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           Background- The liver is a central player in the development of whole body energy production and is responsible for the body’s ability to metabolize carbohydrates, proteins and fatty acids. When energy intake is abundant, we preferentially burn carbohydrates to generate energy in the form of adenosine triphophate (ATP). Surplus glucose, accumulated after replenishing carbohydrate stores called glycogen, is converted to fatty acids (the process is termed lipogenesis) and are converted as triglycerides (three fatty acids attached to glycerol molecules) in loose connective tissue called white adipose tissue¹. Although white adipose tissue functions essentially as a limitless reservoir to accumulate and store fatty acids as triglycerides, the liver is also able to store significant quantities of fats in an abnormal condition that results with prolonged excess energy consumption or when fatty acid metabolism is impaired. This abnormal storage of fats manifests itself as steatosis. In fasted states, when glucose availability and insulin levels are low, there is a depletion of fats from the hepatic glycogen stores and fatty acid production is reduced. Under these fasting conditions, Fats stored as triglycerides in adipose tissues are hydrolyzed to free fatty acids and mobilized into circulating plasma to reach the liver. In the liver, they undergo oxidation, converted to ketone bodies to be used as a fuel by extra-hepatic tissues^1,2. Fasting or energy restriction results in fat burning.

Fatty Liver: Fatty liver is a common disorder of fatty acid metabolism. The prevalence of Fatty liver disease (FLD), whether it is alcoholic FLD (AFLD) or nonalcoholic FLD (NAFLD) in the United States and other western world is second only to diabetes and obesity.  It has been reported that social and technological changes in the western world, habitual physical inactivity and an unlimited amount of energy (food) in the pattern of daily living has increased the risks of at least 35 chronic health conditions³. 

The pathogenesis of FLD is influenced by the combination of factors such as individual genetic makeup (resting energy expenditure), drug exposure, and life-style choices (alcoholism). This combination of factors is often frequently associated with metabolic syndrome. Metabolic Syndrome means a number of things which include obesity, excess free fatty acids in plasma (dyslipidemia), elevated blood pressure (hypertension), excess fatty acid triglycerides (different from Free fatty acids) in circulation (hypertriglyceridemia), and insulin resistance (cells don’t respond to hormonal action of insulin) leading to diabetes.

FLD encompasses a spectrum of morphological conditions. The Fatty Liver Disease can be anywhere along Steatosis>>Steatohepatitis>>Fibrosis>>Cirrhosis>Hepatocellular Carcinoma. Each condition is briefly explained below

Prolonged excess energy consumption or the impaired fatty acid metabolism initially leads to Steatosis, a state where abnormal fats accumulate in cells and it can occur in any organ including liver cells called hepatocytes. In medical practice, the term steatosis is usually referred to when there is abnormal fat accumulation of fat in liver. Steatosis can be relatively benign and coexist with other medical conditions like obesity, type 2 diabetes, hypertension etc.

When the steatosis or abnormal fat accumulation results in inflammation of hepatic (liver) cells, the condition is termed as Steatohepatitis, which is no longer benign and often termed fatty liver disease. In medical practice this steatohepatitis condition is classified either as alcoholic steatohepatitis (because of excess alcoholic consumption) or Non Alcoholic Steatohepatitis (NASH) which is the result of non alcoholic reasons. It is generally difficult to distinguish AFLD from NAFLD on morphological grounds alone despite the distinctions implied by these etiological designations. Remarkably similar pathological features of alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH) suggests the pathogenic mechanism of both AFLD and NAFLD possibly converge at some critical juncture that enables the progression of ASH and NASH toward cirrhosis and liver cancer.

Steatohepatitic condition progresses to a more severe Fibrosis stage when the connective tissues start scarring because of continued fatty acid accumulation and ever increasing inflammation of hepatocytes.

Fatty Liver can progress to a still more serious condition called Cirrhosis when the liver tissues are replaced by scarred tissues that result from continued fibrotic conditions. Cirrhosis is a condition where liver can barely function and it will most likely require liver transplantation. Once fatty liver progresses to the cirrhosis stage, the risk of  hepatocellular carcinoma, a form of liver cancer is significantly higher. Emerging data indicate that the mortality rate of hepatocellular carcinoma (HCC) associated with cirrhosis is rising.  

Carbohydrate consumption: The research reports from multiple disciplinary areas indicate excessive consumption of a carbohydrate diet is the mostly likely cause of modern chronic diseases. Coupled with other factors like a relatively sedentary lifestyle or increased stress, excessive energy rich carbohydrate consumption particularly “refined carbohydrates and sugars” is a key driver of Fatty Liver Disease. The research points to the possibility that even genetic liver diseases like primary biliary cirrhosis are more likely triggered by excessive carbohydrate consumption.

