Abstract
Hepatic fibrosis can result as a pathological response to nonalcoholic steatohepatitis (NASH). Cirrhosis, the late stage of fibrosis, has been linked to poor survival and an increased risk of developing hepatocellular carcinoma, with limited treatment options available. Therefore, there is an unmet need for novel effective antifibrotic compounds. Cyclophilins are peptidyl-prolyl cis-trans isomerases that facilitate protein folding and conformational changes affecting the function of the targeted proteins. Due to their activity, cyclophilins have been presented as key factors in several stages of the fibrotic process. In this study, we investigated the antifibrotic effects of NV556, a novel potent sanglifehrin-based cyclophilin inhibitor, in vitro and in vivo. NV556 potential antifibrotic effect was evaluated in two well-established animal models of NASH, STAM, and methionine-choline-deficient (MCD) mice, as well as in an in vitro 3D human liver ECM culture of LX2 cells, a human hepatic stellate cell line. We demonstrate that NV556 decreased liver fibrosis in both STAM and MCD in vivo models and decreased collagen production in TGFβ1-activated hepatic stellate cells in vitro. Taken together, these results present NV556 as a potential candidate for the treatment of liver fibrosis.
Highlights
Hepatic fibrosis is a pathological response to chronic liver injuries, including chronic alcohol consumption, viral infections such as Hepatitis B (HBV) and C (HCV), or nonalcoholic fatty liver disease (NAFLD) and its severe form, nonalcoholic steatohepatitis (NASH)
We demonstrate that NV556 administration was able to decrease liver fibrosis in two distinct and well-established NASH in vivo models
NV556 is a potent sanglifehrin-based cyclophilin inhibitor that was produced by combination of bioengineering and semisynthetic approaches
Summary
Hepatic fibrosis is a pathological response to chronic liver injuries, including chronic alcohol consumption, viral infections such as Hepatitis B (HBV) and C (HCV), or nonalcoholic fatty liver disease (NAFLD) and its severe form, nonalcoholic steatohepatitis (NASH). NAFLD to NASH is marked by an excessive accumulation of fat in the liver, leading to necrosis and apoptosis of the hepatocytes, which coincide with the formation of liver fibrosis [1]. These events are characterized by inflammation and hepatic stellate cell (HSCs) activation, leading to tissue remodeling and repair with increased accumulation of fibrillar collagens, especially collagen I and III. Liver transplantation is the only curative treatment for patients with cirrhosis and its clinical complications. The activation of HSCs is characterized by the expression of α-smooth muscle actin (α-SMA) and type I collagen [4]
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