Cyclophilin D Deficiency Ameliorates Hepatic Triglyceride Accumulation

Presentation Number: MON 517
Date of Presentation: April 3rd, 2017

Xiaolei Wang*, Chunxiao Yu, Ling Gao and Jiajun Zhao
Shandong Provincial Hospital affiliated to Shandong University, Jinan, China

Abstract

As the energy factories of the cell and the main source of cellular reactive oxygen species, the mitochondrion is thought to be associated with nonalcoholic fatty liver disease. The mitochondrial permeability transition pore (mPTP) is a non selective channel in the inner membrane, which opens regularly in physiological state. However the excessive opening will lead to impaired mitochondrial respiratory chain function, mitochondrial swelling, oxygen free radical generation and cell apoptosis. Cyclophilin D (CypD), an intra-mitochondrial peptidylprolyl cis–trans-isomerase, is an important component of mPTP, which is an initial factor of mPTP in mitochondrial matrix. mPTP opening is promoted by CypD overexpression and is attenuated by CypD knockout. We used CypD knockout (ppif-/-) mice to investigate the function of CypD in hepatic triglyceride metabolism. Despite mitochondrial function, insulin sensitivity and hepatic triglyceride accumulation was improved in ppif-/- mice. Hepatic ER stress was also relieved, especially the expression of phospho-IRE1α . Sterol regulatory element-binding protein-1c (SREBP1c) and its response genes were down-regulated in the liver from ppif-/- mice . Adenoviral overexpression of CypD (AdV.ppif ) in the mice did increased TG accumulation and SREBP1c expression compared to vector control , which identified CypD as an regulatory protein that enhance the expression of triglyceride synthesis. However, the expression of SREBP1c in liver-specific IRE1α knockout (LKO) mice injected with AdV.ppif were not increased relative to vector control. We speculate that CypD upregulates the expression of SREBP1c, which stimulates TG accumulation in the liver. These actions may be exerted via phospho-IRE1α that trigger SREBP1c expression.

 

Nothing to Disclose: XW, CY, LG, JZ