Abstract
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.
Highlights
Obesity, type 2 diabetes and hyperlipidemia frequently coexist and are associated with significantly increased morbidity and mortality [1]
Metabolism of sugars and fructose occurs primarily in the liver and high fructose flux leads to enhanced hepatic triglyceride accumulation resulting in impaired glucose and lipid metabolism and increased proinflammatory cytokine expression [2,3,4,5,6]
We demonstrate that addition of fructose to human hepatic HepG2 cells and primary murine hepatic cell cultures incubated in physiologic and diabetic-range glucose concentrations in vitro disrupts normal glucose metabolism and leads to hepatic triglyceride accumulation in association with reduced hepatic expression of phosphorylated acetyl CoA carboxylase, phopshorylated hormone sensitive lipase and total adipose triglyceride lipase (ATGL) in comparison to glucose alone
Summary
Type 2 diabetes and hyperlipidemia frequently coexist and are associated with significantly increased morbidity and mortality [1]. The role that triglycerides play as an independent risk factor for CAD is still not well defined but a substantial number of individuals who maintain total plasma cholesterol concentrations within acceptable values (< 5.17 mmol/L or 200 mg/dL) still develop CAD [7,8]. Some of these patients have low HDL -cholesterol concentrations (< 0.91 mmol/L or 35 mg/dL) [9,10] and a decline in HDL-cholesterol often accompanies an increase in VLDL triglyceride, reflecting an interchange of cholesterol. Fructose-fed athymic Nu/Nu mice exhibited increased hepatic steatosis in association with reduced hepatic ATGL expression in comparison to glucose- and standard defined diet-fed mice
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