It is important to realize that carbohydrate, beyond its role as a source of energy, has an important regulatory function in a living organism. Dietary carbohydrate stimulates insulin secretion, and/or affects the availability of energy substrates such as free fatty acids, ketone bodies and glycogen. Carbohydrates through insulin alone, affects the expression of more than 150 genes. Carbohydrates are also a direct source of glucose and fructose, both of which serve as cellular stimulators and regulators.  Carbohydrates further indirectly modulate a number of other hormones. For instance carbohydrates modulate leptin, a hormone responsible for hunger, appetite and energy expenditures and TSH (Thyroid Stimulating Hormone), another important hormone responsible for metabolism. In addition it modulates Growth Hormone (GH), an array of Insulin like Growth Factors (IGF) and Fibroblast Growth Factor 21 which stimulates glucose uptake in adipocytes etc. Thus, when carbohydrate is consumed in excess, particularly in the form of free sugar and fructose, it is a major source of disjointed expression of genes responsible for fatty acid, carbohydrate and protein metabolisms. Disjointed carbohydrate, fats and protein metabolism in turn leads to imbalanced energy production & consumption, oxidative stress and inflammation. Research indicates excessive carbohydrate may have strong effects on 35 chronic and modern diseases⁴.

Fatty liver Disease is also one of the under diagnosed disorders.  While Fasting plasma glucose and cardiovascular risk markers are monitored during routine doctor visits, liver function tests are seldom performed unless there are other overt symptoms. Liver bears the brunt of dietary abuse because of its role as an energy hub. It is a crossroad for metabolism of fats and carbohydrates, cholesterol biosynthesis, TCA Cycle (A key cycle that generate energy), Lipogenesis (Fatty acid synthesis) and Glycolysis (Glucose metabolism). Hepatic fat and glucose metabolism are closely interrelated with inflammatory, proliferative and programmed cell death (apoptosis) signaling within the liver⁵. In the liver, these catabolic (breaking down molecules) and anabolic (synthesizing new molecules) pathways are highly interrelated and very hard to separate from one another. They share intermediate metabolites and receptor signaling, and go hand in hand in the pathogenesis of the most common liver diseases.

Fatty liver disease is caused by excess carbohydrate consumption and this finds evidences from several direct and indirect research studies.

1) Scientists have been widely using an animal model to study the origination and progression of fatty liver disease. In this model, animals (mostly rodents) are fed with a special diet called MCD diets. MCD diets are deficient in two nutrients Methionine, an amino acid and Choline, a vitamin B family nutrient. The idea behind this model is if the animals are starved of these two vital nutrients, they develop fatty liver disease and eventually liver cancer. This MCD diet animal model is used to study the pathophysiology of fatty liver disease in human beings. However, in a recent research study, a team of scientists demonstrated that it is the sucrose which is normally present in MCD diet that is responsible for the development of steatohepatitis in the MCT diet fed animals. When the animals are fed with starch, instead of a sucrose based MCD diet, they didn’t develop steatohepatitis at all⁶.

2)  The rising incidence of obesity and diabetes coincides with a marked increase in fructose consumption. Fructose consumption is higher in individuals with nonalcoholic fatty liver disease (NAFLD) than in age-matched and body mass index (BMI)-matched controls. FLD has an inherent propensity to progress toward the development of cirrhosis and hepatocellular carcinoma with fructose consumption. It has now been found that increased fructose consumption is associated with the severity of Fibrosis⁷.

3)  It has been found that liver cells (hepatocytes) are the first victims of excessive carbohydrate/fructose’s diet. Once a certain threshold is crossed, the excess consumption of carbohydrates starts affecting muscles, heart, brain and other organs. High-fructose diets significantly increased fasting glucose and fatty acid triglycerides in blood, conversion of carbohydrates to fats (called de novo lipogenesis) by six fold, and even caused increased endogenous glucose production (EGP). Further, the data shows it impairs insulin-induced suppression of fatty acid metabolism in adipose tissue. The exposure to large amounts of fructose for several weeks impairs muscle insulin sensitivity as well⁸. This has been demonstrated by an interesting study of feeding fructose and sucrose rich diets to healthy human volunteers²⁷.

