Modulation of Fatty Acid and Bile Acid Metabolism By Peroxisome Proliferator-Activated ReceptorαProtects Against Alcoholic Liver Disease

Abstract

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 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 wild-type mice. Results The results showed that in the presence of PPARα, 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 PPARα. 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 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 of ALD.

A lipidomic and metabolomic serum signature from nonhuman primates exposed to ionizing radiation

“…For global lipid profiling, samples were injected (1 µl) and analyzed by UPLC with a Waters Acquity CSH C18 1.7 µm, 2.1 × 100 mm column coupled to a Synapt ® G2-Si HDMS QTOF-MS (Waters, Milford, MA) and analyzed in the modes above with chromatographic conditions as previously described (Li et al 2014; supplemental information). Select lipids were analyzed by quadrupole mass filtered tandem MS. Leucine enkephalin (556.2771 [M+H] + or 554.2615 [M-H] − ) was used to calibrate accurate mass on both instruments.…”

Endocrine Adiponectin‐FGF15/19 Axis in Ethanol-Induced Inflammation and Alcoholic Liver Injury

“…Abnormal bile acid homeostasis contributes to the development and progression of experimental alcoholic steatohepatitis in rodents. 49,50 Clinically, alcohol consumption induces cholestasis in all stages of ALD in patients. 51 …”

Pathogenesis of Alcoholic Liver Disease

“…Alcohol also downregulates the negative regulators of SREBP-1c, including 5' adenosine monophosphate-activated protein kinase (AMPK), Sirtuin 1, adiponectin, and signal transducer and activator of transcription 3 (STAT3). Alcohol inhibits fatty acid oxidation by inhibiting the transcriptional activity and DNA-binding ability of peroxisome proliferator-activated receptor alpha (PPAR-α) 20 . Alcohol can downregulate PPAR-α directly via its metabolite acetaldehyde, or indirectly via the cytochrome P450 2E1-derived oxidative stress, adenosine, downregulation of adiponectin, and zinc deficiency.…”

“…Lipid peroxidation products, such as malondialdehyde and 4-hydroxynonenal, can form protein adducts and serve as antigens to activate adaptive immunity. Antibodies against lipid peroxidation adducts and increased numbers of T cells in liver inflammation have been reported 20 .…”