A Silent Epidemic of Nutritional Imbalance

Over seventy million Americans may have nonalcoholic fatty liver disease.¹ The disease begins with the accumulation of fat within the cells of the liver, but can progress to inflammation, the development of scar tissue, and in some cases death from liver failure or cancer.^2-4 Simple accumulation of fat within the liver generally proceeds without producing any overt symptoms, but it is not necessarily harmless. The liver regulates blood glucose and blood cholesterol levels, plays a critical role in burning fat for fuel, helps eliminate excess nitrogen, contributes to the metabolism of endocrine hormones, stores vitamin A, protects against infections, and detoxifies drugs and environmental toxins.

Any type of damage to the liver is thus likely to impact whole-body health. Indeed, fatty liver disease increases the risk of cardiovascular disease three-fold in men, fourteen-fold in women, and seven- to ten-fold in type-one diabetics.^5-6 Fatty liver is thus a dangerous silent epidemic, and as we will see, it is likely caused by the overabundance of calorie-rich, nutrient-poor refined foods and the banishment of traditional sources of choline like liver and egg yolks from the modern American menu.

Relation to Obesity, Diabetes, and Insulin Resistance

Samuel Zelman, a medical doctor from Topeka, Kansas, published the first human case series connecting fatty liver disease to obesity in 1952.⁷ Zelman decided to examine a group of obese patients for fatty liver after observing the disease in a hospital aide who drank twenty or more bottles of Coca-Cola per day. This obscene amount of soda provided 1,600 calories of sugar and the caloric equivalent of a pint or more of whisky per day. Obese people were so hard to find at the time that it took Zelman a full year and a half to find twenty obese people who were not alcoholics. All of his subjects showed some degree of liver damage, and about half had a significant degree of fatty liver disease.

Zelman knew that fatty liver occurred in the earliest animal models of obesity involving genetics or surgical damage to the hypothalamus,^8-9 and suggested that hypothalamic damage, biological inheritance, and “psychological factors” contributed to obesity in humans. He proposed that obesity increased the caloric requirement and led to cravings for energy-dense, nutrient-poor foods that increased the need for choline and B vitamins. These foods then overloaded the liver with energy but failed to provide the nutrients needed to process that energy, resulting in fatty liver.

Zelman’s obese subjects universally preferred a diet rich in carbohydrate and fat but poor in protein. The one exception was a man who “related a fantastic story of fondness for the ingestion of huge beefsteaks,” but Zelman distrusted his story because the man’s psychiatrist had accused him of being a pathological liar. Zelman prescribed a diet containing “as much protein as possible,” emphasizing beef liver, lean fish, and lowfat dairy products such as skim milk and cottage cheese, as well as extra B vitamins and choline.

Zelman was likely on the right track when he identified nutrient density as an important component of a therapeutic diet, but his opposition to both fat and carbohydrate likely contributed to his regimen’s ultimate lack of success. He reported “as much difficulty and discouragement in dealing with the craving for carbohydrate- and fat-rich foods manifested by the obese as with the craving for alcohol of the chronic alcoholic.” Only two of his twenty subjects lost weight. He retested them for fatty liver and found some improvement, but he never reported completely successful resolution of obesity in any of his patients and consequently failed to document the success of his program in treating fatty liver.

Although type-one diabetes is much less common than obesity, it had been connected to fatty liver disease as early as 1784¹⁰ and the resolution of diabetic fatty liver was an early objective of insulin therapy.¹¹ Physicians identified the connection between alcohol consumption and fatty liver disease in the 1830s,¹² however, and in the middle of the twentieth century the connection to obesity and diabetes was lost from mainstream consciousness as alcohol came to be seen as the exclusive cause of the disease. At least as early as the 1970s, this exclusive association of fatty liver with alcoholism had become so ingrained that physicians simply accused their patients of lying if they presented with fatty liver but denied drinking alcohol.¹³

In 1980, Jurgen Ludwig and other physicians from the Mayo Clinic produced a report of twenty patients with nonalcoholic fatty liver disease.¹³ Ninety percent of the patients were obese, 35 percent had heart disease, 30 percent had gall bladder problems, and 25 percent had type-two diabetes. These physicians coined the term “nonalcoholic steatohepatitis,” to describe the disease and abbreviated it “NASH.” The creation of a specific term for the nonalcoholic manifestation of the disease promoted greater awareness of this form, facilitated the organization of an entire research field devoted to its study, prevented doctors from accusing patients of lying about their alcohol intake, and, in the words of the Mayo Clinic physicians themselves, spared doctors “the embarrassment (or worse) that may result from the ensuing verbal exchanges.”

