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Effects of Farnesoid X Receptor Activation on Arachidonic Acid Metabolism, NF-kB Signaling, and Hepatic Inflammation.

  • Gai Z Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland (Z.G., M.V., S.H., C.H., G.A.K.-U.); Experiment Center, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China (T.G.); Department of Endocrinology, Chinese PLA 309 Hospital, Peking, China (L.Z.); Department of General and Visceral Surgery, Rotkreuzklinikum Munich, Munich, Germany (W.E.T.); Department of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, Zurich, Switzerland (I.H., A.C.); and Mechanistic Safety, Novartis Global Drug Development, Basel, Switzerland (G.A.K.-U.).
  • Visentin M Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland (Z.G., M.V., S.H., C.H., G.A.K.-U.); Experiment Center, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China (T.G.); Department of Endocrinology, Chinese PLA 309 Hospital, Peking, China (L.Z.); Department of General and Visceral Surgery, Rotkreuzklinikum Munich, Munich, Germany (W.E.T.); Department of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, Zurich, Switzerland (I.H., A.C.); and Mechanistic Safety, Novartis Global Drug Development, Basel, Switzerland (G.A.K.-U.).
  • Gui T Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland (Z.G., M.V., S.H., C.H., G.A.K.-U.); Experiment Center, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China (T.G.); Department of Endocrinology, Chinese PLA 309 Hospital, Peking, China (L.Z.); Department of General and Visceral Surgery, Rotkreuzklinikum Munich, Munich, Germany (W.E.T.); Department of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, Zurich, Switzerland (I.H., A.C.); and Mechanistic Safety, Novartis Global Drug Development, Basel, Switzerland (G.A.K.-U.).
  • Zhao L Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland (Z.G., M.V., S.H., C.H., G.A.K.-U.); Experiment Center, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China (T.G.); Department of Endocrinology, Chinese PLA 309 Hospital, Peking, China (L.Z.); Department of General and Visceral Surgery, Rotkreuzklinikum Munich, Munich, Germany (W.E.T.); Department of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, Zurich, Switzerland (I.H., A.C.); and Mechanistic Safety, Novartis Global Drug Development, Basel, Switzerland (G.A.K.-U.).
  • Thasler WE Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland (Z.G., M.V., S.H., C.H., G.A.K.-U.); Experiment Center, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China (T.G.); Department of Endocrinology, Chinese PLA 309 Hospital, Peking, China (L.Z.); Department of General and Visceral Surgery, Rotkreuzklinikum Munich, Munich, Germany (W.E.T.); Department of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, Zurich, Switzerland (I.H., A.C.); and Mechanistic Safety, Novartis Global Drug Development, Basel, Switzerland (G.A.K.-U.).
  • Häusler S Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland (Z.G., M.V., S.H., C.H., G.A.K.-U.); Experiment Center, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China (T.G.); Department of Endocrinology, Chinese PLA 309 Hospital, Peking, China (L.Z.); Department of General and Visceral Surgery, Rotkreuzklinikum Munich, Munich, Germany (W.E.T.); Department of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, Zurich, Switzerland (I.H., A.C.); and Mechanistic Safety, Novartis Global Drug Development, Basel, Switzerland (G.A.K.-U.).
  • Hartling I Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland (Z.G., M.V., S.H., C.H., G.A.K.-U.); Experiment Center, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China (T.G.); Department of Endocrinology, Chinese PLA 309 Hospital, Peking, China (L.Z.); Department of General and Visceral Surgery, Rotkreuzklinikum Munich, Munich, Germany (W.E.T.); Department of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, Zurich, Switzerland (I.H., A.C.); and Mechanistic Safety, Novartis Global Drug Development, Basel, Switzerland (G.A.K.-U.).
  • Cremonesi A Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland (Z.G., M.V., S.H., C.H., G.A.K.-U.); Experiment Center, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China (T.G.); Department of Endocrinology, Chinese PLA 309 Hospital, Peking, China (L.Z.); Department of General and Visceral Surgery, Rotkreuzklinikum Munich, Munich, Germany (W.E.T.); Department of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, Zurich, Switzerland (I.H., A.C.); and Mechanistic Safety, Novartis Global Drug Development, Basel, Switzerland (G.A.K.-U.).
  • Hiller C Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland (Z.G., M.V., S.H., C.H., G.A.K.-U.); Experiment Center, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China (T.G.); Department of Endocrinology, Chinese PLA 309 Hospital, Peking, China (L.Z.); Department of General and Visceral Surgery, Rotkreuzklinikum Munich, Munich, Germany (W.E.T.); Department of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, Zurich, Switzerland (I.H., A.C.); and Mechanistic Safety, Novartis Global Drug Development, Basel, Switzerland (G.A.K.-U.).
  • Kullak-Ublick GA Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland (Z.G., M.V., S.H., C.H., G.A.K.-U.); Experiment Center, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China (T.G.); Department of Endocrinology, Chinese PLA 309 Hospital, Peking, China (L.Z.); Department of General and Visceral Surgery, Rotkreuzklinikum Munich, Munich, Germany (W.E.T.); Department of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, Zurich, Switzerland (I.H., A.C.); and Mechanistic Safety, Novartis Global Drug Development, Basel, Switzerland (G.A.K.-U.) gerd.kullak@usz.ch.
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  • 2018-05-11
Published in:
  • Molecular pharmacology. - 2018
Animals
Arachidonic Acid
Cell Movement
Cells, Cultured
Chenodeoxycholic Acid
Cytochrome P-450 Enzyme System
Diet, High-Fat
Disease Models, Animal
Female
Gene Expression Regulation
Hepatocytes
Humans
Lipid Metabolism
Mice
Non-alcoholic Fatty Liver Disease
Receptors, Cytoplasmic and Nuclear
Signal Transduction
THP-1 Cells
English Inflammation has a recognized role in nonalcoholic fatty liver disease (NAFLD) progression. In the present work, we 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 nuclear factor κ light-chain enhancer of activated B cells (NF-kB) signaling, major modulators of the inflammatory cascade. Mice were fed an HFD to induce NAFLD and then treated with the FXR ligand obeticholic acid (OCA). Histology and gene expression analyses 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 human liver Huh7 cells and primary cultured hepatocytes. NAFLD was characterized by higher (∼25%) proinflammatory [leukotrienes (LTB4)] and lower (∼3-fold) anti-inflammatory [epoxyeicosatrienoic acids (EETs)] eicosanoid levels than in chow mice. OCA induced the expression of several hepatic cytochrome P450 (P450) 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, NAFLD was characterized by an imbalance in arachidonate metabolism. FXR activation reprogramed arachidonate metabolism by inducing P450 epoxygenase expression and EET production. In vitro, FXR-mediated NF-kB inhibition required active P450 epoxygenases.
Language
  • English
Open access status
bronze
Identifiers
Persistent URL
https://folia.unifr.ch/global/documents/94694
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