Abstract
Backgrounds/AimsMitochondrial dysfunction plays an important role inthe pathogenesis of nonalcoholic steatohepatitis (NASH), where uncoupling protein (UCP) is actively involved. We previously reported the uncoupling activity of HDMCP and its role in liver steatosis. We now aim to investigate the degree and therapeutic effect of HDMCP in NASH and the regulatory role of miR-146 on HDMCP.MethodsNASH animal model was established by feeding BALB/c mice with MCD diet while L02 cell was cultured with high concentration of fatty acid (HFFA) for 72h to mimic the steatosis and inflammation of NASH in-vitro appearance. The steatosis level was assessed by H-E/oil-red staining and serum/supernatant marker detection. The inflammation activity was evaluated by levels of Hepatic activity index, transwell, apoptosis degree (TUNEL/flow cytometry) and serum/supernatant marker. HDMCP level was detected by western blot and miRNA expression was tested by qRT-PCR. NASH severity change was recorded after RNA interference while the regulatory role of miR-146 on HDMCP was confirmed by dual luciferase report system. The H2O2 and ATP levels were measured for mechanism exploration.ResultsIncreased HDMCP expression was identified in NASH animal model and HFFA-72h cultured L02 cell. Moreover, under regulation of miR-146, NASH alleviation was achieved after HDMCP downregulation in both in vivo and in vitro, according to the declination of steatosis and inflammation related markers. Though H2O2 and ATP levels were increased and decreased in NASH models, HDMCP down regulation both increased their levels.ConclusionsThe miR-146-HDMCP-ATP/H2O2 pathway may provide novel mechanism and treatment option for NASH.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is defined as a common clinicopathologic condition characterized by lipid deposition in hepatocytes, precluding excessive alcohol intake[1]
Nonalcoholic steatohepatitis (NASH) animal model was established by feeding BALB/c mice with MCD diet while L02 cell was cultured with high concentration of fatty acid (HFFA) for 72h to mimic the steatosis and inflammation of NASH in-vitro appearance
Increased Hepatocellular carcinoma down regulated mitochondrial carrier protein (HDMCP) expression was identified in NASH animal model and HFFA-72h cultured L02 cell
Summary
Nonalcoholic fatty liver disease (NAFLD) is defined as a common clinicopathologic condition characterized by lipid deposition in hepatocytes, precluding excessive alcohol intake[1]. Nonalcoholic steatohepatitis (NASH) is an important stage in NAFLD for its characteristic of inflammation initiation and end-stage liver disease progression. It has been regarded as a significance cause of cryptogenic cirrhosis[4] and liver transplantation[5]. The pathogenesis of NASH is still vague, where accumulating evidences supported the vital role of mitochondrial dysfunction [6]. Hepatic mitochondria are the major site of fatty acid metabolism and the concomitant oxidative stress may accelerate the transition from simple steatosis to NASH. Though mitochondrial morphology change such as structure damage[7] and permeability transition pore opening[8] have been reported, the functional change and specific protein mediated mitochondrial dysfunction were rarely investigated
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