Since the Ludwig group’s landmark paper, numerous studies have confirmed the relation between fatty liver, obesity and diabetes. Autopsy^14-15 and ultrasound^16-17 studies have shown that rates of fatty liver are five- to fifteen-fold greater in obese individuals than in lean individuals and that the disease is present in up to three quarters of obese people. Similar studies have shown that 45 percent of type-one diabetics and 70-85 percent of type-two diabetics have fatty liver.^{6, 18-19} Moreover, even in the absence of diabetes and obesity, those with the lowest insulin sensitivity have the highest accumulation of liver fat.²⁰

Since nonalcoholic fatty liver disease was rarely diagnosed before 1980¹³ and since even today most people with fatty liver are probably not diagnosed,²¹ there is no way to track its prevalence over time. The prevalence of diagnosed diabetes in the United States, however, has increased from five to eight percent since 1988,²² and the prevalence of obesity has increased from about 15 percent to 35 percent since 1960.²³ Given the high prevalence of fatty liver in obese and diabetic populations, we have likely experienced the emergence of a silent epidemic of fatty liver disease as the prevalence of obesity and diabetes has grown over the last few decades to reach epidemic proportions.

Diagnosing Fatty Liver Disease

Biopsy, ultrasound and magnetic resonance spectroscopy (MRS) are all legitimate methods of diagnosing fatty liver,^{6, 16-19, 21, 24-25} although ultrasound can sometimes fail to detect moderate cases of fat accumulation. Even though physicians often refer patients to biopsy when they have elevated liver enzymes,²⁴ nearly 80 percent of patients with fatty liver have normal levels of these enzymes.²¹ In fact, in ten women who recently developed liver problems on an experimental diet low in choline, nine developed fatty liver but only one developed elevated liver enzymes.²⁶ Fatty liver should therefore be suspected on the basis of obesity, diabetes and insulin resistance rather than elevated liver enzymes.

Fatty Liver As a Nutritional Imbalance

A well-functioning liver supports our health in many different ways (see sidebar). It is therefore deeply concerning that fatty liver is an independent risk factor for cardiovascular disease,^5-6 as this would suggest that the disease may in fact compromise liver function and contribute to other degenerative diseases. Learning how to prevent and treat fatty liver, then, is critical.

In order to understand how our livers get fat, we must first realize that fatty liver disease occurs in two distinct stages (see sidebar for more detail). In the first, called simple steatosis, fat accumulates within the cells of the liver. In the second stage, inflammation, the proliferation of fibrous connective tissue (fibrosis), and eventually the formation of scar tissue (cirrhosis) ensue. In modern terminology, “nonalcoholic fatty liver disease (NAFLD)” refers to the full range of these disease states, while “NASH” refers only to the inflammatory stage.²⁷

A number of experimental diets are currently used to study nonalcoholic fatty liver disease in laboratory animals, including diets high in fat, high in fructose, or deficient in choline and methionine. None of these models fully resembles the human situation, probably because they all emphasize single factors carried to extremes, whereas the human situation reflects a combination of several contributing factors (see sidebar).

The totality of the evidence suggests that the initial accumulation of fat in the liver is triggered by nutritional imbalance. As Zelman suggested in the 1950s, fatty liver seems to occur as a result of too much energy flowing through the liver without sufficient nutrients to process it. The accumulation of delicate fats, especially polyunsaturated fatty acids (PUFAs), increases the vulnerability of the liver to oxidative and inflammatory insults in the form of infections, toxins, or poor metabolism. These insults launch the progression from the first stage of simple fat accumulation to the second stage of inflammation.

The key culprits, then, are nutrient-poor refined foods, choline deficiency and polyunsaturated oils. The interaction between these factors can be seen by turning to the history of the development of animal models for fatty liver disease.

The Role of Refined Foods

In 1924, George Burr joined the laboratory of Herbert Evans, where Evans and Katherine Scott Bishop had recently discovered vitamin E.⁶⁶ Evans and Bishop were having trouble reproducing their vitamin E-deficient diet, and Burr helped them develop a highly purified diet based deficiency that vitamin E could not cure, which Burr and his wife Mildred later identified as essential fatty acid (EFA) deficiency.^67-68 Observing the fact that the annual per capita consumption of sugar in the United States had tripled over the preceding decades from 38 pounds to 115 pounds, Clarence Martin Jackson conducted a comprehensive analysis of the anatomy and tissue characteristics of rats fed Burr’s EFA-sufficient, 80 percent sucrose control diet.⁶⁹ He compared them to rats fed 45 percent sucrose or 45 percent starch. Neither the 45 percent sucrose diet nor the 45 percent starch diet produced fatty liver, but the 80 percent sucrose diet produced moderate to severe cases of the disease. He noted that the liberal provision of cod liver oil, dried yeast and wheat germ satisfied the nutritional needs of the rats in all treatment groups, and that smaller amounts of sucrose may contribute to fatty liver in humans consuming nutritionally deficient diets. Indeed, dietary protein, methionine, and choline were later shown to protect against sucrose-induced fatty liver.¹²

