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

Abstract

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

The controversial role of mast cells in fibrosis

“…252 β2-AR agonists have been proposed as a treatment for fibrosis, 253 but activation of RTKs including Kit uncouples β2-ARs. 254,255 In fact, β2-AR agonists increased human lung MC mediator release in co-culture with human ASM cells, 256 [265][266][267] and heart. [268][269][270][271][272][273] Kit and SCF are also obvious targets.…”

Ca2+ signalling in fibroblasts and the therapeutic potential of KCa3.1 channel blockers in fibrotic diseases

“…Specifically, K Ca 3.1 inhibition promoted hepatocyte apoptosis and DNA damage and proliferation of hepatic stellate cells (Moller et al, 2016). In contrast, (Paka et al, 2017). In this model of diet-induced liver disease, senicapoc was anti-fibrotic, decreasing hepatic collagen accumulation.…”

“…These results were confirmed in mice and rats following CCL 4 ‐induced hepatic injury, where the degree of K Ca 3.1 gene expression increased during liver fibrogenesis and with progression of hepatic injury (Moller et al, ). Furthermore, K Ca 3.1 channel expression was also significantly increased in three rat models of liver fibrosis driven by a high‐fat diet, bile duct ligation or thioacetamide (Paka et al, ). Hepatic stellate cells express K Ca 3.1 and the expression is enhanced following activation with TGF‐β1 (Freise et al, ).…”

“…K Ca 3.1 channels have also been investigated in non‐alcoholic liver disease. Mice subjected to a modified high‐fat diet—an l ‐amino acid diet with 60% kcal from fat with 0.1% methionine and no added choline (CDAHFD)—had elevated K Ca 3.1 channel expression (Paka et al, ). In this model of diet‐induced liver disease, senicapoc was anti‐fibrotic, decreasing hepatic collagen accumulation.…”

“…In this model of diet‐induced liver disease, senicapoc was anti‐fibrotic, decreasing hepatic collagen accumulation. Interestingly, senicapoc also had anti‐steatotic effects, inhibiting hepatic triglyceride content in the CDAHFD (Paka et al, ).…”