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.