Liver cyclophilin D deficiency inhibits the progression of early NASH by ameliorating steatosis and inflammation

• Published in: Biochemical and biophysical research communications 2022-02, Vol.594, p.168-176
• Main Authors: Li, Xiaoling, Yang, Mengjiao, Sun, Hang, Ferdous, Md Reyad ul, Gao, Ling, Zhao, Jiajun, Song, Yongfeng
• Format: Article
• Language: English
• Subjects: Animals; Bile Ducts; Cholestasis - metabolism; CypD; Diet, High-Fat; Fatty Liver - metabolism; Fibrosis; Glucose Tolerance Test; Hepatocytes - metabolism; Inflammation; Lipid Metabolism; Lipidomics; Lipids - chemistry; Liver - metabolism; Male; Mice; Mice, Knockout; Mitochondria - metabolism; Mitochondrial Membrane Transport Proteins - metabolism; Mitochondrial Permeability Transition Pore; NASH; Non-alcoholic Fatty Liver Disease - metabolism; Peptidyl-Prolyl Isomerase F - deficiency; Peptidyl-Prolyl Isomerase F - metabolism; RNA-Seq; Steatosis
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2022.01.059

Cyclophilin D (CypD) can stimulate the opening of the membrane permeability transition pore (mPTP) and regulate mitochondrial function. Whole-body knockout of CypD improved high fat diet-induced hepatic steatosis by reducing the excess opening of the mPTP and lipid deposition. However, whether CypD significantly ameliorates nonalcoholic steatohepatitis (NASH) has not been studied. Therefore, we established liver-specific CypD knockout (CypD LKO) mice and fed a HFHC diet to induce NASH. Compared with the wild-type mice, the CypD LKO not only showed improved lipid deposition and insulin resistance by increasing fatty acid oxidation but also displayed ameliorated hepatic inflammation, although the symptoms of fibrosis in the NASH model were not significantly improved. In addition, we used bile duct ligation (BDL) or a 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet to induce cholestatic disease and found that CypD LKO had also no significant effect on acute fibrosis. Thus, CypD LKO can inhibit the progression of early NASH by ameliorating steatosis and inflammatory symptoms. These results suggest a new strategy for the treatment of early NASH. •Liver cyclophilin D knockout can significantly improve liver lipid accumulation induced by long-term HFHC diet, which is consistent with whole-body knockout of cyclophilin D.•Liver cyclophilin D knockout can improve the symptoms of inflammation induced by long-term HFHC diet.•Liver cyclophilin D deficiency did not significantly improve the symptoms of fibrosis.•Liver cyclophilin D deficiency inhibits the progression of early NASH by ameliorating steatosis and inflammation.