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. CONCLUSIONS: Glucose induces apoCIII transcription, which may represent a mechanism linking hyperglycemia, hypertriglyceridemia, and cardiovascular disease in type 2 diabetes.
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 obesehumans, plasma apoCIII protein correlates more closely with plasma fasting glucose and glucose excursion after oral glucose load than with insulin. CONCLUSIONS:Glucose induces apoCIII transcription, which may represent a mechanism linking hyperglycemia, hypertriglyceridemia, and cardiovascular disease in type 2 diabetes.
Authors: Kimber L Stanhope; Valentina Medici; Andrew A Bremer; Vivien Lee; Hazel D Lam; Marinelle V Nunez; Guoxia X Chen; Nancy L Keim; Peter J Havel Journal: Am J Clin Nutr Date: 2015-04-22 Impact factor: 7.045
Authors: Nathan L Meyers; Mikael Larsson; Evelina Vorrsjö; Gunilla Olivecrona; Donald M Small Journal: J Lipid Res Date: 2017-02-03 Impact factor: 5.922
Authors: Allison B Andraski; Sasha A Singh; Lang Ho Lee; Hideyuki Higashi; Nathaniel Smith; Bo Zhang; Masanori Aikawa; Frank M Sacks Journal: Arterioscler Thromb Vasc Biol Date: 2019-09-26 Impact factor: 8.311
Authors: Andrea Kassai; Ranganath Muniyappa; Amy E Levenson; Mary F Walter; Brent S Abel; Michael Ring; Simeon I Taylor; Sudha B Biddinger; Monica C Skarulis; Phillip Gorden; Rebecca J Brown Journal: J Clin Endocrinol Metab Date: 2016-02-22 Impact factor: 5.958
Authors: Helen C Looker; Marco Colombo; Felix Agakov; Tanja Zeller; Leif Groop; Barbara Thorand; Colin N Palmer; Anders Hamsten; Ulf de Faire; Everson Nogoceke; Shona J Livingstone; Veikko Salomaa; Karin Leander; Nicola Barbarini; Riccardo Bellazzi; Natalie van Zuydam; Paul M McKeigue; Helen M Colhoun Journal: Diabetologia Date: 2015-03-05 Impact factor: 10.122