Fructose impairs glucose-induced hepatic triglyceride synthesis
Tóm tắt
Obesity, type 2 diabetes and hyperlipidemia frequently coexist and are associated with significantly increased morbidity and mortality. Consumption of refined carbohydrate and particularly fructose has increased significantly in recent years and has paralled the increased incidence of obesity and diabetes. Human and animal studies have demonstrated that high dietary fructose intake positively correlates with increased dyslipidemia, insulin resistance, and hypertension. Metabolism of fructose occurs primarily in the liver and high fructose flux leads to enhanced hepatic triglyceride accumulation (hepatic steatosis). This results in impaired glucose and lipid metabolism and increased proinflammatory cytokine expression. Here we demonstrate that fructose alters glucose-stimulated expression of activated acetyl CoA carboxylase (ACC), pSer hormone sensitive lipase (pSerHSL) and adipose triglyceride lipase (ATGL) in hepatic HepG2 or primary hepatic cell cultures in vitro. This was associated with increased de novo triglyceride synthesis in vitro and hepatic steatosis in vivo in fructose- versus glucose-fed and standard-diet fed mice. These studies provide novel insight into the mechanisms involved in fructose-mediated hepatic hypertriglyceridemia and identify fructose-uptake as a new potential therapeutic target for lipid-associated diseases.
Tài liệu tham khảo
Bayturan O, Tuzcu EM, Lavoie A, Hu T, Wolski K, Schoenhagen P, Kapadia S, Nissen SE, Nicholls SJ: The metabolic syndrome, its component risk factors, and progression of coronary atherosclerosis. Arch. Intern. Med. 2010, 170: 478-84. 10.1001/archinternmed.2009.551
Basciano H, Federico L, Adeli K: Fructose, insulin resistance, and metabolic dyslipidemia. Nutr. Metab. 2005, 2: 1-14. 10.1186/1743-7075-2-5.
Hallfrisch J: Metabolic effects of dietary fructose. FASEB. 1990, 4: 2652-2660.
Mayes PA: Intermediary metabolism of fructose. Am. J. Clin. Nutr. 1993, 58: Supp 5-
Tetri LH, Basaranoglu M, Brunt EM, Yerian LM, Neuschwander Tetri BA: Severe NAFLD with hepatic necroinflammatory changes in mice fed trans fats and a high-fructose corn syrup equivalent. Am. J. Physiol. Gastrointest. Liver Physiol. 2008, 295: G987-G995. 10.1152/ajpgi.90272.2008
Rutledge AC, Adeli K: Fructose and metabolic syndrome: Pathophysiology and molecular mechanisms. Nutrition Rev. 2007, 65: S13-23. 10.1301/nr.2007.jun.S13-S23.
Ginsburg GS, Safran C, Pasternak RC: Frequency of low serum high-density lipoprotein cholesterol levels in hospitalized patients with "desirable"total cholesterol levels. Am. J. Cardiol. 1991, 1: 187-92. 10.1016/0002-9149(91)90742-4.
Abbot RD, Wilson PWF, Kannel WB, Castelli WP: High density lipoprotein cholesterol, total cholesterol screening, and myocardial infarction. The Framingham Heart Study. Arteriosclerosis. 1988, 8: 207-11.
Castelli WP, Doyle JT, Gordon T, Hames CG, Hjortland MC, Hulley SB, Kagan A, Zukel WJ: HDL cholesterol and other N lipids in coronary hean disease: the cooperative lipoprotein pheno type study. Circulation. 1977, 55: 767-72.
Reckless JPD, Betteridge DJ, Wu P, Payne B, Galton DJ: High-density and low density lipoproteins and prevalence of vascular disease in diabetesmellitus. Br. Med. J. 1978, 1: 883-6. 10.1136/bmj.1.6117.883
Havel RJ: High density lipoproteins, cholesterol transport and coronary heart disease. Circulation. 1979, 60: 1-3.
Nestle PJ, Readon M, Billington T: In vivo transport of cholesterol esters from high density lipoproteins to very low density lipoproteins in man. Biochim. Biophys. Acta. 1979, 573: 403-7.
