Modulation of fatty acid and bile acid metabolism by PPAR 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 (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 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 wild-type mice. Results— The results showed that in the presence of PPAR α , three major metabolic pathways in mitochondria, namely the fatty acid β -oxidation, the tricarboxylic acid cycle (TCA) and the electron transfer chain, were induced in response to two-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, lipidomic profiling showed consistent accumulation of triglycerides in Ppara -null mice, a robust increase of hepatic cholic acid and its derivatives, and a strong induction of fibrogenesis genes 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 of ALD. histological changes in ALD patients although in our mouse model they are less severe. significant increase of hepatic cholic acid and its derivatives be a critical factor activating the inflammatory Indeed hepatic cholestasis bile duct has reported to appear in all stages of ALD. In our study disruption of bile acid homeostasis and other ALD phenotypes were associated with PPAR α deficiency. The fact that PPAR α expression and activity in human liver are less than one-tenth of those in WT mouse liver suggests that lower PPAR α activity in response to alcohol-induced metabolic challenge may contribute to development and progression of ALD in humans. The current study using Ppara-null mice will help to elucidate the role of PPAR α in the molecular changes of alcoholic liver damage and provide novel mechanistic insight for ALD development. Our findings suggest the potential application of PPAR α agonists in preventing ALD progression. This is especially attractive since fibrate drugs have used to treat hyperlipidemia for over 80 years. A recent report showed that PPAR α agonist alleviated liver caused by ingestion combined with carbon tetrachloride intraperitoneal injection in mice et al., 2013), in which carbon tetrachloride may be the major contributor for the observed severe liver injury including fibrosis. Our study suggests that PPAR α agonists or other treatments with the capability to enhance mitochondria metabolic pathways may ameliorate alcoholic liver injury. The data presented here demonstrate the power of transcriptomics in combination with mass spectrometry-based metabolomics/lipidomics using genetic engineered mouse models to capture and elucidate metabolic changes during chronic alcohol consumption for mechanistic understanding of ALD development.