RRC ID 75627
Author Fujinuma S, Nakatsumi H, Shimizu H, Sugiyama S, Harada A, Goya T, Tanaka M, Kohjima M, Takahashi M, Izumi Y, Yagi M, Kang D, Kaneko M, Shigeta M, Bamba T, Ohkawa Y, Nakayama KI.
Title FOXK1 promotes nonalcoholic fatty liver disease by mediating mTORC1-dependent inhibition of hepatic fatty acid oxidation.
Journal Cell Rep
Abstract Nonalcoholic fatty liver disease (NAFLD) is a chronic metabolic disorder caused by overnutrition and can lead to nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). The transcription factor Forkhead box K1 (FOXK1) is implicated in regulation of lipid metabolism downstream of mechanistic target of rapamycin complex 1 (mTORC1), but its role in NAFLD-NASH pathogenesis is understudied. Here, we show that FOXK1 mediates nutrient-dependent suppression of lipid catabolism in the liver. Hepatocyte-specific deletion of Foxk1 in mice fed a NASH-inducing diet ameliorates not only hepatic steatosis but also associated inflammation, fibrosis, and tumorigenesis, resulting in improved survival. Genome-wide transcriptomic and chromatin immunoprecipitation analyses identify several lipid metabolism-related genes, including Ppara, as direct targets of FOXK1 in the liver. Our results suggest that FOXK1 plays a key role in the regulation of hepatic lipid metabolism and that its inhibition is a promising therapeutic strategy for NAFLD-NASH, as well as for HCC.
Volume 42(5)
Pages 112530
Published 2023-5-18
DOI 10.1016/j.celrep.2023.112530
PII S2211-1247(23)00541-7
PMID 37209098
MeSH Animals Carcinoma, Hepatocellular* / metabolism Fatty Acids / metabolism Lipid Metabolism Liver / metabolism Liver Neoplasms* / pathology Mechanistic Target of Rapamycin Complex 1 / metabolism Mice Non-alcoholic Fatty Liver Disease* / metabolism
IF 8.109
Mice RBRC01834
DNA material CSII-CMV-MCS (RDB04377) pCMV-VSV-G-RSV-Rev (RDB04393) pCAG-HIVgp (RDB04394)