Cyclophilin D Deficiency Attenuates Mitochondrial Perturbation and Ameliorates Hepatic Steatosis

Abstract

Physiological opening of the mitochondrial permeability transition pore (mPTP) is indispensable for maintaining mitochondrial function and cell homeostasis, but the role of mPTP and its initial factor, cyclophilin D (CypD) in hepatic steatosis is unclear. Here, we demonstrated that excess mPTP opening mediated by the increase of CypD expression induced hepatic mitochondrial dysfunction. Notably, such mitochondrial perturbation occurred before detectable triglyceride (TG) accumulation in the liver of HFD-fed mice. Moreover, either genetic knockout or pharmacological inhibition of CypD could ameliorate mitochondrial dysfunction, including excess mPTP opening and stress, and downregulate the transcription of sterol regulatory element-binding protein-1c (SREBP-1c), a key factor of lipogenesis. In contrast, the hepatic steatosis in adenoviral overexpression of CypD (AdPPIF)-infected mice were aggravated relative to control group. Blocking p38 MAPK or liver-specific Ire1α knockout could resist CypD-induced SREBP-1c expression and steatosis. Importantly, CypD inhibitor applied prior to or after the onset of TG deposition substantially prevented or ameliorated fatty liver. Conclusion: CypD stimulates mPTP excessive opening, subsequently causing endoplasmic reticulum (ER) stress via p38 MAPK activation, and resultes in enhanced SREBP-1c transcription and hepatic steatosis. This article is protected by copyright. All rights reserved.

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