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

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...

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Published in:World journal of gastroenterology : WJG 2017-06, Vol.23 (23), p.4181-4190
Main Authors: Paka, Latha, Smith, David E, Jung, Dawoon, McCormack, Siobhan, Zhou, Ping, Duan, Bin, Li, Jing-Song, Shi, Jiaqi, Hao, Yong-Jie, Jiang, Kai, Yamin, Michael, Goldberg, Itzhak D, Narayan, Prakash
Format: Article
Language:English
Subjects:
Acetamides - pharmacology
Animals
Apoptosis
Basic Study
Biomarkers, Tumor - metabolism
Diet, High-Fat
Fibrosis
Gene Expression Regulation, Neoplastic
Hep G2 Cells
Humans
Inflammation
Intermediate-Conductance Calcium-Activated Potassium Channels - antagonists & inhibitors
Intermediate-Conductance Calcium-Activated Potassium Channels - metabolism
Liver Cirrhosis - metabolism
Male
Mice
Mice, Inbred C57BL
Non-alcoholic Fatty Liver Disease - drug therapy
Palmitic Acid
Rats
Rats, Wistar
Thioacetamide
Trityl Compounds - pharmacology
Up-Regulation
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Summary: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 aciddriven Hep G2 cell death.(P < 0.05 vs control) supporting the finding that Senicapoc reduces lipiddriven apoptosis in Hep G2 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.
ISSN:1007-9327
2219-2840
DOI:10.3748/wjg.v23.i23.4181