Insulin resistance and type 2 diabetes are pathogenetically linked to increased risk of cardiovascular disease. While insulin resistance is defined by a dysregulation in hepatic insulin signaling, it is unclear how this impairment relates to the development of cardiovascular disease. Recently, there has been evidence showing that in insulin resistant individuals, cardiovascular disease is associated with a defect in reverse cholesterol transport – the cardioprotective process by which excess cholesterol is removed from the periphery, and returned to the liver for biliary excretion. Reverse cholesterol transport is facilitated by high-density lipoprotein (HDL) metabolism. Thus, malfunction in HDL turnover during reverse cholesterol transport may contribute to the buildup of atherosclerotic plaques, and subsequent cardiovascular disease in insulin resistant individuals. In this thesis, we seek to establish a better understanding of HDL metabolism and reverse cholesterol transport, as they relate to key transcription factors that mediate hepatic insulin signaling, namely the insulin-repressible forkhead transcription factors, FoxO1, FoxO3, and FoxO4 (FoxOs).

We demonstrate that mice with liver-specific triple FoxO knockout (L-FoxO1,3,4) have increased HDL-cholesterol (HDL-C), associated with decreased expression of HDL-C clearance factors, scavenger receptor class B type I (SR-BI) and hepatic lipase, and defective selective uptake of HDL-cholesteryl ester by the liver. As such, we uncover a novel mechanism by which HDL-mediated reverse cholesterol transport to the liver is regulated by the hepatic insulin-->FoxO signaling pathway.