Oxysterol sulfation by cytosolic sulfotransferase suppresses liver X receptor/sterol regulatory element binding protein–1c signaling pathway and reduces serum and hepatic lipids in mouse models of nonalcoholic fatty liver disease

It is generally agreed that nonalcoholic fatty liver disease (NAFLD) is a component of metabolic syndrome and is frequently associated with obesity, type 2 diabetes mellitus, atherogenic dyslipidemia, and other components of the syndrome. However, there is no doubt that not all overweight people develop NAFLD and, conversely, the latter may be present in normal weight individuals. The prevalence of NAFLD without obesity in different countries is very variable from 3 to 30%. Its risk factors are considered to be both exogenous (for example, excess intakes of cholesterol and rapidly assimilable fructose) and genetically determined (allelic variants of the genes encoding adiponutrin, the cholesteryl ester transport protein, sterol-regulatory element-binding protein 2). The methods for the diagnosis of NAFLD without obesity do not differ in essence from those for classic NAFLD. Analysis of the conducted investigations gives grounds to claim that lifestyle modification as exercises and dietary restrictions improves biochemical parameters and histological pattern. The efficiency of drug treatments needs further investigation.

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Therapeutic Targeting of Nonalcoholic Fatty Liver Disease by Downregulating SREBP-1C Expression via AMPK-KLF10 Axis

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.751938 ◽

2021 ◽

Vol 8 ◽

Author(s):

Yu-Chi Chen ◽

Rong-Jane Chen ◽

Szu-Yuan Peng ◽

Winston C. Y. Yu ◽

Vincent Hung-Shu Chang

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Target Genes ◽

Regulatory Element ◽

Wild Type ◽

Nonalcoholic Fatty Liver

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.

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