Dr. Ron’s Research Review – March 9, 2011

This week’s research review focuses on the fructose – liver controversy.

Dietary exposure to fructose has increased over the past 40 years. (Dekker, Su et al. 2010)

Fructose and the Metabolic Syndrome

Fructose is a highly lipogenic (fat producing) sugar that has profound metabolic effects in the liver and has been associated with many of the components of the metabolic syndrome (insulin resistance, elevated waist circumference, dyslipidemia, and hypertension). (Dekker, Su et al. 2010)

NASH and NAFLD

Fructose exerts various direct effects in the liver, affecting both hepatocytes and Kupffer cells and resulting in non-alcoholic steatotic hepatitis (NASH), a well-known precursor of the metabolic syndrome. (Wiernsperger, Geloen et al. 2010)

A study of patients with Non-Alcoholic Fatty Liver Disease (NAFLD) (n=49) without cirrhosis and controls (n=24) found that consumption of fructose in patients with NAFLD was nearly 2- to 3-fold higher than controls. (Ouyang, Cirillo et al. 2008)

In patients with NAFLD, daily fructose ingestion is associated with reduced hepatic steatosis but increased fibrosis. (Abdelmalek, Suzuki et al. 2010)

The Real Culprit

High fructose corn syrup (HCFS) has been a staple of the American diet since 1970 and accounts for roughly 10% of dietary intake in the US. (Abdelmalek, Suzuki et al. 2010)

The increased consumption of high fructose corn syrup, primarily in the form of soft drinks, is linked with complications of the insulin resistance syndrome. (Ouyang, Cirillo et al. 2008)

Bile Acids

A recent study showed that bile acids had a protective effect of on the onset of fructose-induced hepatic steatosis in mice. (Volynets, Spruss et al. 2010)

Dr. Ron


Articles

Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease

            (Abdelmalek, Suzuki et al. 2010) Download

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. Because fructose elicits metabolic perturbations that may be hepatotoxic, we investigated the relationship between fructose consumption and disease severity in NAFLD. We studied 427 adults enrolled in the NASH Clinical Research Network for whom Block food questionnaire data were collected within 3 months of a liver biopsy. Fructose consumption was estimated based on reporting (frequency x amount) of Kool-aid, fruit juices, and nondietary soda intake, expressed as servings per week, and classified into none, minimum to moderate (<7 servings/week), and daily (> or =7 servings/week). The association of fructose intake with metabolic and histological features of NAFLD was analyzed using multiple linear and ordinal logistic regression analyses with and without controlling for other confounding factors. Increased fructose consumption was univariately associated with decreased age (P < 0.0001), male sex (P < 0.0001), hypertriglyceridemia (P < 0.04), low high-density lipoprotein (HDL) cholesterol (<0.0001), decreased serum glucose (P < 0.001), increased calorie intake (P < 0.0001), and hyperuricemia (P < 0.0001). After controlling for age, sex, BMI, and total calorie intake, daily fructose consumption was associated with lower steatosis grade and higher fibrosis stage (P < 0.05 for each). In older adults (age > or = 48 years), daily fructose consumption was associated with increased hepatic inflammation (P < 0.05) and hepatocyte ballooning (P = 0.05). CONCLUSION: In patients with NAFLD, daily fructose ingestion is associated with reduced hepatic steatosis but increased fibrosis. These results identify a readily modifiable environmental risk factor that may ameliorate disease progression in patients with NAFLD.

Non-Alcoholic Fatty Liver Disease and Fructose: Bad for Us, Better for Mice

            (Anania 2010) Download

The fundamental problem with a corn based syrup or fructose diet is their fate vis-a-vis hepatic intermediary metabolism that converts such ingredients into long chain fatty acids (LCFA) by committing hepatic fructose uptake to fructose-1-phosphate as opposed to fructrose-1,6-bisphosphate

Fructose: a highly lipogenic nutrient implicated in insulin resistance, hepatic steatosis, and the metabolic syndrome

            (Dekker, Su et al. 2010) Download

As dietary exposure to fructose has increased over the past 40 years, there is growing concern that high fructose consumption in humans may be in part responsible for the rising incidence of obesity worldwide. Obesity is associated with a host of metabolic challenges, collectively termed the metabolic syndrome. Fructose is a highly lipogenic sugar that has profound metabolic effects in the liver and has been associated with many of the components of the metabolic syndrome (insulin resistance, elevated waist circumference, dyslipidemia, and hypertension). Recent evidence has also uncovered effects of fructose in other tissues, including adipose tissue, the brain, and the gastrointestinal system, that may provide new insight into the metabolic consequences of high-fructose diets. Fructose feeding has now been shown to alter gene expression patterns (such as peroxisome proliferator-activated receptor-gamma coactivator-1alpha/beta in the liver), alter satiety factors in the brain, increase inflammation, reactive oxygen species, and portal endotoxin concentrations via Toll-like receptors, and induce leptin resistance. This review highlights recent findings in fructose feeding studies in both human and animal models with a focus on the molecular and biochemical mechanisms that underlie the development of insulin resistance, hepatic steatosis, and the metabolic syndrome.

