Objective-Hypertriglyceridemia and fatty liver are common in patients with type 2 diabetes, but the factors connecting alterations in glucose metabolism with plasma and liver lipid metabolism remain unclear. Apolipoprotein CIII (apoCIII), a regulator of hepatic and plasma triglyceride metabolism, is elevated in type 2 diabetes. In this study, we analyzed whether apoCIII is affected by altered glucose metabolism. Methods and Results-Liver-specific insulin receptor-deficient mice display lower hepatic apoCIII mRNA levels than controls, suggesting that factors other than insulin regulate apoCIII in vivo. Glucose induces apoCIII transcription in primary rat hepatocytes and immortalized human hepatocytes via a mechanism involving the transcription factors carbohydrate response element-binding protein and hepatocyte nuclear factor-4␣. ApoCIII induction by glucose is blunted by treatment with agonists of farnesoid X receptor and peroxisome proliferator-activated receptor-␣ but not liver X receptor, ie, nuclear receptors controlling triglyceride metabolism. Moreover, in obese humans, plasma apoCIII protein correlates more closely with plasma fasting glucose and glucose excursion after oral glucose load than with insulin. Conclusion-Glucose induces apoCIII transcription, which may represent a mechanism linking hyperglycemia, hypertriglyceridemia, and cardiovascular disease in type 2 diabetes. Key Words: apolipoproteins Ⅲ lipids Ⅲ metabolism Ⅲ nuclear receptors Ⅲ type II diabetes T ype 2 diabetes is a progressive disease that is due to increased insulin resistance and progressive pancreatic failure. Type 2 diabetic patients often display lipid metabolism abnormalities (namely hypertriglyceridemia; low highdensity lipoprotein-cholesterol levels; and increased small, dense low-density lipoprotein particles) that result in increased cardiovascular disease risk. Epidemiological studies identified hypertriglyceridemia as an independent risk factor for atherosclerosis. 1 The hypertriglyceridemia is due to hepatic overproduction of triglyceride-rich very-low-density lipoprotein particles, 2 as well as impaired intravascular catabolism as a result of decreased lipoprotein lipase activity. 2 See accompanying article on page 471Apolipoprotein CIII (apoCIII) is a 79-amino-acid glycoprotein synthesized in the liver and the intestine 3 that controls triglyceride metabolism in humans 4 and mice. 5 ApoCIII is a component of triglyceride-rich lipoproteins, low-density lipoprotein, and high-density lipoprotein. 6 Plasma triglyceride and apoCIII concentrations positively correlate in normo-and hypertriglyceridemic subjects. 7-10 ApoCIII gene deficiency results in a hypotriglyceridemia because of an accelerated catabolism of triglyceride rich-lipoproteins, 4,5 whereas apo-CIII overexpression in mice leads to hypertriglyceridemia. 11 In vitro and in vivo studies have established that apoCIII delays the catabolism of triglyceride-rich lipoproteins by inhibiting lipoprotein lipase 12,13 and inhibits the hepatic uptake of triglyceride-rich rem...
Metabolic diseases reach epidemic proportions. A better knowledge of the associated alterations in the metabolic pathways in the liver is necessary. These studies need in vitro human cell models. Several human hepatoma models are used, but the response of many metabolic pathways to physiological stimuli is often lost. Here, we characterize two human hepatocyte cell lines, IHH and HepaRG, by analysing the expression and regulation of genes involved in glucose and lipid metabolism. Our results show that the glycolysis pathway is activated by glucose and insulin in both lines. Gluconeogenesis gene expression is induced by forskolin in IHH cells and inhibited by insulin in both cell lines. The lipogenic pathway is regulated by insulin in IHH cells. Finally, both cell lines secrete apolipoprotein B-containing lipoproteins, an effect promoted by increasing glucose concentrations. These two human cell lines are thus interesting models to study the regulation of glucose and lipid metabolism.
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