Carlson LA, Bolliger LE, Ahfeldt PE: Risk factors for myocardial infarction in the Stockholm perspective study: a 14-year follow-up focusing on the role of plasma triglyceride and cholesterol. Acta. N. Med. Scand. 1979, 706: 351-
Fontbonne A, Eschwège E, Cambien F, Richard JL, Ducimetière P, Thibult N, Warnet JM, Claude JR, Rosselin GE: Hypertriglyceridemia as a risk factor of coronary heart disease mortality in subjects with impaired glucose tolerance or diabetes: results from the II-year follow-up of the Paris Prospective Study. Diabetologia. 1989, 32: 34- 10.1007/BF00265546
West KM, Ahuja MM, Bennett PH, Czyzyk A, De Acosta OM, Fuller JH, Grab B, Grabauskas V, Jarrett RJ, Kosaka K: The role of circulating glucose and triglyceride concentrations and their interaction with other "risk factors" as determinants of anerial disease in nine diabetic populations: samples from the WHO multinational study. Diabetes Care. 1983, 6: 361-9. 10.2337/diacare.6.4.361
Hollenbeck CB: Dietary fructose effects on lipoprotein metabolism and risk for coronary artery disease. Am. J. Clin. Nutr. 1993, 58: 800S-809S.
Reaven GM, Lerner RL, Stem MP, Farquhar JW: Role of insulin in endogenous hypenriglyceridemia. J. Clin. Invest. 1967, 46: 175-7. 10.1172/JCI105666.
Olefsky JM, Farquhar JW, Reaven GM: Reappraisal of the role of insulin hypenriglyceridemia. Am. J. Med. 1974, 57: 551- 10.1016/0002-9343(74)90006-0
Tobey TA, Greenfield MA, Kraemer F, Reaven GM: Relationship between insulin resistance, insulin secretion, very low density lipoprotein kinetics and plasma triglyceride levels in normotriglyceridemic men. Metabolism. 1981, 30: 165-7I. 10.1016/0026-0495(81)90167-0
Lavaroni I, Sanders S, Scoll S, Reaven GM: Effect of fructose feeding on insulin secretion and insulin action in the rat. Metabolism. 1980, 29: 970-3. 10.1016/0026-0495(80)90041-4
Storlien LH, Kraegan EW, Jenkins AD, Chisholm OJ: Effects of sucrose vs starch diets on in vivo insulin action, thermogenesis, and obesity in rats. Am. J. Clin. Nutr. 1988, 47: 420-7.
Thorburn AW, Storlien LH, Jenkins AD: Fructose-induced in vivo insulin resistance and elevated plasma triglyceride levels in rats. Am. J. Clin. Nutr. 1989, 49: 1155-63.
Davis RC, Castellani LW, Hosseini M, Ben-Zeev O, Mao HZ, Weinstein MM, Jung DY, Jun JY, Kim JK, Lusis AJ, Péterfy M: Early hepatic insulin resistance precedes the onset of diabetes in obese C57BLKS-db/db mice. Diabetes. 2010, 59: 1616-25. 10.2337/db09-0878
Cascante M, Boros LG, Comin B, Atauri P, Centelles JJ, Lee W-NP: Metabolic control analysis in drug discovery and disease. Nature Biotechnology. 2002, 20: 246-249. 10.1038/nbt0302-243.
Hwang JT, Park IJ, Shin JI, Lee YK, Lee SK, Baik HW, Ha J, Park OJ: Genistein, EGCG, and capsaicin inhibit adipocyte differentiation process via activating AMP-activated protein kinase. Biochem. Biophys. Res. Commun. 2005, 338: 694-699. 10.1016/j.bbrc.2005.09.195
Postic C, Girard J: Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. J. Clin. Invest. 2008, 118: 829- 10.1172/JCI34275
Faeh D, Minehira K, Schwarz JM, Periasamy R, Park S, Tappy L: Effect of fructose overfeeding and fish oil administration on hepatic de novo lipogenesis and insulin sensitivity in healthy men. Diabetes. 2005, 54: 1907-1913. 10.2337/diabetes.54.7.1907
Lê KA, Faeh D, Stettler R, Ith M, Kreis R, Vermathen P, Boesch C, Ravussin E, Tappy L: A 4-wk high-fructose diet alters lipid metabolism without affecting insulin sensitivity or ectopic lipids in healthy humans. Am. J. Clin. Nutr. 2006, 84: 1374-1379.
