Project Summary Hepatic lipid synthesis and catabolism is tightly regulated. Altered lipogenesis, lipid utilization, and lipoprotein secretion in liver can adversely affect local and systemic lipid homeostasis. While the critical role of insulin in promoting hepatic lipid and lipoprotein synthesis is widely studied, major knowledge gaps exist regarding hormones that suppress hepatic lipogenesis and promote fat oxidation. Since our initial discovery of the CTRP family of secreted hormones, we have systematically characterized the metabolic function and mechanisms of action of each CTRP using gain- and loss-of-function mouse models. In this competitive renewal application, we propose focused studies of CTRP1, based on our recent discovery that this hormone plays a critical role in regulating hepatic lipid metabolism. Adipose and liver are the two major tissues that express CTRP1. Even on a control low-fat diet (LFD), aged CTRP1 knockout (KO) mice have strikingly enlarged liver, pronounced hepatic steatosis, and fibrosis. When obesity is induced with a high-fat diet (HFD), Ctrp1-KO mice develop a significantly more severe non-alcoholic fatty liver disease (NAFLD) and this is associated with a deficit in mitochondrial β-oxidation. When challenged with a non-alcoholic steatohepatitis (NASH)-provoking diet, Ctrp1-KO mice have markedly more severe phenotypes. In contrast to the loss-of- function phenotypes, overexpression of CTRP1 in primary mouse hepatocytes suppresses lipid synthesis and promotes fat oxidation and mitochondrial respiration. Collectively, these data indicate that liver is a major target tissue of CTRP1; disrupting CTRP1-regulated pathways in liver affects hepatic lipid metabolism, inflammation, and fibrosis. We propose two specific aims toward understanding the contribution of CTRP1 to hepatic lipid metabolism (Aim 1) and the protective mechanisms of CTRP1 in mitigating the severity of fatty liver, inflammation, and fibrosis in the context of NASH (Aim 2). The completion of these aims will provide major advancement and critical insights into novel pathways regulating hepatic lipid metabolism by the secreted hormone, CTRP1. This knowledge may inform innovative strategies to mitigate NAFLD and NASH in clinical settings.