Leptin deficiency enhances sensitivity of rats to alcoholic steatohepatitis through suppression of metallothionein.
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.
Department of Internal Medicine, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
Kengo
K
Tomita
Toshifumi
T
Azuma
Naoto
N
Kitamura
Gen
G
Tamiya
Satoshi
S
Ando
Hiroshi
H
Nagata
Shinzo
S
Kato
Sayaka
S
Inokuchi
Takeshi
T
Nishimura
Hiromasa
H
Ishii
Toshifumi
T
Hibi
D000818:Animals; D004334:Drug Administration Schedule; D000431:Ethanol / Q000008:administration & dosage; D005234:Fatty Liver / Q000139:chemically induced* / Q000473:pathology; D005456:Fluorescent Dyes; D007150:Immunohistochemistry; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism; D020738:Leptin / Q000172:deficiency*; D008297:Male; D008668:Metallothionein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D015032:Zinc / Q000378:metabolism
D005456:Fluorescent Dyes; D020738:Leptin; C491055:Mt2A protein, rat; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D008668:Metallothionein; D015032:Zinc