FOXK1 promotes nonalcoholic fatty liver disease by mediating mTORC1-dependent inhibition of hepatic fatty acid oxidation
Shun Fujinuma,
Hirokazu Nakatsumi,
Hideyuki Shimizu,
Shigeaki Sugiyama,
Akihito Harada,
Takeshi Goya,
Masatake Tanaka,
Motoyuki Kohjima,
Masatomo Takahashi,
Yoshihiro Izumi,
Mikako Yagi,
Dongchon Kang,
Mari Kaneko,
Mayo Shigeta,
Takeshi Bamba,
Yasuyuki Ohkawa,
Keiichi I. Nakayama
Affiliations
Shun Fujinuma
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
Hirokazu Nakatsumi
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
Hideyuki Shimizu
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
Shigeaki Sugiyama
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
Akihito Harada
Division of Transcriptomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
Takeshi Goya
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Masatake Tanaka
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Motoyuki Kohjima
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Masatomo Takahashi
Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
Yoshihiro Izumi
Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
Mikako Yagi
Department of Clinical Chemistry and Laboratory Medicine, Kyushu University, Fukuoka, Japan; Department of Health Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Dongchon Kang
Department of Clinical Chemistry and Laboratory Medicine, Kyushu University, Fukuoka, Japan
Mari Kaneko
Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan
Mayo Shigeta
Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan
Takeshi Bamba
Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
Yasuyuki Ohkawa
Division of Transcriptomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
Keiichi I. Nakayama
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan; Corresponding author
Summary: 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.
