The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome

Nature Reviews Gastroenterology and Hepatology - Tập 7 Số 5 - Trang 251-264 - 2010
Jung Sub Lim1, Michele Mietus‐Snyder2, Annie Valente2, Jean-Marc Schwarz3, Robert H. Lustig2
1Department of Pediatrics, Korea Cancer Center Hospital, Gongneung-dong 215, Nowon-gu, Seoul 139-706, Republic of Korea.
2Department of Pediatrics, University of California, San Francisco, San Francisco USA
3College of Osteopathic Medicine, Touro University, Vallejo, USA

Tóm tắt

Từ khóa


Tài liệu tham khảo

Adams, L. A. & Lindor, K. D. Nonalcoholic fatty liver disease. Ann. Epidemiol. 17, 863–869 (2007).

Ludwig, J., Viggiano, T. R., McGill, D. B. & Ott, B. J. Nonalcoholic steatohepatitis: Mayo clinic experience with a hitherto unnamed disease. Mayo Clin. Proc. 55, 434–438 (1980).

Moran, J. R., Ghishan, F. K., Halter, S. A. & Greene, H. L. Steatohepatitis in obese children: a cause of chronic liver dysfunction. Am. J. Gastroenterol. 78, 374–377 (1983).

Roberts, E. A. Pediatric nonalcoholic fatty liver disease (NAFLD): a “growing” problem? J. Hepatol. 46, 1133–1142 (2007).

Unger, R. H., Clark, G. O., Scherer, P. E. & Orci, L. Lipid homeostasis, lipotoxicity, and the metabolic syndrome. Biochim. Biophys. Acta 1801, 209–214 (2010).

Wanless, I. R. & Lentz, J. S. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology 12, 1106–1110 (1990).

Kahn, C. R. Banting Lecture. Insulin action, diabetogenes, and the cause of type II diabetes. Diabetes 43, 1066–1084 (1994).

Javor, E. D. et al. Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy. Hepatology 41, 753–760 (2005).

Seppala-Lindroos, A. 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. 87, 3023–3028 (2002).

Marchesini, G. et al. Association of nonalcoholic fatty liver disease with insulin resistance. Am. J. Med. 107, 450–455 (1999).

Marchesini, G. et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 37, 917–923 (2003).

Schwimmer, J. B. et al. Prevalence of fatty liver in children and adolescents. Pediatrics 118, 1388–1393 (2006).

Deivanayagam, S. et al. Nonalcoholic fatty liver disease is associated with hepatic and skeletal muscle insulin resistance in overweight adolescents. Am. J. Clin. Nutr. 88, 257–262 (2008).

Le, K. A. & Bortolotti, M. Role of dietary carbohydrates and macronutrients in the pathogenesis of nonalcoholic fatty liver disease. Curr. Opin. Clin. Nutr. Metab. Care 11, 477–482 (2009).

Fabbrini, E. et al. Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity. Proc. Natl Acad. Sci. USA 106, 15430–15435 (2009).

Fan, J. G. et al. Effects of nonalcoholic fatty liver disease on the development of metabolic disorders. J. Gastroenterol. Hepatol. 22, 1086–1091 (2007).

Musso, G. et al. Should nonalcoholic fatty liver disease be included in the definition of metabolic syndrome? A cross-sectional comparison with Adult Treatment Panel III criteria in nonobese nondiabetic subjects. Diabetes Care 31, 562–568 (2008).

Burgert, T. S. et al. Alanine aminotransferase levels and fatty liver in childhood obesity: associations with insulin resistance, adiponectin, and visceral fat. J. Clin. Endocrinol. Metab. 91, 4287–4294 (2006).

Kotronen, A., Westerbacka, J., Bergholm, R., Pietiläinen, K. H. & Yki-Järvinen, H. Liver fat in the metabolic syndrome. J. Clin. Endocrinol. Metab. 92, 3490–3497 (2007).

Taki, K., Nishio, K., Hamajima, N. & Niwa, T. Metabolic syndrome defined by new criteria in Japanese is associated with increased liver enzymes and C-reactive protein. Nagoya J. Med. Sci. 70, 1–9 (2008).

Bethel, M. A. et al. Metabolic syndrome and alanine aminotransferase: a global perspective from the NAVIGATOR screening population. Diabet. Med. 26, 1204–1211 (2009).

Romeo, S. et al. Genetic variation in PNPLA3 confers susceptibililty to nonalcoholic fatty liver disease. Nat. Genet. 40, 1461–1465 (2008).

Kantartzis, K. et al. Dissociation between fatty liver and insulin resistance in humans carrying a variant of the patatin-like phospholipase 3 gene. Diabetes 58, 2616–2623 (2009).

Pagano, G. et al. Nonalcoholic steatohepatitis, insulin resistance, and metabolic syndrome: further evidence for an etiologic association. Hepatology 35, 367–372 (2002).

