Elimination of FKBP51 attenuates CCl4-induced liver injury via enhancement of mitochondrial function by increased Parkin activity

Abstract

Background & Aims Liver injury is a common feature of most chronic liver diseases. Previously, we found that Fkbp51 knockout (KO) mice resist high fat diet-induced fatty liver and alcohol-induced liver injury. The aim of this research is to identify the mechanism by which Fkbp51 affects liver injury using the carbon tetrachloride (CCl4) injection model. Methods CCl4-induced liver injury was compared between Fkbp51 KO and wild type (WT) mice. Step-wise and in-depth analyses were applied, including liver histology, biochemistry, RNA-Seq, mitochondrial respiration, electron microscopy, and molecular assessments. The selective FKBP51 inhibitor (SAFit2) was tested as a potential treatment to ameliorate liver injury. Results Fkbp51 knockout mice exhibited protection against liver injury, as evidenced by liver histology, reduced fibrosis-associated markers (Collagen I, α-SAM, CTGF, and TIMP1), and lower serum AST and ALT levels. RNA-seq identified differentially expressed genes between KO and WT after liver injury. Pathway and STRING analysis revealed that gene hubs involved in fibrogenesis, inflammation, mitochondria, and oxidative metabolism pathways are significantly altered and predicted the interaction of FKBP51, Parkin, and HSP90. Cellular studies supported co-localization of Parkin and FKBP51 in the mitochondrial network, and Parkin was shown to be expressed higher in the liver of KO mice at baseline and after liver injury relative to WT. Further functional analysis identified that KO mice exhibited increased ATP production and enhanced mitochondrial respiration. KO mice have increased mitochondrial size, increased autophagy/mitophagy and mitochondrial-derived vesicles (MDV), and reduced reactive oxygen species (ROS) production, which supports enhancement of mitochondrial quality control (MQC). Application of SAFit2, an FKBP51 inhibitor, reduced the effects of CCl4-induced liver injury and was associated with increased Parkin and ATP production. Conclusions Downregulation of FKBP51 represents a promising therapeutic target for the treatment of liver disease.