In 1977, the American Institute of Nutrition (AIN), the principal professional organization for nutritional research scientists in the United States, developed standards for cereal-based, purified and chemically defined rodent diets.⁷⁰ The purpose of the purified and chemically defined diets was to standardize diets between studies, so that toxicologists could easily make comparisons between one study and another. The days of cod liver oil, yeast and wheat germ were over. The days of purified vitamin and mineral mixes were now ushered in.

The AIN initially designated the purified diet as “AIN-76,” but they increased the vitamin K concentration ten-fold three years later in response to reports of excessive bleeding.⁷¹ They designated the new diet “AIN-76A.” Both of these diets were 50 percent sucrose and 15 percent starch, much lower in sucrose content than the diet that Jackson had used to induce fatty liver just a few decades earlier. Nevertheless, reports quickly began to surface of fatty liver developing spontaneously in rodents fed the AIN-76A diet.⁷² Reducing the concentration of sucrose from 50 percent to 20 percent resolved the fatty liver. Because of this and several other adverse metabolic effects of sucrose, the AIN released a new diet in 1993 and reduced the sucrose content to 10 percent, with the remainder of the carbohydrate supplied by cornstarch and a small amount of dextrinized cornstarch to aid in pelleting.^73-74 As a result of many other problems that had surfaced with the diets, the AIN also increased the amount of vitamins E, K and B₁₂, increased the calcium-to-phosphorus ratio, substituted soy oil for corn oil, and added various trace minerals not yet known to be essential.

Why did sucrose prove so much more harmful in the context of the purified AIN-76 diet than it did when Jackson provided it in combination with cod liver oil, yeast, and wheat germ? In all likelihood, the provision of these unrefined foods supplied a wide variety of interacting vitamins, minerals, and other nutritional substances that aided in the metabolism of the sugar, helping the liver to burn it for energy, store much of the excess as glycogen, and export any fat made from it into the bloodstream. We will never know the exact nutritional composition of Jackson’s diet. We do know from other studies, however, that supplying extra choline in the diet provides powerful protection against fatty liver, whether induced by sugar, alcohol, or fat.

The Role of Choline

The discovery that choline could prevent the accumulation of fat in the liver was a byproduct of the seminal animal research conducted during the 1920s and 1930s showing that type-one diabetes was a disease of insulin deficiency. Physiologists first identified the role of insulin deficiency in type-one diabetes by studying the disease in dogs. In 1889 they produced diabetes by simply taking out the whole pancreas from these dogs and, after scrambling for a couple decades to identify the active component, they cured the diabetes with insulin in the early 1920s.⁷⁵

Although cured of diabetes, the insulin-treated dogs nevertheless developed severe fatty liver degeneration and ultimately died of liver failure. Adding raw pancreas to their diet, which was composed of lean meat and sucrose, cured the problem. As researchers attempted to discover what it was in raw pancreas that cured the disease, they found in the early 1930s that egg yolk lecithin, which is abundant in choline, could cure it.⁷⁶ Then they found that choline alone could cure it.⁷⁷

It later turned out that the dogs became deficient in choline and methionine without a pancreas because they were not producing the digestive enzymes needed to free up those nutrients from the foods they were eating. Thus, simply providing them with the digestive enzyme trypsin could cure the fatty liver.⁷⁸

In 1932 a group of researchers decided to replicate the fatty liver seen in the dogs in a nondiabetic rat model. What better way to stuff their livers with fat? Feed them fat! It seemed simple enough and it did indeed work. Although they had trouble reproducing the fatty liver with different colonies of rats or during the summer heat, they produced fatty liver in certain colonies of rats during the winter by replacing 40 percent of their ordinary cereal-based diet with beef drippings. Choline-rich lecithin derived from egg yolk or beef liver or simply choline itself cured the disease.^79-80

