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

Kengo Tomita, Toshifumi Azuma, Naoto Kitamura, Gen Tamiya, Satoshi Ando, Hiroshi Nagata, Shinzo Kato, Sayaka Inokuchi, Takeshi Nishimura, Hiromasa Ishii, Toshifumi Hibi

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28 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)G1078-G1085
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Issue number5 50-5
Publication statusPublished - 2004 Nov
Externally publishedYes


  • Oxidative stress
  • Tumor necrosis factor-α
  • Zinc

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)


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