FXR modulators for enterohepatic and metabolic diseases

Wang, Hong; He, Qingxian; Wang, Guangji; Xu, Xiaowei; Hao, Haiping

doi:10.1080/13543776.2018.1527906

Cited by 69 publications

(53 citation statements)

References 111 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, a more recent clinical trial indicated that low dose (5–10 mg) of OCA exert little beneficial effect on liver fibrosis 11 . Thus, how to improve the clinical efficiency of OCA in a relative safe and low dosage is an urgent question to be solved 8 . In this study, we demonstrated that in combination with IDN-6556, another drug candidate for liver fibrosis, OCA could exert enhanced beneficial effect against fibrosis even at low dosage, providing a promising strategy for the therapy of liver fibrosis, and in the combination, OCA can be effective at low dosage with minimized side-effect.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Combined obeticholic acid and apoptosis inhibitor treatment alleviates liver fibrosis

Zhou

Huang

Guo

et al. 2019

Acta Pharmaceutica Sinica B

Self Cite

View full text Add to dashboard Cite

Obeticholic acid (OCA), the first FXR-targeting drug, has been claimed effective in the therapy of liver fibrosis. However, recent clinical trials indicated that OCA might not be effective against liver fibrosis, possibly due to the lower dosage to reduce the incidence of the side-effect of pruritus. Here we propose a combinatory therapeutic strategy of OCA and apoptosis inhibitor for combating against liver fibrosis. CCl 4 -injured mice, d-galactosamine/LPS (GalN/LPS)-treated mice and cycloheximide/TNF α (CHX/TNF α )-treated HepG2 cells were employed to assess the effects of OCA, or together with IDN-6556, an apoptosis inhibitor. OCA treatment significantly inhibited hepatic stellate cell (HSC) activation/proliferation and prevented fibrosis. Elevated bile acid (BA) levels and hepatocyte apoptosis triggered the activation and proliferation of HSCs. OCA treatment reduced BA levels but could not inhibit hepatocellular apoptosis. An enhanced anti-fibrotic effect was observed when OCA was co-administrated with IDN-6556. Our study demonstrated that OCA inhibits HSCs activation/proliferation partially by regulating BA homeostasis and thereby inhibiting activation of HSCs. The findings in this study suggest that combined use of apoptosis inhibitor and OCA at lower dosage represents a novel therapeutic strategy for liver fibrosis.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Obeticholic acid (OCA) is the first FXR modulator that has been licensed by the FDA and EMEA for primary biliary cholangitis (PBC) patients. Besides, trials of OCA in several other liver diseases, including fibrosis, are under way 8. , 9.…”

Section: Introductionmentioning

confidence: 99%

Combined obeticholic acid and apoptosis inhibitor treatment alleviates liver fibrosis

Zhou

Huang

Guo

et al. 2019

Acta Pharmaceutica Sinica B

Self Cite

View full text Add to dashboard Cite

show abstract

“…Natural BAs and OCA BAs are considered as important endogenous FXR agonists in different tissues. The potency of natural BAs to activate FXR follows the order CDCA>DCA>LCA>CA (Wang et al, 2018). Some studies have found that replacing the carboxylic group on the side chain of CDCA with 6a-alkyl significantly enhances its activating potency and efficacy on FXR, which is consistent with the hydrophobic nature of the pocket in FXR that is complementary to the 6a position (Pellicciari et al, 2006).…”

Section: Bile Acid Agonists and Its Analoguesmentioning

confidence: 68%

“…Therefore, increasingly more attention has been paid lately to the therapeutic role of FXR in cardiovascular physiology and pathology. Moreover, FXR also showed effective therapeutic effect on nonalcoholic fatty liver disease (NAFLD) and metabolic diseases including obesity, diabetes, and hypercholesterolemia (Wang et al, 2018). In this review, we will focus on the potential mechanisms of FXR agonists in the treatment of cardiometabolic disease.…”

Section: Introductionmentioning

confidence: 99%

Farnesoid X Receptor Agonists as Therapeutic Target for Cardiometabolic Diseases

Yang

Wang

et al. 2020

Front. Pharmacol.

View full text Add to dashboard Cite

Cardiometabolic diseases are characterized as a combination of multiple risk factors for cardiovascular disease (CVD) and metabolic diseases including diabetes mellitus and dyslipidemia. Cardiometabolic diseases are closely associated with cell glucose and lipid metabolism, inflammatory response and mitochondrial function. Farnesoid X Receptor (FXR), a metabolic nuclear receptor, are found to be activated by primary BAs such as chenodeoxycholic acid (CDCA), cholic acid (CA) and synthetic agonists such as obeticholic acid (OCA). FXR plays crucial roles in regulating cholesterol homeostasis, lipid metabolism, glucose metabolism, and intestinal microorganism. Recently, emerging evidence suggests that FXR agonists are functional for metabolic syndrome and cardiovascular diseases and are considered as a potential therapeutic agent. This review will discuss the pathological mechanism of cardiometabolic disease and reviews the potential mechanisms of FXR agonists in the treatment of cardiometabolic disease.

show abstract

“…FXR has been exploited as a promising target for the treatment of various liver diseases 11 , including liver fibrosis 12 . FXR agonists with diverse chemical structures were developed [13][14][15] , notably obeticholic acid (OCA) 16 , a representative FXR agonist, that was approved for primary biliary cholangitis (PBC) 17,18 . More recently, OCA completed phase III clinical trial for nonalcoholic steatohepatitis (NASH) with fibrosis.…”

mentioning

confidence: 99%

SUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis

Zhou

Cui

et al. 2020

Nat Commun

Self Cite

View full text Add to dashboard Cite

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 CCl 4 , 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.

show abstract

FXR modulators for enterohepatic and metabolic diseases

Cited by 69 publications

References 111 publications

Combined obeticholic acid and apoptosis inhibitor treatment alleviates liver fibrosis

Combined obeticholic acid and apoptosis inhibitor treatment alleviates liver fibrosis

Farnesoid X Receptor Agonists as Therapeutic Target for Cardiometabolic Diseases

SUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis

Contact Info

Product

Resources

About