FRI037 Time-restricted Feeding Prevents Progression Of Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis Through IPMK

Disclosure: I. Jung: None. F. Anokye-Danso: None. S. Jin: None. R.S. Ahima: None. S. Kim: None. Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide, with a broad spectrum ranging from simple steatosis to advanced stage of nonalcoholic steatohepatitis (NASH). Although many clinical trials for NAFLD treatment are undergoing, there are currently no approved therapies. Insulin resistance is central to the progression of NAFLD and implicated in disease progression from steatosis to NASH. Therefore, modulation of insulin resistance represents a potential strategy for NAFLD treatment. We have reported that inositol polyphosphate multikinase (IPMK), a key enzyme in inositol polyphosphate biosynthesis, plays a role in regulating hepatic insulin signaling and gluconeogenesis both in vitro and in vivo. However, the roles of IPMK in hepatic lipid metabolism were not investigated. To determine the role of IPMK in NAFLD/NASH, we fed high fat diet (HFD) or methionine-choline deficient diet (MCDD) in both wild type (WT) and liver-specific IPMK knockout (LKO) mice. We also examined the effect of time-restricted feeding (TRF), which is known to be beneficial for metabolic disease without influencing the food intake, in NAFDL/NASH. Here, we show that hepatic IPMK protein was decreased in WT mice fed a MCDD compared to a normal chow diet (ND) and loss of IPMK in the liver augments hepatic steatosis and steatohepatitis in mice fed a HFD as well as MCDD. Compared to the WT mice, triglycerides (TG) and pro-inflammatory gene expression in the liver increase significantly in the LKO mice fed HFD. Importantly, MCDD-fed LKO mice exhibit exacerbated NAFLD/NASH accompanied by an increase in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), hepatic TG accumulation and fibrosis, and pro-inflammatory gene expression. Finally, TRF by limiting a food access only during the dark cycle led to an increase in expression hepatic IPMK protein in MCDD mice. Importantly, TRF alleviates NAFLD/NASH reflected by reduced hepatic TG accumulation, lowered serum ALT and AST levels, downregulated pro-inflammatory gene expression compared with ad libitum mice. Our results demonstrate that loss of IPMK mediates the progression of NAFLD/NASH and may be potentially targeted for treatment of NAFLD/NASH. Presentation: Friday, June 16, 2023