Li Xiaoling, Yang Mengjiao, Sun Hang, Ferdous Md Reyad Ul, Gao Ling, Zhao Jiajun, Song Yongfeng
Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China; Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, 250021, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, 250021, China; Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China.
Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, 250021, China; Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, 250021, China; Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China.
Biochem Biophys Res Commun. 2022 Feb 26;594:168-176. doi: 10.1016/j.bbrc.2022.01.059. Epub 2022 Jan 18.
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.
亲环素D（CypD）可刺激线粒体通透性转换孔（mPTP）开放并调节线粒体功能。全身敲除CypD可通过减少mPTP过度开放和脂质沉积来改善高脂饮食诱导的肝脂肪变性。然而，CypD是否能显著改善非酒精性脂肪性肝炎（NASH）尚未得到研究。因此，我们构建了肝脏特异性CypD敲除（CypD LKO）小鼠，并给予高脂高胆固醇（HFHC）饮食以诱导NASH。与野生型小鼠相比，CypD LKO不仅通过增加脂肪酸氧化改善了脂质沉积和胰岛素抵抗，还减轻了肝脏炎症，尽管NASH模型中的纤维化症状没有得到显著改善。此外，我们使用胆管结扎（BDL）或0.1% 3,5 - 二乙氧羰基 - 1,4 - 二氢可力丁（DDC）饮食诱导胆汁淤积性疾病，发现CypD LKO对急性纤维化也没有显著影响。因此，CypD LKO可通过改善脂肪变性和炎症症状来抑制早期NASH的进展。这些结果提示了一种治疗早期NASH的新策略。
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