Background: Nonalcoholic fatty liver disease and hepatic insulin resistance precede diabetes and may further develop into nonalcoholic steatohepatitis and liver fibrosis/cirrhosis. The activation of hepatic stellate cells (HSC), which is characterized by the loss of retinyl-ester stores, plays a crucial role in the pathophysiology of this process. Since cGMP-dependent protein kinase I (cGKI) deficient (cGKI-KO) mice displayed hepatic insulin resistance and disturbed glucose metabolism, as well as, cGKI is only detected in HSC but not in hepatocytes, we hypothesized that cGKI modulates HSC activation and its metabolic consequences.

Methods: First, retinol storage and gene expression were studied in cGKI-KO mice. Second, we investigated the effects of cGKI-silencing on gene expression and cellular activation in the human stellate cell line LX2. Finally, cGKI expression was investigated in human liver biopsies covering a wide range of liver fat content.

Results: Retinyl-ester level in the liver of cGKI-KO mice was lower compared to wild type animals, which was associated with increased inflammatory gene expression. Activation of LX2 cells showed increased α-smooth muscle actin and matrix metalloproteinase 2 expression, which was augmented by silencing cGKI. On the other hand, activation of LX2 cells by TGFβ suppressed cGKI expression. Furthermore, we detected a negative correlation between cGKI mRNA and liver fat content in human biopsies.

Conclusions: The lower mRNA level of cGKI either in TGFβ activated LX2 cells or in liver biopsies with high fat content suggest that cGKI function might be impaired during HSC activation. Furthermore, the higher expression of inflammatory genes and low retinyl-ester levels in cGKI-KO mice as well as the higher levels of activation markers in cGKI-silenced LX2 cells indicate that cGKI inhibits HSC activation. Since cGKI is a downstream target of nitric oxide (NO), it is conceivable that NO may exert protective effects inhibiting liver fibrosis via cGKI.


A. Franko: None. M. Kovarova: None. R. Wagner: None. C. Weigert: None. R. Feil: None. S. Feil: None. H. Haering: None. S.Z. Lutz: None. A. Peter: None.

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