Tomita Kengo, Azuma Toshifumi, Kitamura Naoto, Tamiya Gen, Ando Satoshi, Nagata Hiroshi, Kato Shinzo, Inokuchi Sayaka, Nishimura Takeshi, Ishii Hiromasa, Hibi Toshifumi
Department of Internal Medicine, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
Am J Physiol Gastrointest Liver Physiol. 2004 Nov;287(5):G1078-85. doi: 10.1152/ajpgi.00107.2004.
Oxidative stress is stated to be a central mechanism of hepatocellular injury in alcohol-induced liver injury. Recent reports have shown that Kupffer cell dysfunction in the leptin-deficient state contributes partly to the increased sensitivity to endotoxin liver injury. Here we report that leptin also plays a key role in the development of alcoholic liver injury and that leptin signaling in hepatocytes is involved in cellular mechanisms that mediate ethanol-induced oxidative stress. We found that chronic ethanol feeding in leptin receptor-deficient Zucker (fa/fa) rats for 6 wk resulted in a much more severe liver injury and augmented accumulation of hepatic lipid peroxidation compared with control littermates. The hepatic induction of stress-response and antioxidant proteins, such as metallothionein (MT)-1 and -2, was significantly suppressed in fa/fa rats after chronic ethanol feeding. Zinc concentration in liver was also decreased in fa/fa rats, compared with control littermates. In primary cultured hepatocytes from fa/fa rats, incubation with ethanol significantly suppressed MT-1 and -2 expressions. Addition of leptin to leptin-deficient ob/ob mouse primary hepatocytes led to an increase in MT-1 and -2 mRNA levels and a decrease in oxidative stress after incubation with ethanol. In conclusion, leptin deficiency enhances sensitivity of rats to alcohol-induced steatohepatitis through hepatocyte-specific interaction of MT-1 and -2 and resultant exaggeration of oxidative stress in hepatocytes. These findings suggest that leptin resistance in hepatocytes is an important mechanism of alcohol-induced liver injury.
氧化应激被认为是酒精性肝损伤中肝细胞损伤的核心机制。最近的报告表明，瘦素缺乏状态下库普弗细胞功能障碍部分导致对内毒素肝损伤的敏感性增加。在此我们报告，瘦素在酒精性肝损伤的发生发展中也起关键作用，并且肝细胞中的瘦素信号传导参与介导乙醇诱导的氧化应激的细胞机制。我们发现，与对照同窝仔鼠相比，给瘦素受体缺陷的Zucker（fa/fa）大鼠长期喂食乙醇6周会导致更严重的肝损伤，并增加肝脏脂质过氧化的积累。长期喂食乙醇后，fa/fa大鼠肝脏中应激反应和抗氧化蛋白如金属硫蛋白（MT）-1和-2的诱导明显受到抑制。与对照同窝仔鼠相比，fa/fa大鼠肝脏中的锌浓度也降低。在来自fa/fa大鼠的原代培养肝细胞中，用乙醇孵育会显著抑制MT-1和-2的表达。向瘦素缺乏的ob/ob小鼠原代肝细胞中添加瘦素，在与乙醇孵育后会导致MT-1和-2 mRNA水平升高以及氧化应激降低。总之，瘦素缺乏通过MT-1和-2的肝细胞特异性相互作用以及肝细胞中氧化应激的加剧增强了大鼠对酒精性脂肪性肝炎的敏感性。这些发现表明，肝细胞中的瘦素抵抗是酒精性肝损伤的重要机制。
