294-OR: The Role of Inositol Polyphosphate Multikinase in Progression of Nonalcoholic Steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease globally, ranging from simple steatosis to the advanced stage of nonalcoholic steatohepatitis (NASH). Despite ongoing clinical trials exploring NAFLD treatments, there are currently no approved therapies. We have reported that inositol polyphosphate multikinase (IPMK), a crucial enzyme in inositol polyphosphate biosynthesis, is involved in regulating hepatic insulin signaling both in vitro and in vivo. Given the central role of Insulin resistance in the progression of NAFLD, and implicated in disease progression from steatosis to NASH, we examined how IPMK contributes to the progression of NAFLD/NASH. To investigate the role of IPMK in NAFLD/NASH, we explored the impact of IPMK on lipid metabolism by studying primary mouse hepatocytes (PMH) from wild-type (WT) and liver-specific IPMK knockout (LKO) mice after treating free fatty acids (FFA). Moreover, we subjected both WT and liver-specific IPMK knockout LKO mice to a high-fat diet (HFD) or a methionine-choline deficient diet (MCDD). Here, we demonstrate that an excess of FFA reduces IPMK protein levels and enhances lipid accumulation in PMH. In addition, loss of IPMK leads to a significant increase in lipid accumulation compared to WT. Consistent with PMH, IPMK protein levels decreased in the liver from WT mice fed both HFD and MCDD compared to a normal chow diet (ND). In both HFD and MCDD conditions, LKO mice showed a significant increase in triglycerides (TG) and elevated expression of pro-inflammatory genes compared to their WT mice. Notably, LKO mice exhibited worsened MCDD-induced NAFLD/NASH, as evidenced by elevated serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), along with hepatic TG accumulation, fibrosis, and increased pro-inflammatory gene expression. Our results demonstrate that loss of IPMK mediates the progression of NAFLD/NASH and may be potentially targeted for the treatment of NAFLD/NASH.