proceeds via a gluconic acid intermediate and a complex set of rearrangements that proceed via a pentose intermediate ( Figure 1 ).

Figure 1 . The glycolytic pathways of Escherichia coli. The pathway farthest to the left is the Emden-Meyerhof-Parnas pathway the one farthest to the right is the Entner-Doudoroff pathway. The genes that code for the major enzymes of the pathways are shown in italics. Bold arrows indicate the production or consumption of high-energy bonds (in the form of ATP or PEP) or reducing power (as NADH or NADPH). The curved, bold line near the top of the figure represents the cytoplasmic membrane reactions above that curved line occur in the periplasm, those beneath it occur in the cytoplasm.

The EMP pathway is present in organisms from every branch of the bacteria, archaea, and eukarya. Clearly, this is an early evolutionary adaptation, probably present in the ancestor of all current life forms. This suggests that the EMP pathway evolved in an anaerobic, fermentative world. However, the pathway also functions efficiently as the basis for aerobic respiration of glucose. The differences between fermentation and respiration lie largely in the differing fates of the pyruvate produced (see later). For simplicity, this discussion focuses on the EMP pathway in the well-known bacterium Escherichia coli, though the basic features of the pathway are nearly universal.

Before glucose metabolism begins, it must be transported into the cell and phosphorylated. In E. coli, these two processes are intimately coupled such that the glucose is phosphorylated by the phosphotransferase system (PTS) as it passes into the cell. Since glucose-6-phosphate (G-6-P), like most if not all sugar phosphates, is toxic at high cellular concentrations, this transport process is tightly regulated. Transcription of the glucose-specific transporter gene, ptsG, is maximal only when cyclic adenosine monophosphate (cAMP) (signaling energy limitation) accumulates. Moreover, translation of ptsG messenger RNA (mRNA) is inhibited by the small RNA sgrS, which is produced when G-6-P accumulates. Thus, the import and concomitant phosphorylation to G-6-P is reduced whenever the demand for more energy is low or the concentration of G-6-P is dangerously high.

In the absence of a PtsG protein, other PTS-linked transporters, especially the mannose-specific transporter, ManXYZ, can also transport and phosphorylate glucose. However, ptsG mutants grow more slowly on glucose than on wild-type strains. Free glucose can also accumulate intracellularly from the degradation of glucose-containing oligosaccharides such as lactose or maltose. Entry of intracellular glucose into the EMP pathway occurs via a hexokinase encoded by the glk gene.

The next two steps in the EMP pathway prepare the G-6-P for cleavage into two triose phosphates. First, a reversible phosphoglucose isomerase (pgi gene) converts G-6-P to fructose-6-phosphate. A pgi mutant can still grow slowly on glucose by using other glycolytic pathways (see later), but the EMP pathway is blocked in a pgi mutant. The resulting fructose-6-phosphate is further phosphorylated at the C1 position to fructose-1,6,-bisphosphate at the expense of adenosine triphosphate (ATP) by a phosphofructokinase encoded by pfkA. A second minor isozyme of phosphofructokinase encoded by pfkB allows slow growth of pfkA mutants. A potentially competing set of phosphatases that remove the C1 phosphate from fructose-1,6,-bisphosphate function during gluconeogenesis but are controlled during glycolysis by a variety of feedback mechanisms to prevent futile cycling.

The next reaction in the pathway is the cleavage of fructose-1,6-bisphosphate to two triose phosphates that gives the pathway its name (glycolysis = sugar breakage). This reversible reaction is carried out by fructose bisphosphate aldolase (fbaA gene) and yields dihydroxyacetone phosphate (DHAP) and glyceraldehyde phosphate (GAP) as products. A second, unrelated aldolase (fbaB gene) is made only during gluconeogenesis and thus plays no role in glycolysis. The two triose phosphates are freely interconvertible via triosephosphate isomerase (tpi gene). DHAP is a key substrate for lipid biosynthesis. GAP is an important node in glycolysis two other common glycolytic pathways (see below) join the EMP pathway at GAP.

Up to this point, the EMP pathway can be regarded as a biosynthetic pathway since it yields three key biosynthetic building blocks (G-6-P, fructose-6-phosphate, and DHAP) at the expense of ATP and without any oxidative steps. The next step is the oxidative phosphorylation of GAP to 1,3-diphosphoglyceric acid, a high-energy compound. The incorporation of inorganic phosphate by GAP dehydrogenase (gapA gene) is coupled to the reduction of NAD + to NADH. Under aerobic conditions, this NADH is reoxidized using the respiratory chain to yield ATP. Under anaerobic conditions, this NADH is reoxidized by coupling to the reduction of products derived from pyruvate or other EMP pathway intermediates. The enzyme phosphoglycerate kinase (pgk gene) then phosphorylates adenosine diphosphate (ADP) to ATP at the expense of the C1 phosphate of 1,3-diphosphoglycerate. This is the first of two substrate-level phosphorylations where phosphate is transferred from a highly reactive substrate directly to ADP without the involvement of the membrane ATP synthase.

