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

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


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.

MeSH terms

  • Acetamides / pharmacology*
  • Animals
  • Apoptosis
  • 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


  • Acetamides
  • Biomarkers, Tumor
  • Intermediate-Conductance Calcium-Activated Potassium Channels
  • Kcnn4 protein, rat
  • Trityl Compounds
  • Thioacetamide
  • Palmitic Acid
  • senicapoc