Knocking out Fkbp51 decreases CCl4-induced liver injury through enhancement of mitochondrial function and Parkin activity.

BACKGROUND AND AIMS: Previously, we found that FK506 binding protein 51 (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 of Fkbp51 in liver injury. METHODS: Carbon tetrachloride (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 and lower serum liver enzyme levels. RNA-seq identified differentially expressed genes and involved pathways, such as fibrogenesis, inflammation, mitochondria, and oxidative metabolism pathways 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, pAKT, and ATP production. CONCLUSIONS: Downregulation of FKBP51 represents a promising therapeutic target for liver disease treatment.

Adolescent alcohol and nicotine exposure alters the adult response to alcohol use.

Adolescence through young adulthood is a unique period of neuronal development and maturation. Numerous agents can alter this process, resulting in long-term neurological and biological consequences. In the clinical literature, it is frequently reported that adolescent alcohol consumption increases the propensity to develop addictions, including alcohol use disorder (AUD), during adulthood. A general limitation of both clinical and human pre-clinical adolescent alcohol research is the high rate of co-using/abusing more than one drug during adolescence, such as co-using/abusing alcohol with nicotine. A primary goal of basic research is elucidating neuroadaptations produced by adolescent alcohol exposure/consumption that promote alcohol and other drug self-administration in adulthood. The long-term goal is to develop pharmacotherapeutics for the prevention or amelioration of these neuroadaptations. This review will focus on studies that have examined the effects of adolescent alcohol and nicotine exposure on adult alcohol consumption, the hypersensitivity of the mesolimbic dopaminergic system, and enhanced responses not only to alcohol but also to nicotine during adulthood. Again, the long-term goal is to identify potential cholinergic agents to prevent or ameliorate the consequences of, peri-adolescent alcohol abuse.