Zhou Haoxiong, Wan Sizhe, Luo Yujun, Liu Huiling, Jiang Jie, Guo Yunwei, Xiao Jia, Wu Bin
Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China.
Alcoholic Liver Disease Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China.
Gastroenterol Rep (Oxf). 2023 Mar 1;11:goad006. doi: 10.1093/gastro/goad006. eCollection 2023.
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.
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.
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 alcohol-fed 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.
Our study demonstrated that HBx-induced ubiquitin-dependent degradation of mitochondrial ALDH2 aggravates alcoholic steatohepatitis.
过量饮酒合并乙型肝炎病毒（HBV）感染会加速慢性肝病进展，且HBV感染患者更易患酒精性肝病。乙型肝炎病毒X蛋白（HBx）在疾病发病机制中起关键作用，但其在酒精性肝病（ALD）进展中的具体作用尚未阐明。在此，我们研究了HBx在ALD发生发展中的作用。
将HBx转基因（HBx-Tg）小鼠及其野生型同窝小鼠暴露于慢性加暴饮酒精喂养。使用原代肝细胞、细胞系和人类样本研究HBx与乙醛脱氢酶2（ALDH2）之间的相互作用。通过液相色谱-质谱法评估小鼠肝脏和细胞中的脂质谱。
我们发现HBx显著加重了小鼠酒精性脂肪性肝炎、氧化应激和脂质过氧化。此外，脂质组学分析显示，在酒精性脂肪性肝炎中，HBx诱导产生更差的脂质谱，伴有高溶血磷脂生成。重要的是，酒精喂养的HBx-Tg小鼠血清和肝脏中的乙醛明显更高。乙醛通过肝细胞中的氧化应激诱导溶血磷脂生成。机制上，HBx直接与线粒体ALDH2结合，诱导其泛素-蛋白酶体降解，导致乙醛积累。更重要的是，我们还发现HBV感染患者肝脏中的ALDH2蛋白水平降低。
我们的研究表明，HBx诱导的线粒体ALDH2泛素依赖性降解加重了酒精性脂肪性肝炎。
