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The effects of farnesoid X receptor activation on arachidonic acid metabolism, NF-kB signaling and hepatic inflammation


Gai, Zhibo; Visentin, Michele; Gui, Ting; Zhao, Lin; Thasler, Wolfgang E; Hausler, Stephanie; Hartling, Ivan; Cremonesi, Alessio; Hiller, Christian; Kullak-Ublick, Gerd A (2018). The effects of farnesoid X receptor activation on arachidonic acid metabolism, NF-kB signaling and hepatic inflammation. Molecular Pharmacology, 94(2):802-811.

Abstract

Inflammation has a recognized role in non-alcoholic fatty liver disease (NAFLD) progression. The present work studied the effect of high fat diet (HFD) on arachidonic acid metabolism in the liver and investigated the role of the farnesoid X receptor (FXR, NR1H4) in eicosanoid biosynthetic pathways and NF-kB signaling, major modulators of the inflammatory cascade. Mice were fed a HFD to induce NAFLD, then, treated with the FXR ligand obeticholic acid (OCA). Histology and gene expression analysis were performed on liver tissue. Eicosanoid levels were measured from serum and urine samples. The molecular mechanism underlying the effect of FXR activation on arachidonic acid metabolism and NF-kB signaling was studied in Huh7 cells and primary cultured hepatocytes. NAFLD was characterized by higher (~25%) pro-inflammatory (leukotrienes, LTB4) and lower (~3fold) anti-inflammatory (epoxyeicosatrienoic acids, EETs) eicosanoid levels than in chow mice. OCA induced the expression of several hepatic Cyp450 epoxygenases, the enzymes responsible for EET synthesis, and mitigated HFD-induced hepatic injury. In vitro, induction of CYP450 epoxygenases was sufficient to inhibit NF-kB signaling and cell migration. The CYP450 epoxygenase pan-inhibitor gemfibrozil fully abolished the protective effect of OCA indicating that OCA-mediated inhibition of NF-kB signaling was EET-dependent. In summary non-alcoholic fatty liver disease (NAFLD) was characterized by an imbalance in arachidonate metabolism. Farnesoid X receptor (FXR) activation reprogramed arachidonate metabolism by inducing CYP450 epoxygenase expression and EET production. In vitro, FXR-mediated NF-kB inhibition, required active CYP450 epoxygenases.

Abstract

Inflammation has a recognized role in non-alcoholic fatty liver disease (NAFLD) progression. The present work studied the effect of high fat diet (HFD) on arachidonic acid metabolism in the liver and investigated the role of the farnesoid X receptor (FXR, NR1H4) in eicosanoid biosynthetic pathways and NF-kB signaling, major modulators of the inflammatory cascade. Mice were fed a HFD to induce NAFLD, then, treated with the FXR ligand obeticholic acid (OCA). Histology and gene expression analysis were performed on liver tissue. Eicosanoid levels were measured from serum and urine samples. The molecular mechanism underlying the effect of FXR activation on arachidonic acid metabolism and NF-kB signaling was studied in Huh7 cells and primary cultured hepatocytes. NAFLD was characterized by higher (~25%) pro-inflammatory (leukotrienes, LTB4) and lower (~3fold) anti-inflammatory (epoxyeicosatrienoic acids, EETs) eicosanoid levels than in chow mice. OCA induced the expression of several hepatic Cyp450 epoxygenases, the enzymes responsible for EET synthesis, and mitigated HFD-induced hepatic injury. In vitro, induction of CYP450 epoxygenases was sufficient to inhibit NF-kB signaling and cell migration. The CYP450 epoxygenase pan-inhibitor gemfibrozil fully abolished the protective effect of OCA indicating that OCA-mediated inhibition of NF-kB signaling was EET-dependent. In summary non-alcoholic fatty liver disease (NAFLD) was characterized by an imbalance in arachidonate metabolism. Farnesoid X receptor (FXR) activation reprogramed arachidonate metabolism by inducing CYP450 epoxygenase expression and EET production. In vitro, FXR-mediated NF-kB inhibition, required active CYP450 epoxygenases.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
04 Faculty of Medicine > University Hospital Zurich > Clinic for Clinical Pharmacology and Toxicology
Dewey Decimal Classification:610 Medicine & health
Uncontrolled Keywords:Molecular Medicine, Pharmacology
Language:English
Date:2018
Deposited On:12 Jun 2018 14:24
Last Modified:22 Jan 2019 17:42
Publisher:American Society for Pharmacology and Experimental Therapeutics
ISSN:0026-895X
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1124/mol.117.111047
PubMed ID:29743187

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