Schwimmer, J. B. et al. Obesity, insulin resistance, and other clinicopathological correlates of pediatric nonalcoholic fatty liver disease. J. Pediatr. 143, 500–505 (2005).

Marra, F. & Bertolani, C. Adipokines in liver diseases. Hepatology 50, 957–969 (2009).

Jimba, S. et al. Prevalence of non-alcoholic fatty liver disease and its association with impaired glucose metabolism in Japanese adults. Diabet. Med. 22, 1141–1145 (2005).

Zivkovic, A. M., German, J. B. & Sanyal, A. J. Comparative review of diets for the metabolic syndrome: implications for nonalcoholic fatty liver disease. Am. J. Clin. Nutr. 86, 285–300 (2007).

Cave, M. et al. Nonalcoholic fatty liver disease: predisposing factors and the role of nutrition. J. Nutr. Biochem. 18, 184–195 (2007).

Alkouri, N., Dixon, L. J. & Feldstein, A. E. Lipotoxicity in nonalcoholic fatty liver disease: not all lipids are created equal. Expert Rev. Gastroenterol. Hepatol. 3, 445–451 (2009).

Tetri, L. H., Basaranoglu, M., Brunt, E. M., Yerian, L. M. & Neuschwander-Tetri, B. A. Severe NAFLD with hepatic necroinflammatory changes in mice fed trans fats and a high-fructose corn syrup equivalent. Am. J. Physiol. Gastrointest. Liver Physiol. 295, G987–G995 (2008).

Nagao, K., Inoue, N., Wang, Y. M., Shirouchi, B. & Yanagita, T. Dietary conjugated linoleic acid alleviates nonalcoholic fatty liver disease in Zucker (fa/fa) rats. J. Nutr. 135, 9–13 (2005).

Assy, N., Nassar, F., Nasser, G. & Grosovski, M. Olive oil consumption and non-alcoholic fatty liver disease. World J. Gastroenterol. 15, 1809–1815 (2009).

Cussons, A. J., Watts, G. F., Mori, T. A. & Stuckey, B. G. Omega-3 fatty acid supplementation decreases liver fat content in polycystic ovary syndrome: a randomized controlled trial employing proton magnetic resonance spectroscopy. J. Clin. Endocrinol. Metab. 94, 3842–3848 (2009).

Zandbergen, F. & Plutzky, J. PPARalpha in atherosclerosis and inflammation. Biochim. Biophys. Acta 1771, 972–982 (2007).

Assy, N. et al. Soft drink consumption linked with fatty liver in the absence of traditional risk factors. Can. J. Gastroenterol. 22, 811–816 (2008).

Abid, A. et al. Soft drink consumption is associated with fatty liver disease independent of metabolic syndrome. J. Hepatol. 51, 918–924 (2009).

Ouyang, X. et al. Fructose consumption as a risk factor for non-alcoholic fatty liver disease. J. Hepatol. 48, 993–999 (2008).

Thuy, S. et al. Nonalcoholic fatty liver disease in humans is associated with increased plasma endotoxin and plasminogen activator inhibitor 1 concentrations and with fructose intake. J. Nutr. 138, 1452–1455 (2008).

Dhingra, R. et al. Soft drink consumption and risk of developing cardiometabolic risk factors and the metabolic syndrome in middle-aged adults in the community. Circulation 116, 480–488 (2007).

James, O. F. & Day, C. P. Non-alcoholic steatohepatitis (NASH): a disease of emerging identity and importance. J. Hepatol. 29, 495–501 (1998).

Lieber, C. S. Alcoholic fatty liver: its pathogenesis and mechanism of progression to inflammation and fibrosis. Alcohol 34, 9–19 (2004).

Burt, A. D., Mutton, A. & Day, C. P. Diagnosis and interpretation of steatosis and steatohepatitis. Semin. Diagn. Pathol. 15, 246–258 (1998).

Syn, W. K., Choi, S. S. & Diehl, A. M. Apoptosis and cytokines in non-alcoholic steatohepatitis. Clin. Liver Dis. 13, 565–580 (2009).

Brunt, E. M. Histopathology of non-alcoholic fatty liver disease. Clin. Liver Dis. 13, 533–544 (2009).

Patton, H. M. et al. Pediatric nonalcoholic fatty liver disease: a critical appraisal of current data and implications for future research. J. Pediatr. Gastroenterol. Nutr. 43, 413–427 (2006).

Bradbury, M. W. & Berk, P. D. Lipid metabolism in hepatic steatosis. Clin. Liver Dis. 8, 639–671 (2004).

Koteish, A. & Diehl, A. M. Animal models of steatosis. Semin. Liver Dis. 21, 89–104 (2001).

Lieber, C. S. et al. Model of nonalcoholic steatohepatitis. Am. J. Clin. Nutr. 79, 502–509 (2004).

