Abstract IA04: Metabolic control of HCC initiation and progression

Abstract Non-alcoholic steatohepatitis (NASH) is quickly becoming the leading HCC etiology. NASH can lead to HCC by altering liver metabolism, inducing oncogenic mutations, causing tumor promoting inflammation as well as the immunosuppression of anti-HCC immunity. We have established an accurate model for studying NASH-induced HCC development, the MUP-uPA mouse, and used it to show that elevated TNF production by liver macrophages contributes to both NASH and HCC progression. The major cause of TNF induction during NASH is gut-derived endotoxin, whose infiltration into the portal circulation is enhanced by barrier disrupting diets that are high in fats or fructose. By disrupting autophagy and activating NF-kB, HFD feeding of MUP-uPA mice results in accumulation of p62, the major constituent of Mallory-Denk bodies, within hepatocytes. Accumulation of p62 is not required for induction of hepatosteatosis but it greatly accelerates and enhances NASH to HCC progression through the activation of NRF2 and mTORC1. Conditional activation of NRF2 in hepatocytes results in hepatomegaly due to induction of EGF and PDGF family members as well as altered liver metabolism, in part by triggering the degradation of fructose-1,6 bisphosphate phosphatase (FBP1). FBP1 is rate limiting for gluconeogenesis and its germ-line inherited deficiency results in a complex metabolic disorder that includes hypoglycemia, lactic acidosis, hepatomegaly, hepatosteatosis, hyperlipidemia and liver damage and is manifested only in response to glucose starvation. By generating Fbp1ΔHep mice, we found that FBP1 has enzymatic and non-enzymatic activities, the latter of which are due to formation of a multiprotein complex with aldolase B (ALDOB) and PP2A-C that interacts with AKT, dephosphorylates it and inhibits its activation. By inhibiting AKT activation, FBP1 and ALDOB suppress HCC development. Citation Format: Michael Karin, Li Gu, Yahui Zhu. Metabolic control of HCC initiation and progression [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA04.