Abdel-Sayed A, Binnert C, Lê KA, Bortolotti M, Schneiter P, Tappy L: A high-fructose diet impairs basal and stress-mediated lipid metabolism in healthy male subjects. Br. J. Nutr. 2008, 100: 393-399. 10.1017/S000711450789547X
Teff KL, Elliott SS, Tschöp M, Kieffer TJ, Rader D, Heiman M, Townsend RR, Keim NL, D'Alessio D, Havel PJ: Dietary fructose reduces circulating insulin and leptin, attenuates postprandial suppression of ghrelin, and increases triglycerides in women. J. Clin. Endocrinol. Metab. 2004, 89: 2963-72. 10.1210/jc.2003-031855
Swarbrick MM, Stanhope KL, Elliott SS, Graham JL, Krauss RM, Christiansen MP, Griffen SC, Keim NL, Havel PJ: Consumption of fructose sweetened beverages for 10 weeks increases postprandial triacylglycerol and apolipoprotein-B concentrations in overweight and obese women. Br. J. Nutr. 2008, 100: 947-52. 10.1017/S0007114508968252
Stanhope KL, Schwarz JM, Keim NL, Griffen SC, Bremer AA, Graham JL, Hatcher B, Cox CL, Dyachenko A, Zhang W, McGahan JP, Seibert A, Krauss RM, Chiu S, Schaefer EJ, Ai M, Otokozawa S, Nakajima K, Nakano T, Beysen C, Hellerstein MK, Berglund L, Havel PJ: Effects of consuming fructose- or glucose-sweetened beverages for 10 weeks on lipids, insulin sensitivity and adiposity. J. Clin. Invest. 2009, 119: 1322-1334. 10.1172/JCI37385
Lê KA, Ith M, Kreis R, Faeh D, Bortolotti M, Tran C, Boesch C, Tappy L: 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. 2009, 89: 1760-1765.
Teff KL, Grudziak J, Townsend RR, Dunn TN, Grant RW, Adams SH, Keim NL, Cummings BP, Stanhope KL, Havel PJ: 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. Endo. Metab. 2009, 94: 1562-1569. 10.1210/jc.2008-2192.
Schaffer JE: Lipotoxicity: when tissues overeat. Curr. Opin. Lipidol. 2003, 14: 281-287. 10.1097/00041433-200306000-00008
Unger RH: Minireview: Weapons of lean body mass destruction: the role of ectopic lipids in the metabolic syndrome. Endocrinology. 2003, 144: 5159-5165. 10.1210/en.2003-0870
Van Herpen NA, Schrauwen-Hinderling VB: Lipid accumulation in non-adipose tissue and lipotoxicity. Physiol. Behav. 2008, 94: 231-241. 10.1016/j.physbeh.2007.11.049
Zimmermann R, Strauss JG, Haemmerle G, Schoiswohl G, Birner-Gruenberger R, Riederer M, Lass A, Neuberger G, Eisenhaber F, Hermetter A, Zechner R: Fat mobilizationin adipose tissue is promoted by adipose triglyceride lipase. Science. 2004, 306: 1383-6. 10.1126/science.1100747
Watt MJ: Storing up trouble: does intramyocellular trigelyceride accumulation protect skeletal muscle form insulin resistance?. Proc. Aust. Physiol. Soc. 2008, 39: 149-57.
Van Schaftingen E: Glycolysis revisited. Diabetologia. 1993, 36: 581-8. 10.1007/BF00404065
Dirlewanger M, Schneiter P, Jéquier E, Tappy L: Effects of fructose on hepatic glucose metabolism in humans. Am. J. Physiol. Endocrinol. Metab. 2000, 279: E907-11.
Zeidler A, Tosco C, Kumar D, Slavin B, Parker J: Spontaneous hyperglycemia and impaired glucose tolerance in athymic nude BALB/c mice. Diabetes. 1982, 31: 821-5. 10.2337/diabetes.31.9.821
Zeidler A, Kumar D, Johnson C, Parker J: Development of a diabetes-like syndrome in an athymic nude Balb/c mouse colony. Exp. Cell Biol. 1984, 52: 145-9.
Buschard K: The thymus-dependent immune system in the pathogenesis of type 1 (insulin-dependent) diabetes mellitus. Animal model and human studies. Danish Med. Bull. 1985, 32: 139-51.
Tuch BE, Ng AB, Jones A, Turtle JR: Histologic differentiation of human fetal pancreatic explants transplanted into nude mice. Diabetes. 1984, 33: 1180-7. 10.2337/diabetes.33.12.1180
Herzberg GR, Rogerson M: Interaction of the level of dietary fat and type of carbohydrate in the regulation of hepatic liopgenesis in the mouse. Can. J. Physiol. Pharmacol. 1982, 60: 912-9.