Hepatitis B virus X protein induces ALDH2 ubiquitin-dependent degradation to enhance alcoholic steatohepatitis

Background:Excessive alcohol intake with hepatitis B virus(HBV)infection accelerates chronic liver disease progression and patients with HBV infection are more susceptible to alcohol-induced liver disease.Hepatitis B virus X protein(HBx)plays a crucial role in disease pathogenesis,while its specific role in alcoholic liver disease(ALD)progression has not yet been elucidated.Here,we studied the role of HBx on the development of ALD.Methods:HBx-transgenic(HBx-Tg)mice and their wild-type littermates were exposed to chronic plus binge alcohol feeding.Primary hepatocytes,cell lines,and human samples were used to investigate the interaction between HBx and acetaldehyde dehydrogenase 2(ALDH2).Lipid profiles in mouse livers and cells were assessed by using liquid chromatography–mass spectrometry.Results:We identified that HBx significantly aggravated alcohol-induced steatohepatitis,oxidative stress,and lipid peroxidation in mice.In addition,HBx induced worse lipid profiles with high lysophospholipids generation in alcoholic steatohepatitis,as shown by using lipidomic analysis.Importantly,serum and liver acetaldehyde were markedly higher in alcoholfed HBx-Tg mice.Acetaldehyde induced lysophospholipids generation through oxidative stress in hepatocytes.Mechanistically,HBx directly bound to mitochondrial ALDH2 to induce its ubiquitin–proteasome degradation,resulting in acetaldehyde accumulation.More importantly,we also identified that patients with HBV infection reduced ALDH2 protein levels in the liver.Conclusions:Our study demonstrated that HBx-induced ubiquitin-dependent degradation of mitochondrial ALDH2 aggravates alcoholic steatohepatitis.

NF-κB/HDAC1/SREBP1c pathway mediates the inflammation signal in progression of hepatic steatosis

The transcription factor nuclear factor kappa B(NF-κB)is activated in hepatoctes in the pathogenesis of hepatic steatosis.However,the action mechanism of NF-κB remains to be established in the hepatic steatosis.In this study,the P50 subunit of NF-κB was found to promote the hepatic steatosis through regulation of histone deacetylase 1(HDAC1)in hepatocytes.The activity was supported by the phenotypes of P50 knockout(P50-KO)mice and P65 knockout(P65-KO)mice.Hepatic steatosis was reduced in the P50-KO mice,but not in the P65-KO mice.The reduction was a result of inhibition of HDAC1 activity in the P50-KO cells.Knockdown of Hdac1 gene led to suppression of hepatocyte steatosis in HepG2 cells.A decrease in sterol-regulatory element binding protein lc(SREBP1 c)protein was observed in the liver of P50-KO mice and in cell with Hdac1 knockdown.The decrease was associated with an increase in succinylation of SREBP1 c protein.The study suggests that P50 stabilizes HDAC1 to support the SREBP1 c activity in hepatic steatosis in the pathophysiological condition.Interruption of this novel pathway in the P50-KO,but not the P65-KO mice,may account for the difference in hepatic phenotypes in the two lines of transgenic mice.