4)  Bile acids are the end products of cholesterol metabolism. They are synthesized in the liver and secreted via bile into the intestine, where they aid in the absorption of fat-soluble vitamins like vitamin D, E and K and dietary fat consumption. Subsequently, bile acids return to the liver to complete their enterohepatic circulation. In an elegant study, it was shown that two critical events 1) fatty acid production from carbohydrates (de novo lipogenesis) and 2) cholesterol biosynthesis pathways were decoupled by high carbohydrate diets. In mice fed either a low-fat, high-carbohydrate diet or a high-fat, carbohydrate-free diet, high carbohydrate diet group was found to have a significantly up-regulated de novo lipogenesis (by tenfold) and a significantly down-regulated cholesterol biosynthesis⁹. It is known that reduced turnover of the BA(biliary acid) pool is an important feature in patients with primary biliary cirrhosis (PBC), a genetic liver disease. Thus, it is reasonable to infer high carbohydrate diets down-regulates cholesterol biosynthesis genes and up-regulates genes responsible for de novo lipogenesis (fatty acid production from carbohydrates). Thus ironically the low fat, high carbohydrate diet, which is the staple American diet because of dietary guidelines of 40 years, actually results in increased production of fats in the body. While we may have a low fat diet on the plate, the end result in the body is the exact opposite.

5)  It has been shown that two weeks of dietary intervention reduces fatty acid triglycerides by more than 42% in subjects with non alcoholic fatty liver disease. The study compared the effect of carbohydrate restriction against caloric restriction. The reductions in triglycerdies were significantly greater with dietary carbohydrate restriction than with calorie restriction. This may have been due, in part, to enhanced hepatic and whole-body fatty acid oxidation¹⁰ with low carbohydrate diet.

Finally, while the results from animal models may not always be replicable in humans, it has been found that a high protein diet in mice not only prevents but reverses hepatic steatosis¹¹.

Though the mechanisms are not clear, but the end results are unequivocal. In the absence of scientific evidence, we can only speculate the mechanism by which carbohydrate restriction helps prevent or reverse fatty liver disease. It appears that excessive carbohydrate/ fructose consumption results in changes to the way fatty acids are metabolized in body. Excess consumption appears to increase fatty acid metabolism peripheral issues, up-regulates fatty acid transporters, increases fatty acid production from carbohydrates in the liver, and  causes a switch from mitochondrial fatty acid β-oxidation (a normal fat burning process in healthy liver) process to ω-oxidation in liver. This switch appears to be crucial because peroxisomal β-oxidation and fatty acid ω-oxidation promote Fatty acid toxicity and release reactive molecules which are likely results in the induction of hepatocyte apoptosis, the invasion and activation of inflammatory cells, as well as initiation of fibrosis^5.

When fatty acid and glucose consumption and deposition are out of sync with one another, it is likely to lead to energy dysfunction. It has now been recognized that liver diseases ALFD, NALFD, primary biliary cirrhosis, chronic liver failure, nonalcoholic steatohepatitis (NASH), all have dysfunctional energy metabolism characterized by increased fatty acid oxidation¹², which is primarily toxic ω-oxidation in endoplasmic reticulum (ER). The increased expression of genes responsible for peroxisomal β-oxidation and ω-oxidation in ER pathways provide a metabolically adaptive mechanism to remove excessive fatty acids. There is strong evidence to link fatty liver disease to dysfunction in mitochondria (which is responsible for beta-oxidation of fatty acid)¹³ and inflammation^{14, 15}.  This disruption of equilibrium among processes that control 1) glucose production from non-carbohydrate sources (gluconeogenesis), 2) fatty acid production from carbohydrates (de novo lipogenesis), 3) energy production from TCA cycle and oxidative phosporylation, and 4) fatty acid oxidation, is more likely the mechanism that leads to fatty liver diseases¹⁶. Impairment of mitochondrial β-oxidation is suggested to be an important mechanism of fatty acid induced liver injury. 

Dietary Changes: Liver-support dietary strategies need to achieve two goals. First diet ingredients must facilitate the mitochondrial and peroxisomal β-oxidation of fatty acid (instead ω-oxidation in endoplasmic reticulum (ER)) and the second goal must be to prevent inflammation in liver.

A simpler way to achieve these goals is to change from high carbohydrate diets to high protein–high fat diets. This is contrary to what most of the dieticians and nutritionist preach in their practice. There are four simple dietary changes that can provide significant support for a healthy liver 1) Zero Sugar, 2) Minimal carbohydrates, 3) High fat, high protein diet and 4) Lot of vegetables and fruits.

