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

Am J Physiol Gastrointest Liver Physiol. 2004 Nov;287(5):G1078-85. doi: 10.1152/ajpgi.00107.2004.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • RNA, Messenger / antagonists & inhibitors
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Zucker
  • Tumor Necrosis Factor-alpha / genetics
  • Zinc / metabolism

Substances

  • Fluorescent Dyes
  • Leptin
  • Mt2A protein, rat
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • Ethanol
  • Metallothionein
  • Zinc