The role of GJs in liver fibrogenesis was

The role of GJs in liver fibrogenesis was studied recently. Studies showed a significant decrease in liver fibrosis in Cx32 knockout mice compared to wild-type mice. Although the mechanism underlying this protective effect of Cx32 deletion is not clear, reduced oxidative stress was suggested as a possible explanation. In experimental models of cirrhosis induced by carbon tetrachloride, a downregulation of Cx32 was observed. In humans, reduced expression, as well as a re-localization from the membrane to the cytoplasm were also observed. This evidence argues for a protective role of Cx32.
In models of fibrosis such as after Schistosoma mansoni inoculation or common bile duct ligation,[23], [55], [86] Cx43 expression was increased while the expression of Cx26 and Cx32 decreased.[23], [55], [87], [88] By contrast, others have observed decreased expression,[84], [86] or aberrant Cx43 positioned within the cytoplasm of cells, after chronic carbon tetrachloride administration. Phenobarbital, which itself decreases GJs, is usually co-administrated to promote fibrosis, possibly explaining the observed discrepancy. Current evidence points towards a role of Cx43 in collagen matrix deposition. Administration of chronic carbon tetrachloride to Cx43 deficient mice resulted in a similar grade of fibrosis as observed in wild-type animals. Nevertheless, an intensification of collagen deposition and nodule formation with retraction of the liver mglur antagonist was more evident in Cx43 deficient animals. In apparent contradiction, another study evaluating the role of Cx43 in fibrosis, aimed at discriminating between GJs and hemichannels. In both cases when Cx43 was inhibited, mice treated chronically with thioacetamide exhibited less fibrosis. Additionally, the authors concluded that hemichannel blockade mediated reduced stellate cell activation and reduced deposition of collagen. To add more complexity, pannexins are involved in the transport of ATP to the extracellular space where it is converted to adenosine, which acts on its receptors to stimulate fibrosis. In another recent study, tenofovir, acting as a pannexin hemichannel blocker had a direct antifibrotic effect.
Cirrhosis and its complications
Cholestatic disease GJs are involved in bile secretion and regulation of bile flow,[116], [117], [118], [119] and any alteration in intercellular transmission of secondary messengers might be expected to result in cholestasis. After bile duct ligation, GJ expression was decreased.[120], [121] This was associated with a marked reduction in protein levels of Cx26 and Cx32,[23], [55], [87], [88] which seems to be related to the associated inflammatory response. In addition, an increase in cholestatic bile acids such as taurolithocholate, taurolithocholate-sulfate and taurochenodeoxycholate promotes the closed state of GJs and worsens intercellular communication, making cholestasis worse. However, the expression of Cx43 increases following bile duct ligation[55], [87] and after the development of cirrhosis.[23], [86] The protein expression of Cx43 was further increased following LPS challenge and reduced following treatment with anti-TNF drugs. These data suggest that the activation and infiltration of macrophages contribute to this adaptive response, which involves the in the synthesis and recycling of Cx43.
Non-alcoholic fatty liver disease Non-alcoholic fatty liver disease comprises a complex disease spectrum, including hepatic steatosis, non-alcoholic steatohepatitis (NASH), cirrhosis and eventually HCC. Intracellular signalling cascades favour the deposition of fat in hepatocytes and induce inflammation. Since GJs can modulate the transfer of molecules, Cxs potentially have an important role in NASH. Cx32 knockout rats with diet induced non-alcoholic fatty liver disease developed more pronounced oxidative stress, inflammation and liver injury than wild-type controls,[124], [125] suggesting that GJ plays a protective role by maintaining homeostasis through cell-to-cell communication. However, using specific peptides to block Cx hemichannels decreased triglycerides, cholesterol, and inflammatory markers compared to controls, in animals fed a high-fat diet. This apparently paradoxical observation may be explained by the fact that hemichannels are constitutively closed and open after a pathological stimulus contrary to Cx forming GJs. During injury different deleterious molecules are exchanged between the extracellular and intracellular environment of cells, so blocking hemichannels may be responsible for the beneficial phenotype reported in these studies. In keeping with this study, genetically modified obese rats treated with carbenoxolone, a non-specific blocker of Cx, had decreased liver steatosis, along with a significantly decreased body fat percentage, hypertriglyceridemia, hypercholesterolemia and insulin resistance.