In addition to these dietary changes, the β-oxidation of fatty acids in mitochondria is facilitated by adding Medium Chain Fatty Acids (MCFAs) to diet.  MCFAs are called so because of the number of carbon atoms in their fatty acid chain is from 6 to 16. MCFAs are usually present in coconut or palm kernel oils. MCFAs are used as dietary oils and are used to treat refractory epilepsy in children for decades. More recently they have been found useful in neurodegenerative, cardiovascular and athletic applications. MCFAs are usually used in the form of Medium Chain Triglycerides. MCTs do not require a transporter to enter mitochondria and undergo β-oxidation¹⁷.  MCTs are known to generate unique energy products called ketone bodies upon β-oxidation in liver. The liver can’t use ketone bodies and releases them into circulation. The ketone bodies are used by extra-hepatic cells like neurons, retinal cells, nephrons, cardiomyocytes potentially addressing other aspects of metabolic syndrome and degenerative diseases that are usually co-morbid with fatty liver disease. MCTs when used in combination with high dose docosaahexaenoic acid (1 gram) is even more beneficial¹⁸. 

The second supplement that may help liver is the use of Omega-3 polyunsaturated acids to our diets. Omega-3 fatty acids like EPA, DHA are known to enhance peroxisomal β-oxidation^{19, 20}.  The support for increasing MCT + Omega fats in our diet comes from three sources.

 1) Docosahexaenoic acid (DHA) was found effective in reducing liver fat content in children with fatty liver diseases in a randomized controlled clinical study²¹. It is a well designed and sufficiently large sized study that provides significant support for using DHA. Further inflammation caused by steatotosis as result abnormal accumulation of fats in liver is reversed by using DHA. Docosahexaenoic Acid is known to attenuate Hepatic Inflammation, Oxidative Stress, and Fibrosis in a Mouse Model of Western Diet-Induced Nonalcoholic Steatohepatitis²².

2)  It has been found that dietary medium chain triglycerides prevent nonalcoholic fatty liver disease in a rat model²³ while long term treatment with soybean oil rich parenteral nutrition (PN) causes PN associated liver disease and hepatobiliary dysfunction²⁴.

3)  Evidence comes from the study of MCT in children with cystic fibrosis that found MCTs reduced steatorrhea without altering any changes to the plasma lipid profile²⁵. Although this is a relatively older study, the study design was excellent

4) The final support relates to recent findings on bile acids receptors called FXR receptors. FXR receptors are a nuclear receptor and are considered a molecular link between bile acid and glucose/fatty acid metabolism. Farnesoid X receptor (FXR) is dysfunctional in fatty liver because bile acids are not able to effectively modulate them. It was found in a recent clinical study, that obeticholic acid, a semi-synthetic derivative of the primary human bile acid chenodeoxycholic acid, is effective in treating fatty liver disease and primary biliary cirrhosis²⁶. DHA is a ligand for FXR similar to obeticholic acid and chenodeoxycholic acid and studies show Omega-3 fatty acids regulate bile acids ^28.

5) It is especially helpful to add these supplements together to diet to enhance whole hepatocyte beta-oxidation at both mitochondria and peroxisomes

           There are number of ways, one could supplement DHA and MCT into their diet including MCT Omega Protein Shakes, MCT Bars, and of course DHA Capsules, DHA Tablets and MCT Oils on Amazon or on private stores. However, most of the DHA capsules and tablets that are available have low dose DHA requiring one to consume a number of them over extended period of them.

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References;

1.        Reddy JK et al, Fatty acid oxidation and peroxisome proliferator-activated receptor: an adaptive metabolic system. Annu Rev Nutr 21: 193–230, 2001.

2.        Hashimoto T, et al. Defect in peroxisome proliferator-activated receptor -inducible fatty acid oxidation determines the severity of hepatic steatosis. J Biol Chem 275: 28918–28928, 2000.

3.        Booth FW, et al, Waging war on physical inactivity: using modern molecular ammunition against an ancient enemy. J Appl Physiol 93: 3–30, 2002.

4.        Booth FW, et al, Effects of exercise and diet on chronic disease,  J Appl. Physiol. 93: 3–30, 2002

5.        Lars P Bachmann et al, The interaction of hepatic lipid and glucose metabolism in liver diseases, Journal of Hepatology 2012 vol. 56, 952–964.

6.        Michael K. Pickens, et al, Dietary sucrose is essential to the development of liver injury in the methionine choline-deficient model of steatohepatitis. J. Lipid Res. 2009. 50: 2072–2082.

7.        Manal F. Abdelmalek, et al, Increased Fructose Consumption Is Associated with Fibrosis Severity in Patients with Nonalcoholic Fatty Liver Disease, Hepatology 2010 ;51: 1961-1971.

