Deficiency of DJ-1 Ameliorates Liver Fibrosis through Inhibition of Hepatic ROS Production and Inflammation

Abstract

Liver fibrosis is a global health problem and previous studies have demonstrated that reactive oxygen species (ROS) play important roles in fibrogenesis. Parkinson disease (autosomal recessive, early onset) 7 (Park7) also called DJ-1 has an essential role in modulating cellular ROS levels. DJ-1 therefore may play functions in liver fibrogenesis and modulation of DJ-1 may be a promising therapeutic approach. Here, wild-type (WT) and DJ-1 knockout (DJ-1 KO) mice were administrated with carbon tetrachloride (CCl4) to induce liver fibrosis or acute liver injury. Results showed that DJ-1 depletion significantly blunted liver fibrosis, accompanied by marked reductions in liver injury and ROS production. In the acute CCl4 model, deficiency of DJ-1 showed hepatic protective functions as evidenced by decreased hepatic damage, reduced ROS levels, diminished hepatic inflammation and hepatocyte proliferation compared to WT mice. In vitro hepatic stellate cells (HSCs) activation assays indicated that DJ-1 has no direct effect on the activation of HSCs in the context of with or without TGFβ treatment. Thus our present study demonstrates that in CCl4-induced liver fibrosis, DJ-1 deficiency attenuates mice fibrosis by inhibiting ROS production and liver injury, and further indirectly affecting the activation of HSCs. These results are in line with previous studies that ROS promote HSC activation and fibrosis development, and suggest the therapeutic value of DJ-1 in treatment of liver fibrosis.

DJ-1 Deficiency Protects Hepatic Steatosis by Enhancing Fatty Acid Oxidation in Mice

“…Mouse primary hepatocyte were isolated from 6- to 8-weeks WT or DJ-1 -/- mice similarly to a previously published procedure 8 . Isolated primary hepatocytes were seed into 6-well plates with DMEM medium treated with 0.25 mM palmitate (P9767, Sigma-Aldrich) for 48h, as previously reported 15 .…”

“…Later, we have shown that DJ-1 has important roles in progression of liver diseases through modulating ROS and immune response 6 . We have shown that DJ-1 deficiency negatively regulates hepatic progenitor cells (HPC) proliferation by impairing the formation of HPC-associated fibrosis and inflammatory niches 7 ; Deficiency of DJ-1 ameliorates liver fibrosis through inhibition of hepatic ROS production and inflammation 8 ; moreover, DJ-1 ameliorates tumorigenesis and hepatocellular carcinoma cell (HCC) proliferation through regulating hepatic inflammation and decreasing interleukin 6/signal transducer and activator of transcription 3 (IL-6/ STAT3) signaling pathway in a classic diethylnitrosamine (DEN)-induced HCC mice model 9 .Recently, studies have showed that DJ-1 controlled type 2 diabetes mellitus (T2DM) and energy metabolism in various tissues 10 . It was reported that DJ-1 inhibited energy metabolism through PTEN/PI3K/ AKT/FoxO1/Ucp1 pathway and promoted lipid formation and obesity-mediated inflammation in adipose tissue 11 , 12 .…”

Park 7: A Novel Therapeutic Target for Macrophages in Sepsis-Induced Immunosuppression

“…Neutrophil paralysis, similar to macrophage paralysis described above, was described in experimental studies of patients and sepsis animal models and was associated with decreased production of ROS in neutrophils ( 91 , 92 ). In a liver fibrosis model, Park 7 deficiency inhibited ROS production in macrophages ( 93 ). Similarly, Liu et al also observed greatly reduced ROS production in macrophages from park 7 KO mice ( 53 ).…”

DJ-1 exerts anti-inflammatory effects and regulates NLRX1-TRAF6 via SHP-1 in stroke

“…High levels of these cytokines can be detrimental to ischemic recovery because they directly induce apoptosis in neuronal cells [32,33]. In addition, DJ-1 deficiency in other diseases aggravates injury by inducing inflammation [34,35]. Thus, DJ-1 plays a clear anti-inflammatory role in ischemic injury.…”