TY - JOUR
T1 - FOXK1 promotes nonalcoholic fatty liver disease by mediating mTORC1-dependent inhibition of hepatic fatty acid oxidation
AU - Fujinuma, Shun
AU - Nakatsumi, Hirokazu
AU - Shimizu, Hideyuki
AU - Sugiyama, Shigeaki
AU - Harada, Akihito
AU - Goya, Takeshi
AU - Tanaka, Masatake
AU - Kohjima, Motoyuki
AU - Takahashi, Masatomo
AU - Izumi, Yoshihiro
AU - Yagi, Mikako
AU - Kang, Dongchon
AU - Kaneko, Mari
AU - Shigeta, Mayo
AU - Bamba, Takeshi
AU - Ohkawa, Yasuyuki
AU - Nakayama, Keiichi I.
N1 - Funding Information:
We thank S. Karasawa, K. Horisawa, A. Suzuki, M. Suyama, M. Kato, T. Uchiumi, A. Niihara, and K. Tsunematsu for technical assistance; laboratory members for comments on the manuscript; and A. Ohta for help in preparation of the manuscript. This work was supported in part by a KAKENHI grant from Japan Society for the Promotion of Science (JSPS) and the Ministry of Education, Culture, Sports, Science and Technology of Japan to K.I.N. ( JP18H05215 ) as well as by a grant from Takeda Science Foundation to S.F.
Publisher Copyright:
© 2023 The Authors
PY - 2023/5/30
Y1 - 2023/5/30
N2 - 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.
AB - 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.
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U2 - 10.1016/j.celrep.2023.112530
DO - 10.1016/j.celrep.2023.112530
M3 - Article
C2 - 37209098
AN - SCOPUS:85159612328
SN - 2211-1247
VL - 42
JO - Cell Reports
JF - Cell Reports
IS - 5
M1 - 112530
ER -