SUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis

  • Nat Commun. 2020 Jan 13;11(1):240. doi: 10.1038/s41467-019-14138-6.
Jiyu Zhou  1 ,  Shuang Cui  1 ,  Qingxian He  1 ,  Yitong Guo  1 ,  Xiaojie Pan  1 ,  Pengfei Zhang  1 ,  Ningning Huang  1 ,  Chaoliang Ge  1  2 ,  Guangji Wang  3 ,  Frank J Gonzalez  4 ,  Hong Wang  5 ,  Haiping Hao  6
Affiliations
  • 1. State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 210009, Nanjing, China.
  • 2. Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, 230022, Hefei, China.
  • 3. State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 210009, Nanjing, China. [email protected].
  • 4. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
  • 5. State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 210009, Nanjing, China. [email protected].
  • 6. State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 210009, Nanjing, China. [email protected].
PMID: 31932588 DOI: 10.1038/s41467-019-14138-6
Abstract

Farnesoid X receptor (FXR) is a promising target for nonalcoholic steatohepatitis (NASH) and fibrosis. Although various FXR agonists have shown anti-fibrotic effects in diverse preclinical animal models, the response rate and efficacies in clinical trials were not optimum. Here we report that prophylactic but not therapeutic administration of obeticholic acid (OCA) prevents hepatic stellate cell (HSC) activation and fibrogenesis. Activated HSCs show limited response to OCA and Other FXR agonists due to enhanced FXR SUMOylation. SUMOylation inhibitors rescue FXR signaling and thereby increasing the efficacy of OCA against HSC activation and fibrosis. FXR upregulates Perilipin-1, a direct target gene of FXR, to stabilize lipid droplets and thereby prevent HSC activation. Therapeutic coadministration of OCA and SUMOylation inhibitors drastically impedes liver fibrosis induced by CCl4, bile duct ligation, and more importantly NASH. In conclusion, we propose a promising therapeutic approach by combining SUMOylation inhibitors and FXR agonists for liver fibrosis.

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