Fructose consumption as a risk factor for non-alcoholic fatty liver disease

            (Ouyang, Cirillo et al. 2008) Download

BACKGROUND/AIMS: While the rise in non-alcoholic fatty liver disease (NAFLD) parallels the increase in obesity and diabetes, a significant increase in dietary fructose consumption in industrialized countries has also occurred. The increased consumption of high fructose corn syrup, primarily in the form of soft drinks, is linked with complications of the insulin resistance syndrome. Furthermore, the hepatic metabolism of fructose favors de novo lipogenesis and ATP depletion. We hypothesize that increased fructose consumption contributes to the development of NAFLD. METHODS: A dietary history and paired serum and liver tissue were obtained from patients with evidence of biopsy-proven NAFLD (n=49) without cirrhosis and controls (n=24) matched for gender, age (+/-5 years), and body mass index (+/-3 points). RESULTS: Consumption of fructose in patients with NAFLD was nearly 2- to 3-fold higher than controls [365 kcal vs 170 kcal (p<0.05)]. In patients with NAFLD (n=6), hepatic mRNA expression of fructokinase (KHK), an important enzyme for fructose metabolism, and fatty acid synthase, an important enzyme for lipogenesis were increased (p=0.04 and p=0.02, respectively). In an AML hepatocyte cell line, fructose resulted in dose-dependent increase in KHK protein and activity. CONCLUSIONS: The pathogenic mechanism underlying the development of NAFLD may be associated with excessive dietary fructose consumption.

Non-alcoholic fatty liver disease. From insulin resistance to mitochondrial dysfunction

            (Solis Herruzo, Garcia Ruiz et al. 2006) Download

Non-alcoholic fatty liver disease represents a set of liver lesions similar to those induced by alcohol that develop in individuals with no alcohol abuse. When lesions consist of fatty and hydropic degeneration, inflammation, and eventually fibrosis, the condition is designated non-alcoholic steatohepatitis (NASH). The pathogenesis of these lesions is not clearly understood, but they are associated with insulin resistance in most cases. As a result, abdominal fat tissue lipolysis and excessive fatty acid uptake by the liver occur. This, together with a disturbance of triglyceride export as VLDL, results in fatty liver development. Both the inflammatory and hepatocellular degenerative components of NASH are attributed to oxidative stress. Mitochondrial respiratory chain loss of activity plays a critical role in the genesis of latter stress. This may be initiated by an increase in the hepatic TNFalpha, iNOS induction, peroxynitrite formation, tyrosine nitration and inactivation of enzymes making up this chain. Consequences of oxidative stress include: lipid peroxidation in cell membranes, stellate cell activation in the liver, liver fibrosis, chronic inflammation, and apoptosis.

Protective effect of bile acids on the onset of fructose-induced hepatic steatosis in mice

            (Volynets, Spruss et al. 2010) Download

Fructose intake is being discussed as a key dietary factor in the development of nonalcoholic fatty liver disease (NAFLD). Bile acids have been shown to modulate energy metabolism. We tested the effects of bile acids on fructose-induced hepatic steatosis. In C57BL/6J mice treated with a combination of chenodeoxycholic acid and cholic acid (100 mg/kg body weight each) while drinking water or a 30% fructose solution for eight weeks and appropriate controls, markers of hepatic steatosis, portal endotoxin levels, and markers of hepatic lipogenesis were determined. In mice concomitantly treated with bile acids, the onset of fructose-induced hepatic steatosis was markedly attenuated compared to mice only fed fructose. The protective effects of the bile acid treatment were associated with a downregulation of tumor necrosis factor (TNF)alpha, sterol regulatory element-binding protein (SREBP)1, FAS mRNA expression, and lipid peroxidation in the liver, whereas hepatic farnesoid X receptor (FXR) or short heterodimer partner (SHP) protein concentration did not differ between groups fed fructose. Rather, bile acid treatment normalized occludin protein concentration in the duodenum, portal endotoxin levels, and markers of Kupffer cell activation to the level of water controls. Taken together, these data suggest that bile acids prevent fructose-induced hepatic steatosis in mice through mechanisms involving protection against the fructose-induced translocation of intestinal bacterial endotoxin.

Fructose and cardiometabolic disorders: the controversy will, and must, continue

            (Wiernsperger, Geloen et al. 2010) Download

The present review updates the current knowledge on the question of whether high fructose consumption is harmful or not and details new findings which further pushes this old debate. Due to large differences in its metabolic handling when compared to glucose, fructose was indeed suggested to be beneficial for the diet of diabetic patients. However its growing industrial use as a sweetener, especially in soft drinks, has focused attention on its potential harmfulness, possibly leading to dyslipidemia, obesity, insulin resistance/metabolic syndrome and even diabetes. Many new data have been generated over the last years, confirming the lipogenic effect of fructose as well as risks of vascular dysfunction and hypertension. Fructose exerts various direct effects in the liver, affecting both hepatocytes and Kupffer cells and resulting in non-alcoholic steatotic hepatitis, a well known precursor of the metabolic syndrome. Hepatic metabolic abnormalities underlie indirect peripheral metabolic and vascular disturbances, for which uric acid is possibly the culprit. Nevertheless major caveats exist (species, gender, source of fructose, study protocols) which are detailed in this review and presently prevent any firm conclusion. New studies taking into account these confounding factors should be undertaken in order to ascertain whether or not high fructose diet is harmful.

