Opposite effects of the FXR agonist obeticholic acid on Mafg and Nrf2 mediate the development of acute liver injury in rodent models of cholestasis.
作者： Adriana Carino , Michele Biagioli , Silvia Marchianò , Chiara Fiorucci , Martina Bordoni
DOI: 10.1016/J.BBALIP.2020.158733
关键词:
摘要: The farnesoid-X-receptor (FXR) is validated target in the cholestatic disorders treatment. Obeticholic acid (OCA), first 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. V-Maf avian-musculoaponeurotic-fibrosarcoma-oncogene-homolog-G (Mafg) and nuclear factor-erythroid-2-related-factor-2 (Nrf2) mediates some downstream FXR. In present study we have investigated role FXR/MafG/NRF2 pathway development toxicity caused by OCA rodent models cholestasis. Cholestasis was induced bile duct ligation (BDL) or administration α-naphtyl-isothiocyanate (ANIT) male Wistar rats FXR-/- FXR+/+ mice. Treating BDL ANIT exacerbated severity cholestasis, hepatocytes injury severely downregulated expression basolateral transporters. mice, genetic ablation its pharmacological inhibition 3-(naphthalen-2-yl)-5-(piperidin-4-yl)-1,2,4-oxadiazole rescued from negative regulation MRP4 protected against ANIT. By RNAseq analysis found that antagonism effectively reversed transcription over 2100 genes modulated OCA/ANIT treatment, Mafg Nrf2 their Cyp7a1, Cyp8b1, Mat1a, Mat2a, Gss. Genetic delivery siRNA antisense S-adenosylmethionine damage ANIT/OCA. contrast, induction sulforaphane protective. CONCLUSIONS: Liver agonism cholestasis FXR-dependent induction.
unipg.it
unisa.it参考文章(50)
A. James Hanje, Brett Fortune, Ming Song, Daniell Hill, Craig McClain, The use of selected nutrition supplements and complementary and alternative medicine in liver disease. Nutrition in Clinical Practice. ,vol. 21, pp. 255- 272 ,(2006) , 10.1177/0115426506021003255
Thomas Q de Aguiar Vallim, Elizabeth J Tarling, Hannah Ahn, Lee R Hagey, Casey E Romanoski, Richard G Lee, Mark J Graham, Hozumi Motohashi, Masayuki Yamamoto, Peter A Edwards, None, MAFG Is a Transcriptional Repressor of Bile Acid Synthesis and Metabolism Cell Metabolism. ,vol. 21, pp. 298- 311 ,(2015) , 10.1016/J.CMET.2015.01.007
Michael Trauner, James L. Boyer, Bile Salt Transporters: Molecular Characterization, Function, and Regulation Physiological Reviews. ,vol. 83, pp. 633- 671 ,(2003) , 10.1152/PHYSREV.00027.2002
Heping Yang, Kwangsuk Ko, Meng Xia, Tony W.H. Li, Pilsoo Oh, Jiaping Li, Shelly C. Lu, Induction of avian musculoaponeurotic fibrosarcoma proteins by toxic bile acid inhibits expression of glutathione synthetic enzymes and contributes to cholestatic liver injury in mice Hepatology. ,vol. 51, pp. 1291- 1301 ,(2010) , 10.1002/HEP.23471
Patrick R. Maloney, Derek J. Parks, Curt D. Haffner, Adam M. Fivush, Gyan Chandra, Kelli D. Plunket, Katrina L. Creech, Linda B. Moore, Joan G. Wilson, Michael C. Lewis, Stacey A. Jones, Timothy M. Willson, Identification of a chemical tool for the orphan nuclear receptor FXR. Journal of Medicinal Chemistry. ,vol. 43, pp. 2971- 2974 ,(2000) , 10.1021/JM0002127
Liam Baird, Albena T. Dinkova-Kostova, The cytoprotective role of the Keap1–Nrf2 pathway Archives of Toxicology. ,vol. 85, pp. 241- 272 ,(2011) , 10.1007/S00204-011-0674-5
J.W Fahey, P Talalay, Antioxidant functions of sulforaphane: a potent inducer of Phase II detoxication enzymes. Food and Chemical Toxicology. ,vol. 37, pp. 973- 979 ,(1999) , 10.1016/S0278-6915(99)00082-4
Shailendra Kumar Dhar Dwivedi, Nidhi Singh, Rashmi Kumari, Jay Sharan Mishra, Sarita Tripathi, Priyam Banerjee, Priyanka Shah, Vandana Kukshal, Abdul Malik Tyagi, Anil Nilkanth Gaikwad, Rajnish Kumar Chaturvedi, Durga Prasad Mishra, Arun Kumar Trivedi, Somali Sanyal, Naibedya Chattopadhyay, Ravishankar Ramachandran, Mohammad Imran Siddiqi, Arun Bandyopadhyay, Ashish Arora, Thomas Lundåsen, Sayee Priyadarshini Anakk, David D Moore, Sabyasachi Sanyal, None, Bile acid receptor agonist GW4064 regulates PPARγ coactivator-1α expression through estrogen receptor-related receptor α. Molecular Endocrinology. ,vol. 25, pp. 922- 932 ,(2011) , 10.1210/ME.2010-0512
Heping Yang, Komal Ramani, Meng Xia, Kwang Suk Ko, Tony W.H. Li, Pilsoo Oh, Jiaping Li, Shelly C. Lu, Dysregulation of glutathione synthesis during cholestasis in mice: Molecular mechanisms and therapeutic implications Hepatology. ,vol. 49, pp. 1982- 1991 ,(2009) , 10.1002/HEP.22908
Roberto Pellicciari, Stefano Fiorucci, Emidio Camaioni, Carlo Clerici, Gabriele Costantino, Patrick R. Maloney, Antonio Morelli, Derek J. Parks, Timothy M. Willson, 6α-Ethyl-Chenodeoxycholic Acid (6-ECDCA), a Potent and Selective FXR Agonist Endowed with Anticholestatic Activity Journal of Medicinal Chemistry. ,vol. 45, pp. 3569- 3572 ,(2002) , 10.1021/JM025529G