Men are at higher risk of coronary heart disease (CHD) than age- and BMI-matched women, especially early in life when androgens are high. However, androgens are needed for health in men, particularly in muscle where they promote glucose metabolism and fatty acid utilization. Gap: we don’t know the mechanisms for the disconnect between the protective functions of androgens and the higher risk of CHD in men. Additionally, although men and women share risk factors for CHD (hypertension, high LDL cholesterol and others), there are likely also sex-specific risk factors for the development of diabetes, fatty liver, and cardiovascular disease in both males and females. We don’t know the therapeutic significance of targeting these sex-specific pathways. In the last funding cycle of this project, our group helped define mechanisms for numerous species differences in the risk of metabolic and CHD with obesity. In humans and rodents, endogenous estrogens and androgens have beneficial effects on glucose metabolism. The increased risk of CHD in men is unique to humans. One key species difference is that humans express cholesteryl ester transfer protein (CETP), which mice naturally lack. Using mice transgenic for CETP we “humanized” this pathway and discovered that CETP transduces unique estrogenic pathways in the liver of females that are beneficial. We discovered that CETP also transduces unique effects of androgens in liver of the males, but that these are largely harmful for triglyceride and cholesterol metabolism; thus “humanizing” these aspects of sex-specific CVD risk. Our overarching hypothesis is that hepatic CETP expression drives sex-specific risk of dyslipidemia and CHD by creating gain-of-function androgen signaling and estrogen signaling in in the liver. We propose 3 AIMS to reduce the harmful lipid effects of androgens in males and preserve the beneficial glucose effects. Additionally, we will identify sex-specific risk factors in both males and females and help translate them to therapeutic targets. In AIM1 we will knock-down hepatic androgen receptor, or over-express hepatic CETP, to define if the CETP- androgen interaction that causes dyslipidemia is a direct effect of androgens and CETP in the liver. We will use metabolic tracers to simultaneously define glucose and fatty acid metabolism in both liver and muscle. We found that CETP alters androgen-regulation of ~3900 liver mRNAs, including gain-of-function for cholesterol and triglyceride metabolism. In AIM2 we will target two key factors that are uniquely up-regulated by androgens when CETP is present, LXR and ChREBP. We expect to preserve androgen benefits on muscle glucose and fatty acid metabolism but block the CETP-androgen axis with regard to dyslipidemia and CHD risk. In AIM3 we will take approaches to reduce the key translational barriers in the mouse with regard to lipid metabolism: 1) the absence of CETP; 2) increased metabolic rate; and 3) different bile acid composition. We ...