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World J Gastroenterol. 2017 Jun 21;23(23):4181-4190. doi: 10.3748/wjg.v23.i23.4181.

Anti-steatotic and anti-fibrotic effects of the KCa3.1 channel inhibitor, Senicapoc, in non-alcoholic liver disease.

Author information

1
Latha Paka, David E Smith, Dawoon Jung, Siobhan McCormack, Ping Zhou, Bin Duan, Jing-Song Li, Jiaqi Shi, Yong-Jie Hao, Kai Jiang, Michael Yamin, Itzhak D Goldberg, Prakash Narayan, Department of Research and Development, Angion Biomedica Corp., Uniondale, NY 11553, United States.

Abstract

AIM:

To evaluate a calcium activated potassium channel (KCa3.1) inhibitor attenuates liver disease in models of non-alcoholic fatty liver disease (NAFLD).

METHODS:

We have performed a series of in vitro and in vivo studies using the KCa3.1 channel inhibitor, Senicapoc. Efficacy studies of Senicapoc were conducted in toxin-, thioacetamide (TAA) and high fat diet (HFD)-induced models of liver fibrosis in rats. Efficacy and pharmacodynamic effects of Senicapoc was determined through biomarkers of apoptosis, inflammation, steatosis and fibrosis.

RESULTS:

Upregulation of KCa3.1 expression was recorded in TAA-induced and high fat diet-induced liver disease. Treatment with Senicapoc decreased palmitic acid-driven HepG2 cell death. (P < 0.05 vs control) supporting the finding that Senicapoc reduces lipid-driven apoptosis in HepG2 cell cultures. In animals fed a HFD for 6 wk, co-treatment with Senicapoc, (1) reduced non-alcoholic fatty liver disease (NAFLD) activity score (NAS) (0-8 scale), (2) decreased steatosis and (3) decreased hepatic lipid content (Oil Red O, P < 0.05 vs vehicle). Randomization of TAA animals and HFD fed animals to Senicapoc was associated with a decrease in liver fibrosis as evidenced by hydroxyproline and Masson's trichrome staining (P < 0.05 vs vehicle). These results demonstrated that Senicapoc mitigates both steatosis and fibrosis in liver fibrosis models.

CONCLUSION:

These data suggest that Senicapoc interrupts more than one node in progressive fatty liver disease by its anti-steatotic and anti-fibrotic activities, serving as a double-edged therapeutic sword.

KEYWORDS:

Fibrosis; High fat diet; Inflammation; KCa3.1 channel; Liver; Senicapoc; Steatosis

PMID:
28694658
PMCID:
PMC5483492
DOI:
10.3748/wjg.v23.i23.4181
[Indexed for MEDLINE]
Free PMC Article

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