Opposite effects of the FXR agonist obeticholic acid on Mafg and Nrf2 mediate the development of acute liver injury in rodent models of cholestasis

• Published in: Biochimica et biophysica acta. Molecular and cell biology of lipids 2020-09, Vol.1865 (9), p.158733-158733, Article 158733
• Main Authors: Carino, Adriana, Biagioli, Michele, Marchianò, Silvia, Fiorucci, Chiara, Bordoni, Martina, Roselli, Rosalinda, Di Giorgio, Cristina, Baldoni, Monia, Ricci, Patrizia, Monti, Maria Chiara, Morretta, Elva, Zampella, Angela, Distrutti, Eleonora, Fiorucci, Stefano
• Format: Article
• Language: English
• Subjects: Animals; Chenodeoxycholic Acid - analogs & derivatives; Chenodeoxycholic Acid - pharmacology; Cholestasis; Cholestasis - complications; Cholestasis - genetics; Cholestasis - metabolism; Farnesoid-X-receptor; Hep G2 Cells; Humans; Liver - drug effects; Liver - metabolism; Liver Diseases - etiology; Liver Diseases - genetics; Liver Diseases - metabolism; MafG; MafG Transcription Factor - antagonists & inhibitors; MafG Transcription Factor - genetics; Male; Mice, Inbred C57BL; Mice, Knockout; NF-E2-Related Factor 2 - agonists; NF-E2-Related Factor 2 - genetics; Nrf2; Obeticholic acid; Rats, Wistar; Receptors, Cytoplasmic and Nuclear - agonists; Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors; Receptors, Cytoplasmic and Nuclear - genetics
• ISSN: 1388-1981; 1879-2618
• DOI: 10.1016/j.bbalip.2020.158733

The farnesoid-X-receptor (FXR) is validated target in the cholestatic disorders treatment. Obeticholic acid (OCA), the first in class of FXR agonist approved for clinical use, causes side effects including acute liver decompensation when administered to cirrhotic patients with primary biliary cholangitis at higher than recommended doses. The V-Maf avian-musculoaponeurotic-fibrosarcoma-oncogene-homolog-G (Mafg) and nuclear factor-erythroid-2-related-factor-2 (Nrf2) mediates some of the downstream effects of FXR. In the present study we have investigated the role of FXR/MafG/NRF2 pathway in the development of liver toxicity caused by OCA in rodent models of cholestasis. Cholestasis was induced by bile duct ligation (BDL) or administration of α-naphtyl-isothiocyanate (ANIT) to male Wistar rats and FXR−/− and FXR+/+ mice. Treating BDL and ANIT rats with OCA exacerbated the severity of cholestasis, hepatocytes injury and severely downregulated the expression of basolateral transporters. In mice, genetic ablation FXR or its pharmacological inhibition by 3-(naphthalen-2-yl)-5-(piperidin-4-yl)-1,2,4-oxadiazole rescued from negative regulation of MRP4 and protected against liver injury caused by ANIT. By RNAseq analysis we found that FXR antagonism effectively reversed the transcription of over 2100 genes modulated by OCA/ANIT treatment, including Mafg and Nrf2 and their target genes Cyp7a1, Cyp8b1, Mat1a, Mat2a, Gss. Genetic and pharmacological Mafg inhibition by liver delivery of siRNA antisense or S-adenosylmethionine effectively rescued from damage caused by ANIT/OCA. In contrast, Nrf2 induction by sulforaphane was protective. Liver injury caused by FXR agonism in cholestasis is FXR-dependent and is reversed by FXR and Mafg antagonism or Nrf2 induction. •OCA a FXR agonist, causes side effects when administered in cirrhotic PBC patients.•Mafg and Nrf2 mediates some of the downstream effects of FXR.•Treating BDL and ANIT rats and mice with OCA exacerbated the severity of cholestasis.•Mafg inhibition rescued from damage caused by ANIT/OCA.•Nrf2 induction by sulforaphane was protective from ANIT/OCA induced disease.