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

被引：35

作者：

Carino, Adriana ^{[1
]}

Biagioli, Michele ^{[1
]}

Marchiano, Silvia ^{[1
]}

Fiorucci, Chiara ^{[1
]}

Bordoni, Martina ^{[1
]}

Roselli, Rosalinda ^{[2
]}

Di Giorgio, Cristina ^{[1
]}

Baldoni, Monia ^{[3
]}

Ricci, Patrizia ^{[1
]}

Monti, Maria Chiara ^{[4
]}

Morretta, Elva ^{[4
]}

Zampella, Angela ^{[2
]}

Distrutti, Eleonora ^{[5
]}

Fiorucci, Stefano ^{[1
]}

机构：

[1] Univ Perugia, Dipartimento Sci Biomed & Chirurg, Perugia, Italy

[2] Univ Napoli Federico II, Dipartimento Farm, Naples, Italy

[3] Univ Perugia, Dipartimento Med, Perugia, Italy

[4] Univ Salerno, Dipartimento Farm, Salerno, Italy

[5] Azienda Osped Perugia, SC Gastroenterol Epatol, Perugia, Italy

来源：

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS | 2020年 / 1865卷 / 09期

关键词：

Obeticholic acid; Farnesoid-X-receptor; Cholestasis; MafG; Nrf2; METHIONINE ADENOSYLTRANSFERASE; CHENODEOXYCHOLIC ACID; NUCLEAR RECEPTOR; POTENT; TRANSPORTERS; INDUCTION; PROTEINS; IDENTIFICATION; PHARMACOLOGY; EXPRESSION;

D O I：

10.1016/j.bbalip.2020.158733

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 a-naphtyl-iso- thiocyanate (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 Cyp7a, 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. Conclusions: Liver injury caused by FXR agonism in cholestasis is FXR-dependent and is reversed by FXR and Mafg antagonism or Nrf2 induction.

引用

页数：17

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[1] Interactions between hepatic Mrp4 and Sult2a as revealed by the constitutive androstane receptor and Mrp4 knockout mice [J].