Another group of researchers, however, tried to replicate this experiment in a group of rats who were consuming sufficient protein to maximize growth.⁸¹ They thus fed them 40 percent beef drippings but replaced another 20 percent of their cereal grains with the milk protein casein. This experiment failed miserably (Figure 1a). The researchers suspected that the casein might have been the problem, and they were indeed correct: on a choline-free, 40 percent beef dripping diet, reducing the casein from 20 to 5 percent doubled the level of fat in the liver (Figure 1b).⁸²

We now know that choline is necessary to produce a phospholipid called phosphatidylcholine. This is a critical component of the VLDL particle, which we need to make in order to export fats from our livers. The amino acid methionine can act as a precursor to choline. Thus, the combined deficiency of choline and methionine will severely impair our abilities to package up the fats in our livers and to send them out into the bloodstream.⁸³ This explains why casein was so effective at preventing fatty liver: it provided the rats with methionine that they could use to make choline.

Similarly, in 1949 a group of researchers showed that sucrose and ethanol had equal potential to cause fatty liver, and that increases in dietary protein, extra methionine and extra choline could each completely protect against this effect.¹² Over fifty years later, in our own decade, researchers have shown that choline deficiency likewise causes fatty liver in humans.⁸⁴ Thus, choline eventually proved capable of preventing fatty liver regardless of whether it was induced by feeding sugar, fat, or alcohol. These studies suggested that virtually any form of energy delivered to the liver can cause the accumulation of fat, so long as key nutrients needed to metabolize that energy—such as choline—were missing.

The Role of Polyunsaturated Oils

The initial experiments showing the protective effect of casein suggested that long-chain saturated fats might be more problematic than unsaturated fats or medium-chain fats (Figure 2a). As it turns out, saturated fats actually increase the need for choline slightly more than polyunsaturated fats (Figure 2b).⁸⁵ Why this happens is unclear, but it may be that the body is quick to burn polyunsaturated fats for energy, since having them hang around is so dangerous. After all, if they hang around, they are likely to contribute to oxidative damage.

Figure 1. A. When rats were fed 20 percent casein, none of the different fats tested brought the level of fat in the livers above normal. B. When the amount of casein was reduced, fatty liver ensued. From references 81 and 82.

There is some experimental evidence suggesting that polyunsaturated fats may impair the export of fats from the liver by facilitating oxidative damage of the proteins involved.⁸⁶ This evidence comes from isolated cells and live animals injected with fatty acids. Substituting coconut oil for corn oil prevents steatosis in some,⁵² but not all,³⁷ studies using choline-deficient diets. Polyunsaturated oils are probably most likely to contribute to the accumulation of liver fat when combined with other factors that favor oxidative stress such as alcohol abuse, iron overload, toxin exposure, and poor metabolism.

There is much stronger evidence that polyunsaturated oils are responsible for the progression from simple steatosis to NASH.³⁷ Substitution of carbohydrate, coconut oil or beef tallow for corn oil all prevent the oxidative damage and inflammation that results from methionine and choline deficiency during this stage of the disease.³⁷ High-fat diets, moreover, only cause overt NASH when they are based on corn oil (see sidebar). These effects may result from a high intake of total PUFA, or may result from a high ratio of omega-6 to omega-3 fatty acids. Both of these factors are likely to play a role.

A Combination of Factors

As nonalcoholic fatty liver disease has emerged over the last several decades, refined foods have become commonplace. Liver has virtually disappeared from the American menu, and eggs have fallen victim to the anti-cholesterol campaign. These foods are the principal sources of choline (see Table 1). Total fructose intake has increased 30 percent, and intakes of linoleic acid, the major omega-6 PUFA, have doubled.^{56, 60} It is likely that all these factors have conspired to produce the current epidemic.

Each of the experimental diets often used to induce fatty liver in laboratory animals—diets high in fat, high in fructose, or deficient in choline and methionine—fail to completely capture the picture of human fatty liver disease. When these factors are combined, however, the picture begins to emerge (see sidebar).

The requirement for choline and the propensity to develop fatty liver is influenced by a person’s genetics and background diet. Diets rich in fat or fructose will require more choline than diets rich in starch. Vitamin B₆, folate, vitamin B₁₂ and betaine (a nutrient found most abundantly in spinach and to a lesser extent in wheat and beets) all reduce the requirement for choline. A person’s ability to make choline out of the amino acid methionine depends on his genetics, and preliminary studies suggest that Asians are better able to make this conversion than Caucasians.^87-91

TABLE 1. Choline in Selected Foods
Data taken from the USDA Database for Choline Content of Common Foods. http://www.nal.usda.gov/fnic/foodcomp/Data/Choline/Choline.pdf

References

1. Angulo P. Obesity and nonalcoholic fatty liver disease. Nutr Rev. Jun 2007;65(6 Pt 2):S57-63.

2. Wong VW, Wong GL, Choi PC, et al. Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years. Gut. Jul 2010;59(7):969-974.

