Cellular and Molecular Gastroenterology and Hepatology (Jan 2022)

Hepatic Reduction in Cholesterol 25-Hydroxylase Aggravates Diet-induced SteatosisSummary

  • Zeyu Dong,
  • Fangzhou He,
  • Xiaosong Yan,
  • Yuanming Xing,
  • Yuyang Lei,
  • Jie Gao,
  • Ming He,
  • Dongmin Li,
  • Liang Bai,
  • Zuyi Yuan,
  • John Y-J. Shyy

Journal volume & issue
Vol. 13, no. 4
pp. 1161 – 1179

Abstract

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Background & Aims: Cholesterol 25-hydroxylase (Ch25h), converting cholesterol to 25-hydroxycholesterol (25-HC), is critical in modulating cellular lipid metabolism and anti-inflammatory and antiviral activities. However, its role in nonalcoholic fatty liver disease remains unclear. Methods: Ch25h expression was detected in livers of ob/ob mice and E3 rats fed a high-fat diet (HFD). Gain- or loss-of-function of Ch25h was performed using Ch25h+/+ (wild type [WT]) mice receiving AAV8-Ch25h or Ch25h knockout (Ch25h-/-) mice. WT mice fed an HFD were administered with 25-HC. The Ch25h–LXRα–CYP axis was measured in primary hepatocytes isolated from WT and Ch25h-/- mice. Results: We found that Ch25h level was decreased in livers of ob/ob mice and E3 rats fed an HFD. Ch25h-/- mice fed an HFD showed aggravated fatty liver and decreased level of cytochrome P450 7A1 (CYP7A1), in comparison with their WT littermates. RNA-seq analysis revealed that the differentially expressed genes in livers of HFD-fed Ch25h-/- mice were involved in pathways of positive regulation of lipid metabolic process, steroid metabolic process, cholesterol metabolic process, and bile acid biosynthetic process. As gain-of-function experiments, WT mice receiving AAV8-Ch25h or 25-HC showed alleviated NAFLD, when compared with the control group receiving AAV8-control or vehicle control. Consistently, Ch25h overexpression significantly elevated the levels of primary and secondary bile acids and CYP7A1 but decreased those of small heterodimer partner and FGFR4. Conclusions: Elevated levels of Ch25h and its enzymatic product 25-HC alleviate HFD-induced hepatic steatosis via regulating enterohepatic circulation of bile acids. The underlying mechanism involves 25-HC activation of CYP7A1 via liver X receptor. These data suggest that targeting Ch25h or 25-HC may have therapeutic advantages against nonalcoholic fatty liver disease.

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