Elucidating dietary fructose and alcohol interactions during liver cancer development

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PROJECT SUMMARY/ABSTRACT The primary objective of this NIAAA R01 Supplement is to equip Ms. Miranda Lopez, an underrepresented graduate student candidate, with the skills and knowledge necessary to become a proficient and independent scientist while completing her proposed research project on deciphering mechanisms of alcohol/fructose- induced hepatocellular carcinoma (HCC), a natural extension of the parent R01 award. Dr. Cholsoon Jang, the lead mentor, and Dr. Dequina Nicholas, the co-mentor, possess the requisite proficiency and knowledge to offer an optimal co-mentorship for both the accomplishment of her project and her career growth. Specifically, Dr. Jang has expertise in nutrition and cancer biology and Dr. Nicholas has expertise in immunology and has plenty of experience in mentoring underrepresented minority students. Further, to ensure Ms. Lopez's career development, we have enlisted two senior faculty members to serve on her mentoring committee. During the diversity supplement period, Ms. Lopez will perform experiments to determine the role of specific lipid pathway in alcohol/fructose-induced HCC (Candidate Aim 1). She will also determine whether immunomodulation is involved in HCC tumor growth (Candidate Aim 2). Both aims are a natural extension of Aim 1 of the parent award: “whether and how fructose and alcohol synergistically increase HCC risk”. Although antiviral treatment has proven effective in preventing virus-associated HCC, the origin of the cancer is now transitioning from viral hepatitis to metabolic disorders that stem from lifestyle choices, including non-alcoholic and alcoholic steatohepatitis. In the parent award, we hypothesized that fructose shifts the metabolic fate of alcohol toward carcinogenic metabolite production via induction of acetyl-CoA synthetase 2 (ACSS2), a cytosolic enzyme that catabolizes acetate to acetyl-CoA. In Aim 1, we aim to determine whether and how fructose and alcohol synergistically increase HCC risk. In Aim 2, we aim to determine whether ACSS2 inhibition and/or gut microbiota depletion suppresses fructose and alcohol-induced HCC. In Aim 1 of the parent grant, we discovered, by our unbiased untargeted metabolomic, that alcohol/fructose-induced HCC showed a profound accumulation of very long-chain polyunsaturated fatty acids (VLC-PUFA). Furthermore, blood VLC-PUFA strongly correlates with HCC burden, suggesting an exciting possibility of using serum VLC-PUFA as an HCC diagnostic marker. VLC-PUFA are synthesized by ELOVL2 (elongation of very long chain fatty acids protein 2), and we found that ELOVL2 proteins are 3-fold higher in tumors. Recently, VLC-PUFA has been shown to inhibit dendritic cell differentiation and reduce cytotoxic T cells. Therefore, Mr. Lopez will determine whether blocking ELOVL2 suppresses alcohol/fructose-induced HCC and whether VLC-PUFA-mediated immune suppression is the key underlying mechanisms of HCC progression. As she undertakes the proposed research, she will receive a broad range of training, including developing expertise in experimental techniques, cultivating research independence, honing her scientific communication skills, and mastering the art of grantsmanship, among others.