3. Powell EE, Cooksley WG, Hanson R, Searle J, Halliday JW, Powell LW. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology. Jan 1990;11(1):74-80.

4. Lee RG. Nonalcoholic steatohepatitis: a study of 49 patients. Hum Pathol. Jun 1989;20(6):594-598.

5. Hamaguchi M, Kojima T, Takeda N, et al. Nonalcoholic fatty liver disease is a novel predictor of cardiovascular disease. World J Gastroenterol. Mar 14 2007;13(10):1579-1584.

6. Targher G, Bertolini L, Padovani R, et al. Prevalence of non-alcoholic fatty liver disease and its association with cardiovascular disease in patients with type 1 diabetes. J Hepatol. Oct 2010;53(4):713-718.

7. Zelman S. The liver in obesity. AMA Arch Intern Med. Aug 1952;90(2):141-156.

8. Brobeck JR, Tepperman J, Long CNH. Experimental Hypothalamic Hyperphagia in the Albino Rat. Yale J Biol Med. 1943;15(6):831-853.

9. Fenton PF, Chase HB. Effect of Diet on Obesity of Yellow Mice in Inbred Lines. Proc Soc Exp Biol Med. 1951;77(420-2).

10. Rabinowitch IM. Relationship Between Impairment of Liver Function and Premature Development of Arteriosclerosis in Diabetes Mellitus. Can Med Assoc J. 1948;58(6):547-556.

11. Root HF. Protamine Insulin in the Treatment of Diabetes Mellitus. Trans Am Clin Climatol Assoc. 1936;52:40-51.

12. Best CH, Hartroft WS, Lucas CC, Ridout JH. Liver Damage Produced by Feeding Alcohol or Sugar and Its Prevention by Choline. Br Med J. 1949;2(4635):1001-1006.

13. Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc. Jul 1980;55(7):434-438.

14. Schwimmer JB, Deutsch R, Kahen T, Lavine JE, Stanley C, Behling C. Prevalence of fatty liver in children and adolescents. Pediatrics. Oct 2006;118(4):1388-1393.

15. Wanless IR, Lentz JS. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology. Nov 1990;12(5):1106-1110.

16. Bellentani S, Saccoccio G, Masutti F, et al. Prevalence of and risk factors for hepatic steatosis in Northern Italy. Ann Intern Med. Jan 18 2000;132(2):112-117.

17. Nomura H, Kashiwagi S, Hayashi J, Kajiyama W, Tani S, Goto M. Prevalence of fatty liver in a general population of Okinawa, Japan. Jpn J Med. May 1988;27(2):142-149.

18. Leite NC, Salles GF, Araujo AL, Villela-Nogueira CA, Cardoso CR. Prevalence and associated factors of non-alcoholic fatty liver disease in patients with type-2 diabetes mellitus. Liver Int. Jan 2009;29(1):113-119.

19. Prashanth M, Ganesh HK, Vima MV, et al. Prevalence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus. J Assoc Physicians India. Mar 2009;57:205-210.

20. Seppala-Lindroos A, Vehkavaara S, Hakkinen AM, et al. Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men. J Clin Endocrinol Metab. Jul 2002;87(7):3023- 3028.

21. Browning JD, Szczepaniak LS, Dobbins R, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology. Dec 2004;40(6):1387-1395.

22. Cowie CC, Rust KF, Ford ES, et al. Full accounting of diabetes and pre-diabetes in the U.S. population in 1988-1994 and 2005-2006. Diabetes Care. Feb 2009;32(2):287-294.

23. Ford ES, Li C, Zhao G, Tsai J. Trends in obesity and abdominal obesity among adults in the United States from 1999-2008. Int J Obes (Lond). Sep 7 2010.

24. Daniel S, Ben-Menachem T, Vasudevan G, Ma CK, Blumenkehl M. Prospective evaluation of unexplained chronic liver transaminase abnormalities in asymptomatic and symptomatic patients. Am J Gastroenterol. Oct 1999;94(10):3010-3014.

25. Szczepaniak LS, Nurenberg P, Leonard D, et al. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab. Feb 2005;288(2):E462-468.

26. Fischer LM, da Costa KA, Kwock L, Galanko J, Zeisel SH. Dietary choline requirements of women: effects of estrogen and genetic variation. Am J Clin Nutr. Nov 2010;92(5):1113- 1119.

27. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. Apr 18 2002;346(16):1221-1231. 28. Teli MR, James OF, Burt AD, Bennett MK, Day CP. The natural history of nonalcoholic fatty liver: a follow-up study. Hepatology. Dec 1995;22(6):1714-1719.

29. Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology. Apr 1998;114(4):842-845.

30. Yang SQ, Lin HZ, Lane MD, Clemens M, Diehl AM. Obesity increases sensitivity to endotoxin liver injury: implications for the pathogenesis of steatohepatitis. Proc Natl Acad Sci U S A. Mar 18 1997;94(6):2557-2562.

31. Chung MY, Yeung SF, Park HJ, Volek JS, Bruno RS. Dietary alpha- and gamma-tocopherol supplementation attenuates lipopolysaccharide-induced oxidative stress and inflammatoryrelated responses in an obese mouse model of nonalcoholic steatohepatitis. J Nutr Biochem. Feb 4 2010.

32. Shimomura I, Bashmakov Y, Horton JD. Increased levels of nuclear SREBP-1c associated with fatty livers in two mouse models of diabetes mellitus. J Biol Chem. Oct 15 1999;274(42):30028-30032.

33. Diraison F, Moulin P, Beylot M. Contribution of hepatic de novo lipogenesis and reesterification of plasma non esterified fatty acids to plasma triglyceride synthesis during nonalcoholic fatty liver disease. Diabetes Metab. Nov 2003;29(5):478-485.

34. Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. May 2005;115(5):1343-1351.

35. Savage DB, Choi CS, Samuel VT, et al. Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2. J Clin Invest. Mar 2006;116(3):817-824.

36. Charlton M, Sreekumar R, Rasmussen D, Lindor K, Nair KS. Apolipoprotein synthesis in nonalcoholic steatohepatitis. Hepatology. Apr 2002;35(4):898-904.

37. Lee GS, Yan JS, Ng RK, Kakar S, Maher JJ. Polyunsaturated fat in the methionine-cholinedeficient diet influences hepatic inflammation but not hepatocellular injury. J Lipid Res. Aug 2007;48(8):1885-1896.

38. Letteron P, Fromenty B, Terris B, Degott C, Pessayre D. Acute and chronic hepatic steatosis lead to in vivo lipid peroxidation in mice. J Hepatol. Feb 1996;24(2):200-208.

39. Caldwell SH, Swerdlow RH, Khan EM, et al. Mitochondrial abnormalities in non-alcoholic steatohepatitis. J Hepatol. Sep 1999;31(3):430-434.

40. Cortez-Pinto H, Chatham J, Chacko VP, Arnold C, Rashid A, Diehl AM. Alterations in liver ATP homeostasis in human nonalcoholic steatohepatitis: a pilot study. JAMA. Nov 3 1999;282(17):1659-1664.

41. Perez-Carreras M, Del Hoyo P, Martin MA, et al. Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis. Hepatology. Oct 2003;38(4):999- 1007.

42. Sanyal AJ, Campbell-Sargent C, Mirshahi F, et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology. Apr 2001;120(5):1183-1192.

43. Weltman MD, Farrell GC, Hall P, Ingelman-Sundberg M, Liddle C. Hepatic cytochrome P450 2E1 is increased in patients with nonalcoholic steatohepatitis. Hepatology. Jan 1998;27(1):128-133.

44. Weltman MD, Farrell GC, Liddle C. Increased hepatocyte CYP2E1 expression in a rat nutritional model of hepatic steatosis with inflammation. Gastroenterology. Dec 1996;111(6):1645-1653.

45. Romestaing C, Piquet MA, Bedu E, et al. Long term highly saturated fat diet does not induce NASH in Wistar rats. Nutr Metab (Lond). 2007;4:4.

46. Kirpich IA, Gobejishvili LN, Homme MB, et al. Integrated hepatic transcriptome and proteome analysis of mice with high-fat diet-induced nonalcoholic fatty liver disease. J Nutr Biochem. Mar 19 2010.

47. Zou Y, Li J, Lu C, et al. High-fat emulsion-induced rat model of nonalcoholic steatohepatitis. Life Sci. Aug 8 2006;79(11):1100-1107.

48. Deng QG, She H, Cheng JH, et al. Steatohepatitis induced by intragastric overfeeding in mice. Hepatology. Oct 2005;42(4):905-914.