The next two steps rearrange the resulting 3-phosphoglycerate to the last high-energy intermediate of the pathway, phosphoenolpyruvate (PEP). First, the phosphate is transferred from the C3 position to the C2 position by a phosphoglycerate mutase. There are two evolutionarily unrelated isozymes, one of which (encoded by the gpmA gene) requires a 2,3-bisphosphoglycerate as a cofactor and the other (gpmM gene) does not. Although E. coli, Bacillus subtilis, and some other bacteria have both isozymes, many organisms have only one or the other. For example, the yeast Saccharomyces cerevisiae, the bacterium Mycobacterium tuberculosis, and all vertebrates have only the cofactor-dependent enzyme, whereas higher plants, the archaea, and the bacterium Pseudomonas syringae have only the cofactor-independent enzyme. A third isozyme (ytjC gene) appears to exist in E. coli, though its role is less clear.

The rearranged 2-phosphoglycerate is then dehydrated by an enolase (eno gene) to yield the key intermediate, PEP. Although pyruvate is generally considered to be the end product of the EMP pathway, it can be argued that PEP shares that honor. PEP is the ultimate source of phosphate for the PtsG-mediated transport/phosphorylation of glucose that initiates the pathway. In addition, the enzyme enolase is a required part of the degradasome that functions with the small RNA sgrS (described earlier) to inhibit translation of ptsG mRNA and stimulate degradation of ptsG mRNA. This reduces the generation of the otherwise toxic accumulation of G-6-P.

It is worth noting that PEP is a branch point under both aerobic and anaerobic conditions. The carboxylation of PEP by PEP carboxylase (ppc gene) provides oxaloacetate, which condenses with the acetyl-CoA derived from pyruvate to form citrate for running both the tricarboxylic acid (TCA) cycle and glyoxylate shunt aerobically. During fermentation, this same oxaloacetate is an intermediate in the reductive (NAD regenerating) pathway to succinate. In addition, the PEP-derived oxaloacetate is used (via a portion of the TCA cycle) for the biosynthesis of glutamic acid even under anaerobic conditions.

The last reaction is a substrate-level phosphorylation of ADP to ATP at the expense of PEP to yield pyruvate. The two isozymes of pyruvate kinase (pykA and pykF genes) are activated by sugar phosphates and the product of the pykF gene shows positive cooperativity with respect to the substrate PEP, again tending to prevent accumulation of this phosphorylated intermediate and thus preventing the generation of more G-6-P via the PEP-dependent PtsG transport mechanism.

At the end of the EMP pathway, 1 mol of glucose is converted to 2 mol of pyruvate, which can be used for further catabolism or for biosynthesis. It also yields 2 mol of ATP and 2 mol of NADH (which must be reoxidized for the pathway to continue operating). Since the pathway generates several toxic intermediates, it is not surprising that the flux through the pathway is tightly regulated. The enzymes of the pathway respond rapidly to variations in supply and demand by feedback inhibition and substrate activation of enzyme activities. They also respond (more slowly) by transcriptional regulation of gene expression in response to global regulators that vary from organism to organism.

The EMP pathway functions to generate both biosynthetic intermediates and catabolic energy from glucose. However, it also serves as a central trunk line into which many other catabolic pathways feed. G-6-P, fructose-6-phosphate, DHAP, and GAP are common junction points where catabolic pathways for sugars, alcohols, fats, and organic acids feed into the EMP pathway.


Do some people have a faster metabolism than others?

Body size, age, gender and genes all play a role in the speed of your metabolism.

Muscle cells require more energy to maintain than fat cells, so people with more muscle than fat tend to have a faster metabolism.

As we get older, we tend to gain fat and lose muscle. This explains why your metabolism may slow down as you get older.

In general, men tend to have a faster metabolism because they have more muscle mass, heavier bones and less body fat than women.

Your metabolism may be partly determined by your genes, although this is not yet fully understood.

Genes definitely play a role in muscle size and your ability to grow muscles, both of which affect your metabolism.