Romestaing, C. et al. Long term highly saturated fat diet does not induce NASH in Wistar rats. Nutr. Metab. (Lond.) 4, 4 (2007).

Westerbacka, J. et al. Dietary fat content modifies liver fat in overweight nondiabetic subjects. J. Clin. Endocrinol. Metab. 90, 2804–2809 (2005).

Donnelly, K. L. et al. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J. Clin. Invest. 115, 1343–1351 (2005).

York, L. W., Puthalapattu, S. & Wu, G. Y. Nonalcoholic fatty liver disease and low-carbohydrate diets. Ann. Rev. Nutr. 29, 365–379 (2009).

Anstee, Q. M. & Goldin, R. D. Mouse models in non-alcoholic fatty liver disease and steatohepatitis research. Int. J. Exp. Pathol. 87, 1–16 (2006).

Roden, M. Mechanisms of disease: hepatic steatosis in type 2 diabetes-pathogenesis and clinical relevance. Nat. Clin. Pract. Endocrinol. Metab. 2, 335–348 (2006).

Shoelson, S. E., Lee, J. & Yuan, M. Inflammation and the IKK beta/I kappa B/NF-kappa B axis in obesity- and diet-induced insulin resistance. Int. J. Obes. Relat. Metab. Disord. 27 (Suppl. 3), S49–S52 (2003).

Memon, R. A., Feingold, K. R., Moser, A. H., Fuller, J. & Grunfeld, C. Regulation of fatty acid transport protein and fatty acid translocase mRNA levels by endotoxin and cytokines. Am. J. Physiol. 274, E210–E217 (1998).

Ravikumar, B. et al. Real-time assessment of postprandial fat storage in liver and skeletal muscle in health and type 2 diabetes. Am. J. Physiol. Endocrinol. Metab. 288, E789–E797 (2005).

Perseghin, G. et al. Reduced intrahepatic fat content is associated with increased whole-body lipid oxidation in patients with type 1 diabetes. Diabetologia 48, 2615–2621 (2005).

Schwarz, J. M., Neese, R. A., Turner, S., Dare, D. & Hellerstein, M. K. Short-term alterations in carbohydrate energy intake in humans. Striking effects on hepatic glucose production, de novo lipogenesis, lipolysis, and whole-body fuel selection. J. Clin. Invest. 96, 2735–2743 (1995).

Aarsland, A., Chinkes, D. & Wolfe, R. R. Contributions of de novo synthesis of fatty acids to total VLDL-triglyceride secretion during prolonged hyperglycemia/hyperinsulinemia in normal man. J. Clin. Invest. 98, 2008–2017 (1996).

Hudgins, L. C. et al. Relationship between carbohydrate-induced hypertriglyceridemia and fatty acid synthesis in lean and obese subjects. J. Lipid Res. 41, 595–604 (2000).

Williams, C. D., Oxon, B. M. & Lond, H. Kwashiorkor: a nutritional disease of children associated with a maize diet. 1935. Bull. World Health Organ. 81, 912–913 (2003).

Doherty, J. F., Adam, E. J., Griffin, G. E. & Golden, M. H. Ultrasonographic assessment of the extent of hepatic steatosis in severe malnutrition. Arch. Dis. Child. 67, 1348–1352 (1992).

Shimomura, I., Bashmakov, Y. & Horton, J. D. Increased levels of nuclear SREBP-1c associated with fatty livers in two mouse models of diabetes mellitus. J. Biol. Chem. 274, 30028–30032 (1999).

Araya, J. et al. Increase in long-chain polyunsaturated fatty acid n - 6/n - 3 ratio in relation to hepatic steatosis in patients with non-alcoholic fatty liver disease. Clin. Sci. (Lond.) 106, 635–643 (2004).

Leitch, C. A. & Jones, P. J. Measurement of human lipogenesis using deuterium incorporation. J. Lipid Res. 34, 157–163 (1993).

Hellerstein, M. K. et al. Measurement of de novo hepatic lipogenesis in humans using stable isotopes. J. Clin. Invest. 87, 1841–1852 (1991).

Schwarz, J. M., Linfoot, P., Dare, D. & Aghajanian, K. Hepatic de novo lipogenesis in normoinsulinemic and hyperinsulinemic subjects consuming high-fat, low-carbohydrate and low-fat, high-carbohydrate isoenergetic diets. Am. J. Clin. Nutr. 77, 43–50 (2003).

Glasgow, J. F., Middleton, B., Moore, R., Gray, A. & Hill, J. The mechanism of inhibition of beta-oxidation by aspirin metabolites in skin fibroblasts from Reye's syndrome patients and controls. Biochim. Biophys. Acta 1454, 115–125 (1999).

