Leptin deficiency enhances sensitivity of rats to alcoholic steatohepatitis through suppression of metallothionein

• Published in: American journal of physiology: Gastrointestinal and liver physiology 2004-11, Vol.287 (5), p.G1078-G1085
• Main Authors: Tomita, Kengo, Azuma, Toshifumi, Kitamura, Naoto, Tamiya, Gen, Ando, Satoshi, Nagata, Hiroshi, Kato, Shinzo, Inokuchi, Sayaka, Nishimura, Takeshi, Ishii, Hiromasa, Hibi, Toshifumi
• Format: Article
• Language: English
• Subjects: Animals; Drug Administration Schedule; Ethanol - administration & dosage; Fatty Liver - chemically induced; Fatty Liver - pathology; Fluorescent Dyes; Immunohistochemistry; Kupffer Cells - drug effects; Kupffer Cells - metabolism; Leptin - deficiency; Male; Metallothionein - antagonists & inhibitors; Metallothionein - genetics; Metallothionein - metabolism; Oligonucleotide Array Sequence Analysis; Rats; Rats, Zucker; RNA, Messenger - antagonists & inhibitors; RNA, Messenger - metabolism; Tumor Necrosis Factor-alpha - genetics; Zinc - metabolism
• ISSN: 0193-1857; 1522-1547
• 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.