Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Division of Transcriptomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Cell Rep. 2023 May 30;42(5):112530. doi: 10.1016/j.celrep.2023.112530. Epub 2023 May 18.
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.
非酒精性脂肪性肝病 (NAFLD) 是一种由营养过剩引起的慢性代谢紊乱疾病，可导致非酒精性脂肪性肝炎 (NASH) 和肝细胞癌 (HCC)。叉头框转录因子 K1 (FOXK1) 涉及 mTORC1 下游脂质代谢的调节，但它在 NAFLD-NASH 发病机制中的作用尚未得到充分研究。在这里，我们表明 FOXK1 介导了营养依赖性的肝脏脂质代谢抑制。在喂食 NASH 诱导饮食的小鼠中，特异性敲除肝细胞中的 Foxk1，不仅可以改善肝脂肪变性，还可以改善相关的炎症、纤维化和肿瘤发生，从而提高存活率。全基因组转录组学和染色质免疫沉淀分析确定了几个脂质代谢相关基因，包括 Ppara，是 FOXK1 在肝脏中的直接靶标。我们的结果表明，FOXK1 在肝脏脂质代谢的调节中起着关键作用，其抑制是治疗 NAFLD-NASH 以及 HCC 的一种有前途的治疗策略。