Nutritional modulation of nonalcoholic fatty liver disease and insulin resistance: human data

            (Yki-Jarvinen 2010) Download

PURPOSE OF REVIEW: Concomitant with the obesity epidemic, a fatty liver due to nonalcoholic causes has become the most common liver disorder. Nonalcoholic fatty liver disease (NAFLD) covers a range from benign steatosis to nonalcoholic steatohepatitis (NASH), which in turn may progress to cirrhosis. NAFLD predicts, independent of obesity, the metabolic syndrome and type 2 diabetes and can progress to cirrhosis. This review focuses on studies in humans addressing effects of dietary changes in NAFLD. RECENT FINDINGS: Cross-sectionally, increased intake of fructose and simple sugars characterizes patients with NAFLD compared with weight-matched controls. Increased fructose intake is also associated with hepatic insulin resistance and fibrosis severity in NASH. Intake of saturated fat may also be increased in NAFLD. Dietary intervention studies have shown that liver volume and fat content changes significantly within a few days in response to caloric restriction or excess despite no or small changes in body weight. Weight loss by bariatric surgery decreases liver fat and inflammation but effects on fibrosis are uncertain. Hepatic insulin sensitivity generally changes in parallel with changes in liver fat content in NAFLD. Human data are limited regarding effects of isocaloric changes in diet composition on liver fat content. SUMMARY: Maintenance of normal body weight and avoidance of intake of excess lipogenic simple sugars would seem beneficial for prevention of NAFLD and its metabolic consequences.

Role of alcohol metabolism in non-alcoholic steatohepatitis

            (Baker, Baker et al. 2010) Download

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a serious form of non-alcoholic fatty liver disease (NAFLD), associated with obesity and insulin resistance. Previous studies suggested that intestinal bacteria produced more alcohol in obese mice than lean animals. METHODOLOGY/PRINCIPAL FINDINGS: To investigate whether alcohol is involved in the pathogenesis of NASH, the expression of inflammation, fibrosis and alcohol metabolism related genes in the liver tissues of NASH patients and normal controls (NCs) were examined by microarray (NASH, n = 7; NC, n = 4) and quantitative real-time PCR (NASH, n = 6; NC, n = 6). Genes related to liver inflammation and fibrosis were found to be elevated in NASH livers compared to normal livers. The most striking finding is the increased gene transcription of alcohol dehydrogenase (ADH) genes, genes for catalase and cytochrome P450 2E1, and aldehyde dehydrogenase genes. Immunoblot analysis confirmed the increased expression of ADH1 and ADH4 in NASH livers (NASH, n = 9; NC, n = 4). CONCLUSIONS/SIGNIFICANCE: The augmented activity of all the available genes of the pathways for alcohol catabolism suggest that 1) alcohol concentration was elevated in the circulation of NASH patients; 2) there was a high priority for the NASH livers to scavenge alcohol from the circulation. Our data is the first human evidence that suggests alcohol may contribute to the development of NAFLD.


References

Abdelmalek, M. F., A. Suzuki, et al. (2010). "Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease." Hepatology 51(6): 1961-71.

Anania, F. A. (2010). "Non-Alcoholic Fatty Liver Disease and Fructose: Bad for Us, Better for Mice." J Hepatol.

Baker, S. S., R. D. Baker, et al. (2010). "Role of alcohol metabolism in non-alcoholic steatohepatitis." PLoS One 5(3): e9570.

Dekker, M. J., Q. Su, et al. (2010). "Fructose: a highly lipogenic nutrient implicated in insulin resistance, hepatic steatosis, and the metabolic syndrome." Am J Physiol Endocrinol Metab 299(5): E685-94.

Ouyang, X., P. Cirillo, et al. (2008). "Fructose consumption as a risk factor for non-alcoholic fatty liver disease." J Hepatol 48(6): 993-9.

Solis Herruzo, J. A., I. Garcia Ruiz, et al. (2006). "Non-alcoholic fatty liver disease. From insulin resistance to mitochondrial dysfunction." Rev Esp Enferm Dig 98(11): 844-74.

Volynets, V., A. Spruss, et al. (2010). "Protective effect of bile acids on the onset of fructose-induced hepatic steatosis in mice." J Lipid Res 51(12): 3414-24.

Wiernsperger, N., A. Geloen, et al. (2010). "Fructose and cardiometabolic disorders: the controversy will, and must, continue." Clinics (Sao Paulo) 65(7): 729-38.

Yki-Jarvinen, H. (2010). "Nutritional modulation of nonalcoholic fatty liver disease and insulin resistance: human data." Curr Opin Clin Nutr Metab Care 13(6): 709-14.