Clinical Observations

In 1995, I observed in my surgical practice that even after minor surgery, patients felt sleepy and lethargic in the post-operative period as long as 1 week. I suspect this is from accumulations of the anesthetic drug in the fat cells of the body (fat and brain), which slowly dissipated. One patient after minor surgery felt lethargic and sleepy for over 1 week and he used the sauna cleansing for 4 days and immediately noticed the anesthetic smell in the entire sauna. His lethargy and sleepiness immediately ended. Thereafter in our practice, I have made it a policy to have all our post-operative patients to use the sauna within 5 days and it has proven to be a worthwhile practice to eliminate any residual medications sequestered in the body fat. I have used this method frequently for anyone who has received high doses of medications in the hospital including chemotherapeutic drugs and radiation therapy at a selected time after a therapeutic period. Pharmacokinetics studies look at liver metabolism, blood circulation and excretion through urine, gastrointestinal tract etc. but rarely account for the sequestered chemicals in fatty cells.

A perfect example is one of our patients is an avid swimmer who has had chronic exposures to chlorinated water. The first time using the mobilization, cleanse, and elimination system, she eliminated Chlorine into the sauna room with such intensity that everyone else had to leave the sauna and we had to clean the sauna afterwards. This occurred only the first few times and thereafter there were no more chlorinated smells in the sauna room in the 31-day cleansing program.


Abstract

Background

Ethanol is an important organic solvent and substrate which extensively used in research and industries. It is the main ingredient produced during fermentation of carbohydrates derived from fruits and other biomass substances. Halal status of ethanol is controversial and it is rational use is ambiguous.

Scope and Approach

In this review the issue of ethanol in food industries is addressed. Ethanol is a sensitive, controversial and main issue in the production of Halal (Permitted, Allowed) products. Setting the limit of ethanol in Halal food industries is needed to facilitate food production and complied with certain religious demands. This review gives an overview of ethanol, types, application, advantages and disadvantages. An attempt to set a limit of ethanol in food industries, supported by scientific facts and Islamic rules, is described.

Key Findings and Conclusion

Halal status of ethanol is highly controversial but rarely classified based on its source and concentration. Any ethanol produced by anaerobic fermentation and ranging between 1 and 15% is considered to be Haram (non-Halal, Forbidden), whereas ethanol produced by natural fermentation and less than 1% is considered as preserving agent and its Halal status is allowed. Any ethanolic solution higher than 15% is treated as a toxic solution but still could be used in industries, meanwhile ethanolic solution prepared by dilution from absolute or denatured ethanol is allowed for industrial used but toxic for human consumption. However, any concentration varied from 0.1 to 100% prepared with intention to be used as beverage drink is consider non-Halal.


What To Do About It

Often times, CBS up-regulations need to be prioritized with other existing gene mutations, or methylation pathway abnormalities. The strategy for improving function in these regards is highly individual, and necessitates individualized intervention.

Elimination of sulfur-heavy foods appears important: namely cruciferous vegetables, onions, garlic, eggs.

Many researchers claim that individuals who are CBS ++ or +/- , or who have CBS pathway up-regulations, must eliminate flesh proteins. However I have found this not to be the case, in most instances.

It may be a necessary consideration if one has CBS up-regulations, to reduce one’s total sulfur load, and this may require a reduction in protein, in some instances. From my initial observations, which are limited in number, reducing or eliminating sulfur-heavy vegetables (cruciferous, garlic, onions) and eggs seems to be the biggest factor for most people. More research and observations are needed.

Restriction of supplemental methyl groups is important. We all need methyl groups, but those with active CBS up-regulations need to be cautious with how much sulfur and how many methyl groups they are taking in daily. This includes common supplements such as: L-methionine, L-cysteine, L-taurine, MSM, Glucosamine, L-Glycine, DMSO, SAMe, NAC, methylcobalamin, methyl-folate, Betaine HCL, Choline. Restricting Vitamin B6 may also be warranted in CBS up-regulations. P5P (pyridoxal 5 phosphate), however, does not appear to increase CBS activity.

Strategies and protocols that help the body to manage CBS up-regulations: B-12 Hydroxycobalamin, Yucca root, FOS’s, Dr. Amy Yasko’s Ammonia Support RNA, activated charcoal, GABA, Alpha Ketoglutarate, Ornithine, Arginine (arginine and ornithine may be contraindicated for those with NOS gene mutations), CoQ10. It is clear that the issue of CBS pathway up-regulations are highly clinically significant for many people. CBS genetic mutations appear to be a “loaded gun”. However, gene mutations should not be the only factor that is considered, because the pathways can be obstructed through any number of epigenetic factors.

More research is needed in order to understand the deeper biochemistry of the mechanisms at stake, as well as better suited strategies for handling these imbalances.

Michael McEvoy is taking new clients NOW into his consulting practice. CLICK HERE to learn more about his consulting services.


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