Spiekerkoetter, U., Sun, B., Khuchua, Z., Bennett, M. J. & Strauss, A. W. Molecular and phenotypic heterogeneity in mitochondrial trifunctional protein de-ficiency due to beta-subunit mutations. Hum. Mutat. 21, 598–607 (2003).

Barr, R., Glass, I. H. & Chawla, G. S. Reye's syndrome: massive fatty metamorphosis of the liver with acute encephalopathy. Can. Med. Assoc. J. 98, 1038–1044 (1968).

Schreurs, M., Kuipers, F. & van der Leij, F. R. Regulatory enzymes of mitochondrial beta-oxidation as targets for treatment of the metabolic syndrome. Obes. Rev. doi:10.1111/j.1467-789X.2009.00642.x.

McGarry, J. D. & Brown, N. F. The mitochondrial carnitine palmitoyltransferase system. From concept to molecular analysis. Eur. J. Biochem. 244, 1–14 (1997).

Savage, D. B. 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. 116, 817–824 (2006).

Pessayre, D. Role of mitochondria in non-alcoholic fatty liver disease. J. Gastroenterol. Hepatol. 22, S20–S27 (2007).

Kotronen, A. et al. Liver fat and lipid oxidation in humans. Liver Int. 29, 1439–1446 (2009).

Auten, R. & Davis, J. Oxygen toxicity and reactive oxygen species: the devil is in the details. Pediatr. Res. 66, 121–127 (2009).

Charlton, M., Sreekumar, R., Rasmussen, D., Lindor, K. & Nair, K. S. Apolipoprotein synthesis in nonalcoholic steatohepatitis. Hepatology 35, 898–904 (2002).

Berriot-Varoqueaux, N., Aggerbeck, L. P., Samson-Bouma, M. & Wetterau, J. R. The role of the microsomal triglygeride transfer protein in abetalipoproteinemia. Annu. Rev. Nutr. 20, 663–697 (2000).

[No auhtors listed] Trends in intake of energy and macronutrients--United States, 1971–2000. MMWR Morb. Mortal. Wkly Rep. 53, 80–82 (2004).

Chanmugam, P. et al. Did fat intake in the United States really decline between 1989–1991 and 1994–1996? J. Am. Diet. Assoc. 103, 867–872 (2003).

Larter, C. Z. & Yeh, M. M. Animal models of NASH: getting both pathology and metabolic context right. J. Gastroenterol. Hepatol. 23, 1635–1648 (2008).

Stern, L. et al. The effects of low-carbohydrate versus conventional weight loss diets in severely obese adults: one-year follow-up of a randomized trial. Ann. Intern. Med. 140, 778–785 (2004).

Samaha, F. F. et al. A low-carbohydrate as compared with a low-fat diet in severe obesity. N. Engl. J. Med. 348, 2074–2081 (2003).

Shai, I. et al. Weight loss with a low-carbohydrate, Mediterranean, or low-fat diet. N. Engl. J. Med. 359, 229–241 (2008).

Rasooly, R., Kelley, D. S., Greg, J. & Mackey, B. E. Dietary trans 10, cis 12-conjugated linoleic acid reduces the expression of fatty acid oxidation and drug detoxification enzymes in mouse liver. Br. J. Nutr. 97, 58–66 (2007).

Lee, S. et al. Trends in diet quality for coronary heart disease prevention between 1980–1982 and 2000–2002: The Minnesota Heart Survey. J. Am. Diet. Assoc. 107, 213–222 (2007).

European Commission. Welfare aspects of the production of foie gras in ducks and geese [online], Ch. 4, 24–29 (2002).

Pasquet, P. et al. Massive overfeeding and energy balance in men: the Guru Walla model. Am. J. Clin. Nutr. 56, 483–490 (1992).

Toshimitsu, K. et al. Dietary habits and nutrient intake in non-alcoholic steatohepatitis. Nutrition 23, 46–52 (2007).

Vos, M. B., Kimmons, J. E., Gillespie, C., Welsh, J. & Blanck, H. M. Dietary fructose consumption among US children and adults: the Third National Health and Nutrition Examination Survey. Medscape J. Med. 10, 160 (2008).

Bray, G. A. How bad is fructose? Am. J. Clin. Nutr. 86, 895–896 (2007).

Haley, S., Reed, J., Lin, B.-H. & Cook, A. Sweetner Consumption in the United States: Distribution by Demographic and Product Characteristics. Economic Research Service [online], (2005).

Ludwig, D. S., Peterson, K. E. & Gortmaker, S. L. Relation between consumption of sugar-sweetened drinks and childhood obesity: a prospective, observational analysis. Lancet 357, 505–508 (2001).

Warner, M. L., Harley, K., Bradman, A., Vargas, G. & Eskenazi, B. Soda consumption and overweight status of 2-year-old Mexican-American children in California. Obesity 14, 1966–1974 (2006).

