Peroxisome proliferator-activated receptor alpha protects against alcohol-induced liver damage.
The mechanisms underlying alcoholic liver disease are not completely understood, but lipid accumulation seems to be central to the cause of this disease. The peroxisome proliferator-activated receptor alpha (PPARalpha) plays an important role in the control of lipid homeostasis, metabolism of bioactive molecules, and modulation of inflammatory responses. To investigate the roles of PPARalpha in alcoholic liver injury, wild-type and PPARalpha-null mice were continuously fed a diet containing 4% ethanol, and liver injury was analyzed. PPARalpha-null mice fed ethanol exhibited marked hepatomegaly, hepatic inflammation, cell toxicity, fibrosis, apoptosis, and mitochondrial swelling. Some of these hepatic abnormalities were consistent with those of patients with alcoholic liver injury and were not found in wild-type mice. Next, the molecular mechanisms of ethanol-induced liver injury in PPARalpha-null mice were investigated, and changes related to ethanol and acetaldehyde metabolism, oxidative stress, inflammation, hepatocyte proliferation, fibrosis, and mitochondrial permeability transition activation occurred specifically in PPARalpha-null mice as compared with wild-type mice. In conclusion, these studies suggest a protective role for PPARalpha in alcoholic liver disease. Humans may be more susceptible to liver toxicity induced by ethanol as PPARalpha expression in human liver is considerably lower compared to that of rodents.
Nakajima
Tamie
T
Department of Hygiene and Medical Genetics, Shinshu University School of Medicine, Matsumoto, Japan.
Kamijo
Yuji
Y
Tanaka
Naoki
N
Sugiyama
Eiko
E
Tanaka
Eiji
E
Kiyosawa
Kendo
K
Fukushima
Yoshimitsu
Y
Peters
Jeffrey M
JM
Gonzalez
Frank J
FJ
Aoyama
Toshifumi
T
D000079:Acetaldehyde / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002492:Central Nervous System Depressants / Q000493:pharmacokinetics; D000431:Ethanol / Q000493:pharmacokinetics; D022781:Hepatocytes / Q000166:cytology; D008099:Liver / Q000378:metabolism / Q000503:physiopathology; D008108:Liver Diseases, Alcoholic / Q000378:metabolism* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D008933:Mitochondrial Swelling / Q000187:drug effects; D018384:Oxidative Stress; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*
D002492:Central Nervous System Depressants; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000431:Ethanol; D000079:Acetaldehyde