cGMP-dependent protein kinase 1 (cGK1) modulates human hepatic stellate cell activation

The activation of hepatic stellate cells (HSC) plays a crucial role in non-alcoholic fatty liver disease (NAFLD), which could further develop to non-alcoholic steatohepatitis (NASH) and liver fibrosis/cirrhosis. Since cGMP-dependent protein kinase 1 (cGK1) deficient (cGK1-KO) mice displayed hepatic insulin resistance we hypothesized that cGK1 modulates HSC activation and its metabolic consequences. First, retinol storage and gene expression were studied in cGK1-KO mice. Second, we investigated the effects of cGK1-silencing on gene expression in the human stellate cell line LX2. Finally, cGK1 expression was investigated in human liver biopsies covering a wide range of liver fat content. Retinyl-ester level in the liver of cGK1-KO mice was lower compared to wild-type animals, which was associated with increased inflammatory gene expression. mRNA regulation in cGK1-silenced LX2 cells showed stronger stellate cell activation profile, altered matrix degradation and elevated chemokine level. On the other hand, activation of LX2 cells suppressed cGK1 expression, which was associated with human data, showing a negative correlation between cGK1 mRNA and liver fat content in liver biopsies. These results suggest that the lack of cGK1 could possibly lead to stellate cell activation, which elevates chemokine expression and inflammatory processes, which in turn disturbs hepatic insulin sensitivity.

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