Faith, M. S., Dennison, B. A., Edmunds, L. S. & Stratton, H. H. Fruit juice intake predicts increased adiposity gain in children from low-income families: weight status-by-environment interaction. Pediatrics 118, 2066–2075 (2006).

Le, K. A. & Tappy, L. Metabolic effects of fructose. Curr. Opin. Nutr. Metab. Care 9, 469–475 (2006).

Rutledge, A. C. & Adeli, K. Fructose and the metabolic syndrome: pathophysiology and molecular mechanisms. Nutr. Rev. 65, S13–S23 (2007).

Johnson, R. J. et al. Potential role of sugar (fructose) in the epidemic of hypertension, obesity and the metabolic syndrome, diabetes, kidney disease, and cardiovascular disease. Am. J. Clin. Nutr. 86, 899–906 (2007).

Havel, P. J. Dietary fructose: implications for dysregulation of energy homeostasis and lipid/carbohydrate metabolism. Nutr. Rev. 63, 133–157 (2005).

Gross, L. S., Li, S., Ford, E. S. & Liu, S. Increased consumption of refined carbohydrates and the epidemic of type 2 diabetes in the United States: an ecologic assessment. Am. J. Clin. Nutr. 79, 774–779 (2004).

Elliott, S. S., Keim, N. L., Stern, J. S., Teff, K. & Havel, P. J. Fructose, weight gain, and the insulin resistance syndrome. Am. J. Clin. Nutr. 76, 911–922 (2002).

Brown, C. M., Dulloo, A. G. & Montani, J. P. Sugary drinks in the pathogenesis of obesity and cardiovascular diseases. Int. J. Obes. 32, 528–534 (2008).

Spruss, A. & Bergheim, I. Dietary fructose and intestinal barrier: potential risk factor in the pathogenesis of nonalcoholic fatty liver disease. J. Nutr. Biochem. 20, 657–662 (2009).

Collison, K. S. et al. Diabetes of the liver: the link between nonalcoholic fatty liver disease and HFCS-55. Obesity 17, 2003–2013 (2009).

Lê, K. A. et al. Fructose overconsumption causes dyslipidemia and ectopic lipid deposition in healthy subjects with and without a family history of type 2 diabetes. Am. J. Clin. Nutr. 89, 1760–1765 (2009).

Drouard, V. & Ferraris, R. P. Regulation of the fructose transporter Glut5 in health and disease. Am. J. Physiol. Endocrinol. Metab. 295, E227–E237 (2008).

Wood, I. S., Wang, B., Lorente-Cebrián, S. & Trayhurn, P. Hypoxia increases expression of selective facilitative glucose transporters (GLUT) and 2-deoxy-D-glucose uptake in human adipocytes. Biochem. Biophys. Res. Comm. 361, 468–473 (2007).

Lustig, R. H. The fructose epidemic. The Bariatrician 24, 10–19 (2009).

Nguyen, S., Choi, H. K., Lustig, R. H. & Hsu, C. Y. Sugar sweetened beverages, serum uric acid, and blood pressure in adolescents J. Pediatr. 154, 807–813 (2009).

Gao, X. B. et al. Intake of added sugar and sugar-sweetended drink and serum uric acid concentration in U. S. men and women. Hypertension 50, 306–312 (2007).

Feig, D. I., Soletsky, B. & Johnson, R. J. Effects of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension. JAMA 300, 924–932 (2008).

Perez-Pozo, S. E. et al. Excessive fructose intake induces the features of metabolic syndrome in healthy adult men: role of uric acid in the hypertensive response. Int. J. Obes. doi:10.1038/ijo.2009.259.

Stanhope, K. L. et al. Consuming fructose-, not glucose-sweetened beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. J. Clin. Invest. 119, 1322–1334 (2009).

Wei, Y., Wang, D. & Pagliassotti, M. J. Fructose selectively modulates c-jun N-terminal kinase activity and insulin signaling in rat primary hepatocytes. J. Nutr. 135, 1642–1646 (2005).

Wei, Y., Wang, D., Topczewski, F. & Pagliassotti, M. J. Fructose-mediated stress signaling in the liver: implications for hepatic insulin resistance. J. Nutr. Biochem. 18, 1–9 (2007).

Hirosumi, J. et al. A central role for JNK in obesity and insulin resistance. Nature 420, 333–336 (2002).

Morino, K., Petersen, K. F. & Shulman, G. I. Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction. Diabetes 55, S9–S15 (2006).

Bezerra, R. M. N. et al. A high fructose diet affects the early steps of insulin action in muscle and liver of rats. J. Nutr. 130, 1531–1535 (2000).

Wei, Y. & Pagliassotti, M. J. Hepatospecific effects of fructose on c-jun NH2-terminal kinase: implications for hepatic insulin resistance. Am. J. Physiol. Endocrinol. Metab. 287, E926–E933 (2004).

