Transcriptional Activation of Apolipoprotein CIII Expression by Glucose May Contribute to Diabetic Dyslipidemia

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 31; no. 3; pp. 513 - 519
• Main Authors: Caron, Sandrine, Verrijken, An, Mertens, Ilse, Samanez, Carolina Huaman, Mautino, Gisèle, Haas, Joel T, Duran-Sandoval, Daniel, Prawitt, Janne, Francque, Sven, Vallez, Emmanuelle, Muhr-Tailleux, Anne, Berard, Isabelle, Kuipers, Folkert, Kuivenhoven, Jan A, Biddinger, Sudha B, Taskinen, Marja-Riitta, Van Gaal, Luc, Staels, Bart
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.03.2011; Lippincott Williams & Wilkins
• Subjects: Adult; Animals; Apolipoprotein C-III - blood; Apolipoprotein C-III - genetics; Associated diseases and complications; Atherosclerosis (general aspects, experimental research); Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism; Biological and medical sciences; Blood and lymphatic vessels; Blood Glucose - metabolism; Cardiology. Vascular system; Cells, Cultured; Diabetes Complications - etiology; Diabetes Complications - genetics; Diabetes Complications - metabolism; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Diabetes. Impaired glucose tolerance; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Dyslipidemias - etiology; Dyslipidemias - genetics; Dyslipidemias - metabolism; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Glucose - metabolism; Heat-Shock Proteins - agonists; Heat-Shock Proteins - metabolism; Hepatocyte Nuclear Factor 4 - genetics; Hepatocyte Nuclear Factor 4 - metabolism; Hepatocytes - metabolism; Humans; Insulin - blood; Liver X Receptors; Male; Medical sciences; Mice; Mice, Knockout; Middle Aged; Obesity - blood; Orphan Nuclear Receptors - genetics; Orphan Nuclear Receptors - metabolism; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Promoter Regions, Genetic; Rats; Receptor, Insulin - deficiency; Receptor, Insulin - genetics; Receptors, Cytoplasmic and Nuclear - agonists; Receptors, Cytoplasmic and Nuclear - metabolism; RNA Interference; RNA, Messenger - metabolism; RNA-Binding Proteins - agonists; RNA-Binding Proteins - metabolism; Time Factors; Transcription Factors - agonists; Transcription Factors - metabolism; Transcriptional Activation; Transfection; Up-Regulation; Endocrinopathy; Type 2 diabetes; Nuclear receptor; apolipoproteins; Metabolic diseases; Lipids; Cardiovascular disease; Glucose; Metabolism; type II diabetes; Vascular disease; nuclear receptors; Atherosclerosis; Apolipoprotein CIII; Dyslipemia
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/ATVBAHA.110.220723

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-4α. ApoCIII induction by glucose is blunted by treatment with agonists of farnesoid X receptor and peroxisome proliferator-activated receptor-α 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.