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Modulation of Fatty Acid and Bile Acid Metabolism By Peroxisome Proliferator‐Activated Receptor α Protects Against Alcoholic Liver Disease
Author(s) -
Li HengHong,
Tyburski John B.,
Wang YiWen,
Strawn Steve,
Moon BoHyun,
Kallakury Bhaskar V. S.,
Gonzalez Frank J.,
Fornace Albert J.
Publication year - 2014
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.12424
Subject(s) - peroxisome proliferator activated receptor , fatty liver , alcoholic liver disease , endocrinology , medicine , peroxisome , peroxisome proliferator activated receptor delta , alcoholic fatty liver , cholic acid , fatty acid metabolism , biology , beta oxidation , alcohol dehydrogenase , receptor , lipid metabolism , metabolism , bile acid , biochemistry , alcohol , nuclear receptor , gene , disease , transcription factor , cirrhosis
Background Chronic alcohol intake affects liver function and causes hepatic pathological changes. It has been shown that peroxisome proliferator‐activated receptor α ( PPAR α )‐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 PPAR α 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 PPAR α 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 PPAR α , 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 PPAR α . 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 PPAR α 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 .