Tuncman, G. et al. Functional in vivo interactions between JNK1 and JNK2 isoforms in obesity and insulin resistance. Proc. Natl Acad. Sci. USA 103, 10741–10746 (2006).

Lim, J. H., Lee, H. J., Jung, M. H. & Song, J. Coupling mitochondrial dysfunction to endoplasmic reticulum stress response: a molecular mechanism leading to hepatic insulin resistance. Cell. Signal. 21, 169–177 (2008).

Teff, K. L. et al. Endocrine and metabolic effects of consuming fructose- and glucose-sweetened beverages with meals in obese men and women: influence of insulin resistance on plasma triglyceride responses. J. Clin. Endocrinol. Metab. 94, 1562–1569 (2009).

Krssak, M. et al. Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study. Diabetologia 42, 113–116 (1999).

Montell, E. et al. DAG accumulation from saturated fatty acids desensitizes insulin stimulation of glucose uptake in muscle cells. Am. J. Physiol. Endocrinol. Metab. 280, E229–E237 (2001).

Dong, X. C. et al. Inactivation of hepatic Foxo1 by insulin signaling is required for adaptive nutrient homeostasis and endocrine growth regulation. Cell Metab. 8, 65–76 (2008).

Lindqvist, A., Baelemans, A. & Erlanson-Albertsson, C. Effects of sucrose, glucose and fructose on peripheral and central appetite signals. Regul. Pept. 150, 26–32 (2008).

Avena, N. M., Rada, P. & Hoebel, B. G. Evidence for sugar addiction: behavioral and neurochemical effects of intermittent, excessive sugar intake. Neurosci. Biobehav. Rev. 32, 20–39 (2008).

Teff, K. L. et al. Dietary fructose reduces circulating insulin and leptin, attenuates postprandial suppression of ghrelin, and increases triglycerides in women. J. Clin. Endocrinol. Metab. 89, 2963–2972 (2004).

Cha, S. H., Wolfgang, M., Tokutake, Y., Chohnan, S. & Lane, M. D. Differential effects of central fructose and glucose on hypothalamic malonyl-CoA and food intake. Proc. Natl Acad. Sci. USA 105, 16871–16875 (2008).

Banks, W. A. et al. Triglycerides induce leptin resistance at the blood-brain barrier. Diabetes 53, 1253–1260 (2004).

Lustig, R. H. Childhood obesity: behavioral aberration or biochemical drive? Reinterpreting the first law of thermodynamics. Nat. Clin. Pract. Endocrinol. Metab. 2, 447–458 (2006).

Sabaté, J. M. et al. High prevalence of small intestinal bacterial overgrowth in patients with morbid obesity: a contributor to severe hepatic steatosis. Obes. Surg. 18, 371–377 (2008).

Rao, R. Endotoxemia and gut barrier dysfunction in alcoholic liver disease. Hepatology 50, 638–644 (2009).

Faeh, D. 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).

Scott, C. C., Heckman, C. A. & Snyder, F. Regulation of ether lipids and their precursors in relation to glycolysis in cultured neoplastic cells. Biochim. Biophys. Acta 575, 215–224 (1979).

Dentin, R. et al. Liver-specific inhibition of ChREBP improves hepatic steatosis and insulin resistance in ob/ob mice. Diabetes 55, 2159–2170 (2006).

Zivkovic, A. M., German, J. B. & Sanyal, A. J. Comparative review of diets for the metabolic syndrome: implications for nonalcoholic fatty liver disease. Am. J. Clin. Nutr. 86, 285–300 (2007).

Nagai, Y. et al. The role of peroxisome proliferator-activated receptor gamma coactivator-1 beta in the pathogenesis of fructose-induced insulin resistance. Cell Metab. 9, 252–264 (2009).

Siler, S. Q., Neese, R. A. & Hellerstein, M. K. De novo lipogenesis, lipid kinetics, and whole-body lipid balances in humans after acute alcohol consumption. Am. J. Clin. Nutr. 70, 928–936 (1999).

You, M. & Crabb, D. W. Molecular mechanisms of alcoholic fatty liver: role of sterol regulatory element-binding proteins. Alcohol 34, 39–43 (2004).

Nagai, Y. et al. Amelioration of high fructose-induced metabolic derangements by activation of PPARalpha. Am. J. Physiol. Endocrinol. Metab. 282, E1180–E1190 (2002).

Zhang, D. et al. Mitochondrial dysfunction due to long-chain Acyl-CoA dehydrogenase deficiency causes hepatic steatosis and hepatic insulin resistance. Proc. Natl Acad. Sci. USA 104, 17075–17080 (2007).

Guzmán, M. & Castro, J. Alterations in the regulatory properties of hepatic fatty acid oxidation and carnitine palmitoyltransferase I activity after ethanol feeding and withdrawal. Alcohol Clin. Exp. Res. 14, 472–477 (1990).