8.        David Faeh, et al, Effect of Fructose Overfeeding and Fish Oil Administration on Hepatic De Novo Lipogenesis and Insulin Sensitivity in Healthy Men, Diabetes 54:1907–1913, 2005

9.        Kristian K. Jensen et al, Demonstration of diet-induced decoupling of fatty acid and cholesterol synthesis by combining gene expression array and²H₂O quantification, Endocrinology and Metabolism, Endo January 15, 2012 vol. 302 no. 2 E209-E217,

10.     Jefferey Browing et al, Short-term weight loss and hepatic triglyceride reduction: evidence of a metabolic advantage with dietary carbohydrate restriction, Am J Clin Nutr 2011;93:1048–52.

11.     Sonia C. Garcia-Caraballo, et al, Prevention and reversal of hepatic steatosis with a high-protein diet in mic, Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease (2013), 1832, 5, 685–695

12.     Srinivasan Dasarathy, et al, Elevated hepatic fatty acid oxidation, high plasma fibroblast growth factor 21, and fasting bile acids in nonalcoholic steatohepatitis Eur J Gastroenterol Hepatol. 2011 May; 23(5): 382–388.

13.     Yongzhong Wei, et al, Nonalcoholic fatty liver disease and mitochondrial dysfunction, World J Gastroenterol 2008 January 14; 14(2): 193-199

14.     Janarthana Reddy et al, Lipid Metabolism and Liver Inflammation. II. Fatty liver disease and fatty acid oxidation, Am J Physiol Gastrointest Liver Physiol 290:G852-G858, 2006.

15.     Herbert Tilg et al, Evolution of Inflammation in Nonalcoholic Fatty Liver Disease: The Multiple Parallel Hits Hypothesis, Hepatology, 2010;52:1836-1846)

16.     Feldstein AE. Novel insights into the pathophysiology of nonalcoholic fatty liver disease. Semin Liver Dis 2010; 30: 391–401.

17.     Bach AC, et al. Medium-chain triglycerides: an update. Am J Clin  Nutr. 1982; 36(5):950-962.

18.     Harold Bays, et al, Eicosapentaenoic Acid Ethyl Ester (AMR101) Therapy in Patients With Very High Triglyceride Levels (from the Multi-center, plAcebo-controlled, Randomized, double-blINd, 12-week study with an open-label Extension, The American Journal of Cardiology (2011), 108, 5, 682–690

19.     N Willumsen, et al, Docosahexaenoic acid shows no triglyceride-lowering effects but increases the peroxisomal fatty acid oxidation in liver of rats. The Journal of Lipid Research 1993, 34, 13-22.

20.     Christopher M Depne, et al, Docosahexaenoic acid attenuates hepatic inflammation, oxidative stress, and fibrosis without decreasing hepatosteatosis in a Ldlr(-/-) mouse model of western diet-induced nonalcoholic steatohepatitis. J Nutr. 2013 Mar;143(3):315-23

21.     Nobli et al, Docosahexaenoic acid supplementation decreases liver fat content in children with non-alcoholic fatty liver disease: double-blind randomised controlled clinical trial, Arch Dis Child 2011;96:350-353

22.     Christopher Depner e al, Docosahexaenoic Acid Attenuates Hepatic Inflammation, Oxidative Stress, and Fibrosis without Decreasing Hepatosteatosis in a Ldlr−/− Mouse Modelof Western Diet-Induced Nonalcoholic Steatohepatitis. J. Nutr. March 1, 2013 vol. 143 no. 3 315-323

23.     Ronis MJ, Baumgardner Medium chain triglycerides dose-dependently prevent liver pathology in a rat model of non-alcoholic fatty liver disease, Exp Biol Med (Maywood). 2013 Feb;238(2):151-62.

24.     Beth Carter et al, Mechanisms of Disease: update on the molecular etiology and fundamentals of parenteral nutrition associated cholestasis, Nature Reviews Gastroenterology and Hepatology 4, 277-287 (May 2007.

25.     Kuo et al, The effect of medium chain triglyceride upon fat absorption and plasma lipid and depot fat of children with cystic fibrosis of the pancreas, J Clin Invest. 1965 November; 44(11): 1924–1933

26.     Sunder Mudaliar et al, Efficacy and Safety of the Farnesoid X Receptor Agonist Obeticholic Acid in Patients With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease, Gastroenterology, Volume 145, Issue 3 , Pages 574-582.

27.     Aeberli Iet al, Moderate amounts of fructose consumption impair insulin sensitivity in healthy young men: a randomized controlled trial. Diabetes Care. 2013 Jan;36(1):150-6

28.     Verreault, Mélanie, et al. "371 N-3 Polyunsaturated Fatty Acids (N-3 PUFAS) Stimulate Bile Acid Detoxification." Gastroenterology 144.5 (2013): S-944.