Targeting FoxO1 for Hypertriglyceridemia

Author(s): Dae Hyun Kim , Ting Zhang , Steven Ringquist , H. Henry Dong .

Journal Name: Current Drug Targets

Volume 12 , Issue 9 , 2011

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Abstract:

Hypertriglyceridemia is characterized by increased production and decreased clearance of triglyceride-rich lipoproteins including very low-density lipoprotein (VLDL) and chylomicron. Due to its proatherogenic profile, hypertriglyceridemia contributes to the development of atherosclerosis and coronary artery disease. While the pathophysiology of hypertriglyceridemia remains poorly understood, its close association with obesity and type 2 diabetes implicates insulin resistance in the pathogenesis of hypertriglyceridemia. However, the molecular basis linking insulin resistance to hypertriglyceridemia remains elusive. Preclinical studies show that FoxO1 plays a pivotal role in controlling insulin-dependent regulation of microsomal triglyceride transfer protein (MTP) and apolipoprotein C-III (ApoC-III), two key components that catalyze the rate-limiting steps in the production and clearance of triglyceride-rich lipoproteins. Under physiological conditions, FoxO1 activity is inhibited by insulin. In insulin resistant states, FoxO1 becomes deregulated, contributing to unbridled FoxO1 activity in the liver. This effect contributes to hepatic overproduction of VLDL and impaired catabolism of triglyceride-rich particles, accounting for the pathogenesis of hypertriglyceridemia. These data spur the hypothesis that selective inhibition of FoxO1 activity in the liver would improve triglyceride metabolism and ameliorate hypertriglyceridemia. In this article, we review the role of FoxO1 in insulin action and lipid metabolism, and evaluate the therapeutic potential of targeting FoxO1 for treating hypertriglyceridemia in insulin resistant subjects with obesity and type 2 diabetes.

Keywords: Hypertriglyceridemia, FoxO1, insulin resistance, type 2 diabetes, Microsomal triglyceride transfer protein, high-density lipoprotein, C. elegans, Drosophila, PEPCK, hyperinsulinemia, euglycemia

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Article Details

VOLUME: 12
ISSUE: 9
Year: 2011
Page: [1245 - 1255]
Pages: 11
DOI: 10.2174/138945011796150262
Price: $58

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