Pilot: Identification of Mechanisms Controlling Fatty Acid Metabolism in Sexually Dimorphic Obesity-Driven Liver Cancer

Principal Investigator: Helsley, Robert 18.2 2. PROJECT TITLE: Identification of Mechanisms Controlling Sexually Dimorphic Fatty Acid Metabolism in Obesity-Driven Liver Cancer ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) affects 25% of the world population and is associated with obesity, type II diabetes, and dyslipidemia. As the leading cause of liver disease, NAFLD increases risk stratification for the development of hepatocellular carcinoma (HCC). HCC is the most common primary liver cancer accounting for ~90% of all cases. In parallel with the obesity epidemic, NAFLD is the fastest growing etiology of HCC with an estimated 80-120% increase in prevalence by 2030. Intriguingly, both NAFLD and HCC are sexually dimorphic with a 2-5x greater prevalence in males than females; however, the signaling mechanisms that contribute to this sexual dimorphism remains elusive and is a major focus of this proposal. Carnitine palmitoyltransferase 1a (Cpt1a) is a protein involved in mitochondrial fatty acid oxidation and has been implicated in the progression of both NAFLD and HCC. The data herein establishes a new mouse model that recapitulates the human variant of steatohepatitic- driven HCC. Moreover, we show that liver-specific deletion of Cpt1a promotes profound steatosis only in female LKO mice in response to high fat diet (HFD)-feeding. This increases in steatosis in female LKO mice associates with increased levels of hepatic monounsaturated fatty acids (MUFAs) at the expense of the anti-inflammatory ω3-polyunsaturated fatty acids (PUFAs). Consistently, female LKO mice exhibit increased expression of genes involved in lipid droplet metabolism, inflammation, and carcinogenesis. Our specific aim will determine the contribution of PUFAs on HFD-driven HCC in male and female WT and Cpt1a LKO mice. The novelty of the proposed research is the use of a newly developed liver-specific Cpt1a deficient mouse model in conjunction with lipidomics and bulk RNA-sequencing to identify the mechanisms that contribute to Cpt1a-mediated alterations in HCC progression. This pilot award funded by the American Cancer Society will allow the PI to generate critical preliminary data to support either an U01 (PAR-23- 051) or UH2 (PAR-23-052) application to the National Cancer Institute in the fall of 2023. The major focus of this research project is to identify novel sex-specific mechanisms that contribute to the protection from liver cancer observed in females. Institutional Research Grant American Cancer Society – February 2023