49. Baumgardner JN, Shankar K, Hennings L, Badger TM, Ronis MJ. A new model for nonalcoholic steatohepatitis in the rat utilizing total enteral nutrition to overfeed a highpolyunsaturated fat diet. Am J Physiol Gastrointest Liver Physiol. Jan 2008;294(1):G27-38.

50. Lieber CS, Leo MA, Mak KM, et al. Model of nonalcoholic steatohepatitis. Am J Clin Nutr. Mar 2004;79(3):502-509.

51. Ronis MJ, Korourian S, Zipperman M, Hakkak R, Badger TM. Dietary saturated fat reduces alcoholic hepatotoxicity in rats by altering fatty acid metabolism and membrane composition. J Nutr. Apr 2004;134(4):904-912.

52. Rivera CA, Gaskin L, Allman M, et al. Toll-like receptor-2 deficiency enhances nonalcoholic steatohepatitis. BMC Gastroenterol. 2010;10:52.

53. You M, Considine RV, Leone TC, Kelly DP, Crabb DW. Role of adiponectin in the protective action of dietary saturated fat against alcoholic fatty liver in mice. Hepatology. Sep 2005;42(3):568-577.

54. Nanji AA, Sadrzadeh SM, Yang EK, Fogt F, Meydani M, Dannenberg AJ. Dietary saturated fatty acids: a novel treatment for alcoholic liver disease. Gastroenterology. Aug 1995;109(2):547-554.

55. Stephen AM, Wald NJ. Trends in individual consumption of dietary fat in the United States, 1920-1984. Am J Clin Nutr. Sep 1990;52(3):457-469.

56. Kim SY, Breslow RA, Ahn J, Salem N, Jr. Alcohol consumption and fatty acid intakes in the 2001-2002 National Health and Nutrition Examination Survey. Alcohol Clin Exp Res. Aug 2007;31(8):1407-1414.

57. Cortez-Pinto H, Jesus L, Barros H, Lopes C, Moura MC, Camilo ME. How different is the dietary pattern in non-alcoholic steatohepatitis patients? Clin Nutr. Oct 2006;25(5):816-823.

58. Ackerman Z, Oron-Herman M, Grozovski M, et al. Fructose- induced fatty liver disease: hepatic effects of blood pressure and plasma triglyceride reduction. Hypertension. May 2005;45(5):1012-1018.

59. Sanchez-Lozada LG, Mu W, Roncal C, et al. Comparison of free fructose and glucose to sucrose in the ability to cause fatty liver. Eur J Nutr. Feb 2010;49(1):1-9.

60. Bray GA, Nielsen SJ, Popkin BM. Consumption of highfructose corn syrup in beverages may play a role in the epidemic of obesity. Am J Clin Nutr. Apr 2004;79(4):537- 543.

61. Assy N, Nasser G, Kamayse I, et al. Soft drink consumption linked with fatty liver in the absence of traditional risk factors. Can J Gastroenterol. Oct 2008;22(10):811-816.

62. Ouyang X, Cirillo P, Sautin Y, et al. Fructose consumption as a risk factor for non-alcoholic fatty liver disease. J Hepatol. Jun 2008;48(6):993-999.

63. Rinella ME, Elias MS, Smolak RR, Fu T, Borensztajn J, Green RM. Mechanisms of hepatic steatosis in mice fed a lipogenic methionine choline-deficient diet. J Lipid Res. May 2008;49(5):1068-1076.

64. Rinella ME, Green RM. The methionine-choline deficient dietary model of steatohepatitis does not exhibit insulin resistance. J Hepatol. Jan 2004;40(1):47-51.

65. Pickens MK, Yan JS, Ng RK, et al. Dietary sucrose is essential to the development of liver injury in the methionine- choline-deficient model of steatohepatitis. J Lipid Res. Oct 2009;50(10):2072-2082.

66. Holman RT. George O. Burr and the discovery of essential fatty acids. J Nutr. May 1988;118(5):535-540.

67. Burr GO, Burr MM. A New Deficiency Disease Produced by the Rigid Exclusion of Fat from the Diet. J Biol Chem. 1929;82(2):345-367.

68. Burr GO, Burr MM. On the Nature and Role of the Fatty Acids Essential in Nutrition. J Biol Chem. 1930;86(2):587- 621.

69. Jackson CM. The Effects of High Sugar Diets on the Growth and Structure of the Rat. J Nutr. 1930;3:61-67.

70. Bieri JG, Stoewsand GS, Briggs GM, Phillips RW, Woodard JC, Knapka JJ. Report of the American Institute of Nutrition Ad Hoc Committee on Standards for Nutritional Studes. J Nutr. 1977;107:1340-1348.