Farfán Labonne, B. E. et al. Acetaldehyde-induced mitochondrial dysfunction sensitizes hepatocytes to oxidative damage. Cell Biol. Toxicol. 25, 599–609 (2009).

García-Villafranca, J., Guillén, A. & Castro, J. Ethanol consumption impairs regulation of fatty acid metabolism by decreasing the activity of AMP activated protein kinase in rat liver. Biochimie 90, 460–466 (2008).

Ameen, C. et al. Activation of peroxisome proliferator-activated receptor alpha increases the expression and activity of microsomal triglyceride transfer protein in the liver. J. Biol. Chem. 280, 1224–1229 (2005).

Roglans, N. et al. Impairment of hepatic Stat-3 activation and reduction of PPARalpha activity in fructose-fed rats. Hepatology 45, 778–788 (2007).

Nanji, A. A., Dannenberg, A. J., Jokelainen, K. & Bass, N. M. Alcoholic liver injury in the rat is associated with reduced expression of peroxisome proliferator-alpha (PPARalpha)-regulated genes and is ameliorated by PPARalpha activation. J. Pharmacol. Exp. Ther. 310, 417–424 (2004).

Koo, H. Y. et al. Dietary fructose induces a wide range of genes with distinct shift in carbohydrate and lipid metabolism in fed and fasted rat liver. Biochim. Biophys. Acta 1782, 341–348 (2008).

Gambino, R., Cassader, M., Pagano, G., Durazzo, M. & Musso, G. Polymorphism in microsomal triglyceride transfer protein: a link between liver disease and atherogenic postprandial lipid profile in NASH? Hepatology 45, 1097–1107 (2007).

Taghibiglou, C. et al. Hepatic very low density lipoprotein-ApoB overproduction is associated with attenuated hepatic insulin signaling and overexpression of protein-tyrosine phosphatase 1B in a fructose fed hamster model of insulin resistance. J. Biol. Chem. 277, 793–803 (2002).

Tsai, J. et al. Inflammatory NF-kappaB activation promotes hepatic apolipoprotein B100 secretion: evidence for a link between hepatic inflammation and lipoprotein production. Am. J. Physiol. Gastrointest. Liver Physiol. 296, 1287–1298 (2009).

Hirano, T., Mamo, J. C., Poapst, M. E., Kuksis, A. & Steiner, G. Impaired very low-density lipoprotein-triglyceride catabolism in acute and chronic fructose-fed rats. Am. J. Physiol. 256, E559–E565 (1989).

Sozio, M. & Crabb, D. W. Alcohol and lipid metabolism. Am. J. Physiol. Endocrinol. Metab. 295, E10–E16 (2008).

Steinberg, D., Pearson, T. A. & Kuller, L. H. Alcohol and atherosclerosis. Ann. Intern. Med. 114, 967–976 (1991).

Svegliati-Baroni, G. et al. A model of insulin resistance and nonalcoholic steatohepatitis in rats: role of peroxisome proliferator-activated receptor-alpha and n-3 polyunsaturated fatty acid treatment on liver injury. Am. J. Pathol. 169, 846–860 (2006).

Lau, P. P., Cahill, D. J., Zhu, H. J. & Chan, L. Ethanol modulates apolipoprotein B mRNA editing in the rat. J. Lipid Res. 36, 2069–2078 (1995).

Haidari, M. et al. Fasting and postprandial overproduction of intestinally derived lipoproteins in an animal model of insulin resistance. Evidence that chronic fructose feeding in the hamster is accompanied by enhanced intestinal de novo lipogenesis and ApoB48-containing lipoprotein overproduction. J. Biol. Chem. 277, 31646–31655 (2002).

Duez, H. et al. Hyperinsulinemia is associated with increased production rate of intestinal apolipoprotein B-48-containing lipoproteins in humans. Arterioscler. Thromb. Vasc. Biol. 26, 1357–1363 (2006).

Jurgens, H. et al. Consuming fructose-sweetened beverages increases body adiposity in mice. Obes. Res. 13, 1146–1156 (2005).

Ackerman, Z. et al. Fructose-induced fatty liver disease: hepatic effects of blood pressure and plasma triglyceride reduction. Hypertension 45, 1012–1018 (2005).

Valente, A., Mietus-Snyder, M. L., Lim, J. S. & Lustig, R. H. Association between sugar sweetened beverage consumption and serum alanini aminotransferase in obese children [abstract]. Ped. Acad. Soc. 3854.45 (2009).

Romeo, S. et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 40, 1461–1465 (2008).

Shin, M. J., Kanaya, A. M. & Krauss, R. M. Polymorphisms in the peroxisome proliferator activated receptor alpha gene are associated with levels of apolipoprotein CIII and triglyceride in African-Americans but not Caucasians. Atherosclerosis 198, 313–319 (2008).

