FoxO1 mediates insulin-dependent regulation of hepatic VLDL production in mice
Open Access
- 1 May 2008
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 118 (6), 2347-2364
- https://doi.org/10.1172/jci32914
Abstract
Excessive production of triglyceride-rich VLDL is attributable to hypertriglyceridemia. VLDL production is facilitated by microsomal triglyceride transfer protein (MTP) in a rate-limiting step that is regulated by insulin. To characterize the underlying mechanism, we studied hepatic MTP regulation by forkhead box O1 (FoxO1), a transcription factor that plays a key role in hepatic insulin signaling. In HepG2 cells, MTP expression was induced by FoxO1 and inhibited by exposure to insulin. This effect correlated with the ability of FoxO1 to bind and stimulate MTP promoter activity. Deletion or mutation of the FoxO1 target site within the MTP promoter disabled FoxO1 binding and resulted in abolition of insulin-dependent regulation of MTP expression. We generated mice that expressed a constitutively active FoxO1 transgene and found that increased FoxO1 activity was associated with enhanced MTP expression, augmented VLDL production, and elevated plasma triglyceride levels. In contrast, RNAi-mediated silencing of hepatic FoxO1 was associated with reduced MTP and VLDL production in adult mice. Furthermore, we found that hepatic FoxO1 abundance and MTP production were increased in mice with abnormal triglyceride metabolism. These data suggest that FoxO1 mediates insulin regulation of MTP production and that augmented MTP levels may be a causative factor for VLDL overproduction and hypertriglyceridemia in diabetes.Keywords
This publication has 82 references indexed in Scilit:
- Inhibition of apolipoprotein B100 secretion by lipid-induced hepatic endoplasmic reticulum stress in rodentsJCI Insight, 2008
- Impaired Regulation of Hepatic Glucose Production in Mice Lacking the Forkhead Transcription Factor Foxo1 in LiverCell Metabolism, 2007
- PPARα mediates the hypolipidemic action of fibrates by antagonizing FoxO1American Journal of Physiology-Endocrinology and Metabolism, 2007
- Aberrant Forkhead Box O1 Function Is Associated with Impaired Hepatic MetabolismEndocrinology, 2006
- Dual role of transcription factor FoxO1 in controlling hepatic insulin sensitivity and lipid metabolismJCI Insight, 2006
- Coactivation of Foxa2 through Pgc-1β promotes liver fatty acid oxidation and triglyceride/VLDL secretionCell Metabolism, 2006
- Post-transcriptional Stimulation of the Assembly and Secretion of Triglyceride-rich Apolipoprotein B Lipoproteins in a Mouse with Selective Deficiency of Brown Adipose Tissue, Obesity, and Insulin ResistancePublished by Elsevier BV ,2001
- Essentiality of circulating fatty acids for glucose-stimulated insulin secretion in the fasted rat.JCI Insight, 1996
- Interaction between free fatty acids and insulin in the acute control of very low density lipoprotein production in humans.JCI Insight, 1995
- Role of insulin in lipoprotein secretion by cultured rat hepatocytes.JCI Insight, 1983