| Metabolic syndrome is a major health concern in the US, affecting a third of all adults and amplifying the risk of cardiovascular disease and diabetes. The central pathophysiological root of metabolic syndrome is widely considered to be insulin resistance, though the mechanisms linking insulin resistance to this clinical constellation of obesity, dyslipidemia, hypertension and hepatic steatosis are poorly understood. In insulin resistance, insulin suppression of the forkhead box protein O1 (FOXO1) transcription factor is lost, and FoxO1 remains inappropriately over-active. FoxO1 has an established role activating gluconeogenesis, however, its regulation of lipid metabolism, especially of cholesterol metabolism, has remained largely unstudied. Here, we investigate the role of hepatic FoxO1 in mediating the dysregulation of lipid metabolism.;Using a mouse model liver-specific knockout of the insulin receptor and FoxO1, we show that loss of hepatic FoxO1 restores normal gene expression of gluconeogenic and cholesterologenic, but not lipogenic genes. We identify Cyp8b1 as a target of exquisitely sensitive control by FoxO1. Cyp8b1 expression is increased in a mouse model of metabolic syndrome and decreased with acute knockdown of FoxO1, and also increased in humans with metabolic syndrome. Via Cyp8b1, FoxO1 controls cholic acid synthesis, which in turn increases dietary cholesterol absorption, intrahepatic cholesterol, and secretion of FGF15 and GLP1 from the small intestine. To confirm this extrahepatic role of hepatic FoxO1 as a regulator of cholesterol metabolism, we re-introduced CYP8B1 in the absence of FoxO1.;To further investigate the well-documented association between insulin resistance and cardiovascular disease, we used non-biased profiling methods to identify the enzyme flavin-containing monooxygenase 3 (Fmo3) to be a target of insulin. FMO3 produces trimethylamine N-oxide (TMAO), which has recently been suggested to promote atherosclerosis in mice and humans. We show that FMO3 is suppressed by insulin in vitro, increased in obese/insulin resistant mice, and increased in obese/insulin resistant humans. Knockdown of FMO3 in insulin-resistant mice suppressed FoxO1, and entirely prevented the development of hyperglycemia, hyperlipidemia, and atherosclerosis. Overall, this dissertation examines the role of hepatic FoxO1 as a potent mediator of the metabolic dysfunction in insulin resistance and metabolic syndrome, and the development of cardiovascular disease. |
