| First Author | Dong Z | Year | 2022 |
| Journal | Cell Mol Gastroenterol Hepatol | Volume | 13 |
| Issue | 4 | Pages | 1161-1179 |
| PubMed ID | 34990887 | Mgi Jnum | J:330427 |
| Mgi Id | MGI:7378581 | Doi | 10.1016/j.jcmgh.2021.12.018 |
| Citation | Dong Z, et al. (2022) Hepatic Reduction in Cholesterol 25-Hydroxylase Aggravates Diet-induced Steatosis. Cell Mol Gastroenterol Hepatol 13(4):1161-1179 |
| abstractText | 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-LXRalpha-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. |