Wieckowska, A. & Feldstein, A. E. Diagnosis of nonalcoholic fatty liver disease: invasive versus noninvasive. Semin. Liver Dis. 28, 386–395 (2008).

Radetti, G., Kleon, W., Stuefer, J. & Pittschieler, K. Non-alcoholic fatty liver disease in obese children evaluated by magnetic resonance imaging. Acta Paediatr. 95, 833–837 (2006).

Schwarz, J. M. et al. Effects of short-term feeding with high- vs low-fructose isoenergetic diets on hepatic de novo lipogenesis, liver fat content and glucose regulation [abstract]. Am. Diabetes Assoc. 1476P (2009).

Dills, W. L. Protein fructosylation: fructose and the Maillard reaction. Am. J. Clin. Nutr. 58, 779S–787S (1993).

Ahmed, N. & Furth, A. J. Failure of common glycation assays to detect glycation by fructose. Clin. Chem. 38, 1301–1303 (1992).

Schalkwijk, C. G., Stehouwer, C. D. & van Hinsbergh, V. W. Fructose-mediated non-enzymatic glycation: sweet coupling or bad modification. Diabetes Metab. Res. 20, 369–382 (2004).

Nagai, R. et al. Hydroxyl radical mediates N epsilon-(carboxymethyl)lysine formation from Amadori product. Biochem. Biophys. Res. Comm. 234, 167–172 (1997).

Bunn, H. F. & Higgins, P. J. Reaction of monosaccharides with proteins: possible evolutionary significance Science 213, 222–224 (1981).

Bose, T. & Chakraborti, A. S. Fructose-induced structural and functional modifications of hemoglobin: implication for oxidative stress in diabetes mellitus. Biochim. Biophys. Acta 1780, 800–808 (2008).

Levi, B. & Werman, M. J. Fructose and related phosphate derivatives impose DNA damage and apoptosis in L5178Y mouse lymphoma cells. J. Nutr. Biochem. 14, 49–60 (2003).

Lee, O. et al. Fructose and carbonyl metabolites and endogenous toxins. Chem. Biol. Interact. 178, 332–339 (2009).

Koteish, A. & Diehl, A. M. Animal models of steatohepatitis. Best Pract. Res. Clin. Gastroenterol. 16, 679–690 (2002).

Zeisel, S. H. Dietary choline: biochemistry, physiology, and pharmacology. Ann. Rev. Nutr. 1, 95–121 (1981).

Pickens, M. K. et al. Dietary sucrose is essential to the development of liver injury in the MCD model of steatohepatitis. J. Lipid Res. 50, 2072–2082 (2009).

Romestaing, C. et al. Mitochondrial adaptations to steatohepatitis induced by a methionine- and choline-deficient diet. Am. J. Physiol. Endocrinol. Metab. 294, E110–E119 (2008).

Frary, C. D., Johnson, R. K. & Wang, M. Q. Children and adolescents' choices of foods and beverages high in added sugars are associated with intakes of key nutrients and food groups. J. Adol. Health 34, 56–63 (2004).

Garcia, O. P., Long, K. Z. & Rosado, J. L. Impact of micronutrient deficiencies on obesity. Nutr. Rev. 67, 559–572 (2009).

Manari, A. P., Preedy, V. R. & Peters, T. J. Nutritional intake of hazardous drinkers and dependent alcoholics in the UK. Addict. Biol. 8, 201–210 (2003).

Godin, D. V. & Wohaieb, S. A. Nutritional deficiency, starvation, and tissue antioxidant status. Free Radic. Biol. Med. 5, 165–176 (1988).

Powell, C. L. et al. Mechanism for prevention of alcohol-induced liver injury by dietary methyl donors. Toxicol. Sci. doi:10.1093/toxsci/kfq031.

Gentile, C. L. & Pagliassotti, M. J. The role of fatty acids in the development and progression of nonalcoholic fatty liver disease. J. Nutr. Biochem. 19, 567–576 (2008).

Santos, C. X., Tanaka, L. Y., Wosniak, J. & Laurindo, F. R. Mechanisms and implications of reactive oxygen species generation during the unfolded protein response: roles of endoplasmic reticulum oxidoreductases, mitochondrial electron transport, and NADPH oxidase. Antioxid. Redox Signal. 11, 2409–2427 (2009).

Kapoor, A. & Sanyal, A. J. Endoplasmic reticulum stress and the unfolded protein response. Clin. Liver Dis. 13, 581–590 (2009).

Lazo, M. & Clark, J. M. The epidemiology of nonalcoholic fatty liver disease: a global perspective. Semin. Liver Dis. 28, 339–350 (2008).

Johnson, R. K. et al. Dietary sugars intake and cardiovascular health. A scientific statement from the American Heart Association. Circulation 120, 1011–1020 (2009).

Bantle, J. P. Dietary fructose and metabolic syndrome and diabetes. J. Nutr. 139, 1263S–1268S (2009).