Ch25h and 25-HC prevent liver steatosis through regulation of cholesterol metabolism and inflammation

Acta Biochim Biophys Sin (Shanghai). 2022 Apr 25;54(4):504-513. doi: 10.3724/abbs.2022030.

Abstract

Non-alcoholic fatty liver disease (NAFLD) is currently the most prevalent metabolic disorder all over the world, and lipid metabolic disorders and inflammation are closely associated and contribute to the pathogenesis of NAFLD. Cholesterol 25-hydroxylase (Ch25h) and its product, 25-hydroxycholesterol (25-HC), play important roles in cholesterol homeostasis and inflammation, but whether Ch25h and 25-HC are involved in NAFLD remains uncertain. In this study, we use Ch25h knockout mice, hepatic cells and liver biopsies to explore the role of Ch25h and 25-HC in lipid metabolism and accumulation in liver, determine the molecular mechanism of lipid accumulation and inflammation influenced by Ch25h and 25-HC, and assess the regulatory effects of Ch25h and 25-HC on human NAFLD. Our results indicate that mice lacking Ch25h have normal cholesterol homeostasis with normal diet, but under the condition of high fat diet (HFD), the mice show higher total cholesterol and triglyceride in serum, and prone to hepatic steatosis. Ch25h deficiency reduces the cholesterol efflux regulated by liver X receptor α (LXRα), increases the synthesis of cholesterol mediated by sterol-regulatory element binding protein 2 (SREBP-2), and increases the activation of NLRP3 inflammasome, therefore promotes hepatic steatosis. Collectively, our data suggest that Ch25h and 25-HC play important roles in lipid metabolism and inflammation, thereby exerting anti-NAFLD functions.

Keywords: 25-HC; Ch25h; LXRα; NLRP3 inflammasome; high fat diet.

MeSH terms

  • Animals
  • Cholesterol / metabolism
  • Diet, High-Fat
  • Humans
  • Inflammasomes* / metabolism
  • Inflammation / metabolism
  • Lipid Metabolism
  • Liver / metabolism
  • Liver X Receptors / genetics
  • Liver X Receptors / metabolism
  • Mice
  • Mice, Knockout
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Non-alcoholic Fatty Liver Disease* / etiology
  • Non-alcoholic Fatty Liver Disease* / metabolism
  • Non-alcoholic Fatty Liver Disease* / prevention & control
  • Sterol Regulatory Element Binding Protein 1 / metabolism
  • Triglycerides / metabolism

Substances

  • Liver X Receptors
  • cholesterol 25-hydroxylase
  • Sterol Regulatory Element Binding Protein 1
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Cholesterol
  • Triglycerides

Grants and funding

This work was supported by the grant from the National Science Foundation of China (No. 31070146).