Abstract
Krüppel-like factor 10 (KLF10) is a phospho-regulated transcriptional factor involved in many biological processes including lipogenesis; however, the transcriptional regulation on lipogenesis by KLF10 remains largely unclear. Lipogenesis is important in the development of nonalcoholic fatty liver disease (NAFLD) which was known regulated mainly by AMP-activated protein kinase (AMPK) and sterol regulatory element-binding protein (SREBP-1C). Interesting, our previous study using phosphorylated site prediction suggested a regulation of AMPK on KLF10. Therefore, we aimed to study the protein–protein interactions of AMPK on the regulation of KLF10, and to delineate the mechanisms of phosphorylated KLF10 in the regulation of NAFLD through SREBP-1C. We performed in vitro and in vivo assays that identified AMPK phosphorylates KLF10 at Thr189 and subsequently modulates the steady state level of KLF10. Meanwhile, a chromatin immunoprecipitation–chip assay revealed the novel target genes and signaling cascades of corresponding to phosphorylated KLF10. SREBP-1C was identified as a target gene suppressed by phosphorylated KLF10 through promoter binding. We further performed high-fat-diet-induced NAFLD models using hepatic-specific KLF10 knockout mice and wild-type mice and revealed that KLF10 knockout markedly led to more severe NAFLD than that in wild-type mice. Taken together, our findings revealed for the first time that AMPK activates and stabilizes the KLF10 protein via phosphorylation at Thr189, thereby repressing the expression of SREBP-1C and subsequent lipogenesis pathways along with metabolic disorders. We suggested that the targeted manipulation of liver metabolism, particularly through increased KLF10 expression, is a potential alternative solution for treating NAFLD.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of fat in the liver that can lead to a more advanced stages of nonalcoholic steatohepatitis (NASH), including cirrhosis, end-stage liver disease, and hepatocellular carcinoma (Friedman et al, 2018)
NAFLD encompasses a spectrum of diseases including simple steatosis or nonalcoholic fatty liver (NAFL), the nonalcoholic steatohepatitis (NASH) which is a more progressive and severe stage of NAFLD and is often accompanied by fibrosis that can progress to cirrhosis or hepatocellular carcinoma (HCC) (Huang et al, 2021)
The development of NAFLD and the following NASH is a complex process that accumulation of lipid droplets within hepatocytes occurs as a result of a dysregulated lipid metabolism, which is closely associated with a metabolic syndrome including obesity, insulin resistance, dyslipidemia and hypertension (Filali-Mouncef et al, 2021)
Summary
Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of fat in the liver that can lead to a more advanced stages of nonalcoholic steatohepatitis (NASH), including cirrhosis, end-stage liver disease, and hepatocellular carcinoma (Friedman et al, 2018). De novo lipogenesis is one of the major mechanisms contributing to increased fatty acid (FA) transportation and accumulation in the liver (Moon, 2017) This pathway is mainly regulated by transcription factors including sterol regulatory element binding protein-1C (SREBP-1C), carbohydrate-responsive element-binding protein (ChREBP), liver X receptor α (LXR-α), and peroxisome proliferatoractivated receptor γ (PPAR-γ) (Moon, 2017). Interesting, we recently reported that Krüppel-like factor 10 (KLF10) expression is upregulated upon activation of AMPK (Chang et al, 2017), and KLF10 could suppress lipogenic gene expression (Iizuka et al, 2011) In this regard, we proposed the potential mechanism of AMPK-KLF10 axis in regulating NAFLD via downregulation of SREBP-1C
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