Modulation of fatty acid and bile acid metabolism by peroxisome proliferator-activated receptor α protects against alcoholic liver disease.
BACKGROUND
Chronic alcohol intake affects liver function and causes hepatic pathological changes. It has been shown that peroxisome proliferator-activated receptor α (PPARα)-null mice developed more pronounced hepatic changes than wild-type (WT) mice after chronic exposure to a diet containing 4% alcohol. The remarkable similarity between the histopathology of alcoholic liver disease (ALD) in Ppara-null model and in humans, and the fact that PPARα expression and activity in human liver are less than one-tenth of those in WT mouse liver make Ppara-null a good system to investigate ALD.


METHODS
In this study, the Ppara-null model was used to elucidate the dynamic regulation of PPARα activity during chronic alcohol intake. Hepatic transcriptomic and metabolomic analyses were used to examine alterations of gene expression and metabolites associated with pathological changes. The changes triggered by alcohol consumption on gene expression and metabolites in Ppara-null mice were compared with those in WT mice.


RESULTS
The results showed that in the presence of PPARα, 3 major metabolic pathways in mitochondria, namely the fatty acid β-oxidation, the tricarboxylic acid cycle, and the electron transfer chain, were induced in response to a 2-month alcohol feeding, while these responses were greatly reduced in the absence of PPARα. In line with the transcriptional modulations of these metabolic pathways, a progressive accumulation of triglycerides, a robust increase in hepatic cholic acid and its derivatives, and a strong induction of fibrogenesis genes were observed exclusively in alcohol-fed Ppara-null mice.


CONCLUSIONS
These observations indicate that PPARα plays a protective role to enhance mitochondrial function in response to chronic alcohol consumption by adaptive transcriptional activation and suggest that activation of this nuclear receptor may be of therapeutic value in the treatment for ALD.
Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, District of Columbia.
Heng-Hong
HH
Li
John B
JB
Tyburski
Yi-Wen
YW
Wang
Steve
S
Strawn
Bo-Hyun
BH
Moon
Bhaskar V S
BV
Kallakury
Frank J
FJ
Gonzalez
Albert J
AJ
Fornace
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D000431:Ethanol / Q000009:adverse effects; D005227:Fatty Acids / Q000378:metabolism*; D005355:Fibrosis; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000378:metabolism* / Q000473:pathology; D008297:Male; D055432:Metabolomics; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D047493:PPAR alpha / Q000378:metabolism / Q000502:physiology*
D001647:Bile Acids and Salts; D005227:Fatty Acids; D047493:PPAR alpha; D000431:Ethanol
Fibrogenesis; Metabolic Pathways; Metabolomics; Ppara-Null Mice; Transcriptomics