71. Bieri JG. Second Report of the ad hoc Committee on Standards for Nutrition Studies. J Nutr. 1980;110:1726.

72. Bacon BR, Park CH, Fowell EM, McLaren CE. Hepatic steatosis in rats fed diets with varying concentrations of sucrose. Fundam Appl Toxicol. Oct 1984;4(5):819-826.

73. Reeves PG. Components of the AIN-93 diets as improvements in the AIN-76A diet. J Nutr. May 1997;127(5 Suppl):838S-841S.

74. Reeves PG, Nielsen FH, Fahey GC, Jr. AIN-93 purified diets for laboratory rodents: final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet. J Nutr. Nov 1993;123(11):1939-1951.

75. Banting FG. Diabetes and Insulin. Nobel Lecture. 1923.

76. Hershey JM, Soskin S. Substitution of “lecithin” for raw pancreas in the diet of the depancreatized dog. Am Physiological Soc. 1931;98:74-85.

77. Kaplan A, Chaikoff IL. The Effect of Choline on the Lipid Metabolism of Blood and Liver in the Completely Depancreatized Dog Maintained With Insulin. J Biol Chem. 1937;120(2):647-657.

78. Montgomery ML, Entenman C, Chaikoff IL, Feinberg H. Anti-fatty liver activity of crystalline trypsin in insulin-treated depancreatized dogs. J Biol Chem. Jul 1950;185(1):307-310.

79. Best CH, Hershey JM, Huntsman ME. The effect of lecithine on fat deposition in the liver of the normal rat. J Physiol. 1932;75(1):56-66.

80. Best CH, Huntsman ME. The effects of the components of lecithine upon deposition of fat in the liver. J Physiol. 1932;75(4):405-412.

81. Channon HJ, Wilkinson H. The effect of various fats in the production of dietary fatty livers. Biochem J. 1936;30(6):1033-1039.

82. Channon HJ, Wilkinson H. Protein and the dietary production of fatty livers. Biochem J. 1935;29(2):350-356.

83. Yao ZM, Vance DE. The active synthesis of phosphatidylcholine is required for very low density lipoprotein secretion from rat hepatocytes. J Biol Chem. Feb 25 1988;263(6):2998- 3004.

84. Buchman AL, Ament ME, Sohel M, et al. Choline deficiency causes reversible hepatic abnormalities in patients receiving parenteral nutrition: proof of a human choline requirement: a placebo-controlled trial. JPEN J Parenter Enteral Nutr. Sep-Oct 2001;25(5):260-268.

85. Benton DA, Elvehjem CA, Harper AE, Quiros-Perez F, Spivey HE. Effect of different dietary fats on choline requirement of rats. Proc Soc Exp Biol Med. Jan 1957;94(1):100-103.

86. Pan M, Cederbaum AI, Zhang YL, Ginsberg HN, Williams KJ, Fisher EA. Lipid peroxidation and oxidant stress regulate hepatic apolipoprotein B degradation and VLDL production. J Clin Invest. May 2004;113(9):1277-1287.

87. da Costa KA, Kozyreva OG, Song J, Galanko JA, Fischer LM, Zeisel SH. Common genetic polymorphisms affect the human requirement for the nutrient choline. FASEB J. Jul 2006;20(9):1336-1344.

88. Dong H, Wang J, Li C, et al. The phosphatidylethanolamine N-methyltransferase gene V175M single nucleotide polymorphism confers the susceptibility to NASH in Japanese population. J Hepatol. May 2007;46(5):915-920.

89. Song J, da Costa KA, Fischer LM, et al. Polymorphism of the PEMT gene and susceptibility to nonalcoholic fatty liver disease (NAFLD). FASEB J. Aug 2005;19(10):1266-1271.

90. Xu X, Gammon MD, Zeisel SH, et al. Choline metabolism and risk of breast cancer in a population-based study. FASEB J. Jun 2008;22(6):2045-2052.

91. Zhou YJ, Li YY, Nie YQ, et al. Influence of polygenetic polymorphisms on the susceptibility to non-alcoholic fatty liver disease of Chinese people. J Gastroenterol Hepatol. Apr 2010;25(4):772-777.

This article appeared in Wise Traditions in Food, Farming and the Healing Arts, the quarterly journal of the Weston A. Price Foundation, Spring 2011.

About the Author

[authorbio:masterjohn-chris]

Comments (9)

Subscribe to this comment's feed

Name

Email

Website

Title

Comment

smaller | bigger

Subscribe via email (registered users only)

I have read and agree to the Terms of Usage.

Add Comment Preview