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National Institute of Environmental Health Sciences

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Publication Detail

Title: Farnesol induces fatty acid oxidation and decreases triglyceride accumulation in steatotic HepaRG cells.

Authors: Pant, Asmita; Rondini, Elizabeth A; Kocarek, Thomas A

Published In Toxicol Appl Pharmacol, (2019 02 15)

Abstract: Non-alcoholic fatty liver disease is manifested by hepatic accumulation of triglycerides (TG) and is commonly associated with metabolic syndrome. The isoprenoid farnesol (FOH) modulates lipid metabolism and reduces hepatic TG content in rodents. This effect involves activation of at least two nuclear receptors, peroxisome proliferator-activated receptor α (PPARα) and farnesoid X receptor. We evaluated the effects of FOH (100 μM) in a cellular model of human hepatic steatosis by loading hepatocyte-like HepaRG cells with oleic acid (OA, 0.66 mM). FOH treatment decreased OA-induced TG accumulation by ~25%. Using PCR arrays, we found that FOH treatment modulated the mRNA levels of several lipid-metabolizing enzymes, both alone and when cells were loaded with OA. While FOH activated PPARα and the constitutive androstane receptor (CAR), most of the FOH-mediated effects on lipid-metabolizing genes could be attributed to activation of PPARα. In OA-loaded HepaRG cells, FOH increased fatty acid oxidation, which was accompanied by up-regulation of PPARα target genes involved in mitochondrial fatty acid oxidation, including hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase and acetyl-coenzyme A acyltransferase 2. These effects on gene expression were lost when the cells were co-treated with the PPARα antagonist, GW6471. OA treatment alone decreased the mRNA levels of the drug-metabolizing enzymes, cytochrome P450 (CYP)1A2, 2B6, and 3A4, and increased CYP2E1 expression, all of which were attenuated by FOH co-treatment. These findings show that FOH treatment increases fatty acid oxidation and decreases TG accumulation in steatotic HepaRG cells, which is likely attributable to PPARα-mediated induction of mitochondrial fatty acid oxidation.

PubMed ID: 30611723 Exiting the NIEHS site

MeSH Terms: Cell Line, Tumor; Farnesol/pharmacology*; Fatty Acids/metabolism*; Gene Expression Regulation, Enzymologic/drug effects; Hepatocytes/drug effects*; Hepatocytes/metabolism; Hepatocytes/pathology; Humans; Mitochondria, Liver/drug effects*; Mitochondria, Liver/metabolism; Mitochondria, Liver/pathology; Non-alcoholic Fatty Liver Disease/drug therapy*; Non-alcoholic Fatty Liver Disease/genetics; Non-alcoholic Fatty Liver Disease/metabolism; Non-alcoholic Fatty Liver Disease/pathology; Oleic Acid/toxicity; Oxidation-Reduction; PPAR alpha/agonists; PPAR alpha/genetics; PPAR alpha/metabolism; Receptors, Cytoplasmic and Nuclear/agonists; Receptors, Cytoplasmic and Nuclear/genetics; Receptors, Cytoplasmic and Nuclear/metabolism; Triglycerides/metabolism*

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