RT Journal Article
SR Electronic
T1 Obeticholic acid ameliorates Valproic acid-induced Hepatic Steatosis and Oxidative Stress
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.119.118646
DO 10.1124/mol.119.118646
A1 Zhibo Gai
A1 Evelin Krajnc
A1 Sophia L Samodelov
A1 Michele Visentin
A1 Gerd A Kullak-Ublick
YR 2020
UL http://molpharm.aspetjournals.org/content/early/2020/02/21/mol.119.118646.abstract
AB Farnesoid X receptor (FXR, NR1H4) protects the liver from insults of various etiologies. A role of FXR in drug-induced liver injury (DILI) has also been hypothesized, yet only marginally investigated. The aim of this study was to assess the effect of FXR activation on gene expression and phenotype of the liver of mice treated with valproic acid- (2-propylpentanoic acid, VPA), a prototypical hepatotoxic drug. Obeticholic acid (OCA) was used to activate FXR both in mice and in human hepatocellular carcinoma (Huh-7) cells. Next generation sequencing of mouse liver tissues was performed from control, VPA and VPA+OCA-treated mice. Pathway analysis validation was performed using real time RT-PCR, western blotting, immunohistochemistry and fluorometric assays. FXR activation induced antioxidative pathways, confirmed by a marked reduction in VPA-induced lipid peroxidation and endoplasmic reticulum (ER) stress. In vitro, VPA-induced oxidative stress was independent of lipid accumulation, stemmed from the cytoplasm and was mitigated by OCA. In the liver of the mice treated with OCA, the levels of cytochrome P450 potentially involved in VPA metabolism were increased. The hepatic lipid lowering effect observed in animals co-treated with VPA and OCA in comparison to that of animals treated with VPA was associated with regulation of the genes involved in the steatogenic nuclear receptor peroxisome proliferator-activated γ (PPARγ) pathway. In conclusion, pronounced antioxidant activity, repression of the PPARγ pathway and higher expression of CYP450 enzymes involved in VPA metabolism may underlie the hepatoprotective of FXR activation during VPA treatment.SIGNIFICANCE STATEMENT Valproic acid-induced oxidative stress occurs in absence of lipid accumulation and is not of mitochondrial origin. Valproic acid exposure induces the expression of the steatogenic nuclear receptor peroxisome proliferator-activated γ (PPARγ) and its downstream target genes. Constitutive activation of the farnesoid X receptor reduces PPARγ hepatic expression and induces hepatic antioxidant activity. The variability in FXR expression level/activity, for instance in individuals carrying loss-of-function genetic variants of the FXR gene, could contribute to valproic acid pharmacokinetic and toxicokinetic profile.