Andras Franko1, Marketa Kovarova1, Susanne Feil2, Robert Feil2, Robert Wagner1, Martin Heni1, Alfred Königsrainer3, Marc Ruoß4, Andreas K Nüssler4, Cora Weigert1, Hans-Ulrich Häring1, Stefan Z Lutz5, Andreas Peter1. 1. Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Otfried-Müller-Str 10, 72076 Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, University of Tübingen, Otfried-Müller-Str 10, 72076 Tübingen, Germany; German Center for Diabetes Research (DZD e.V.), Ingolstädter Landstraße 1, 85764 Neuherberg, Germany. 2. Interfakultäres Institut für Biochemie, University of Tübingen, Hoppe-Seyler-Str. 4, 72076 Tübingen, Germany. 3. Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Hoppe-Seyler-Straße 3, 72076 Tübingen, Germany. 4. Department of Traumatology, BG Trauma Clinic, Siegfried Weller Institute for Trauma Research, Eberhard Karls Universität Tübingen, Schnarrenbergstr. 95, 72076 Tübingen, Germany. 5. Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Otfried-Müller-Str 10, 72076 Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, University of Tübingen, Otfried-Müller-Str 10, 72076 Tübingen, Germany; German Center for Diabetes Research (DZD e.V.), Ingolstädter Landstraße 1, 85764 Neuherberg, Germany. Electronic address: stefan.lutz@med.uni-tuebingen.de.
Abstract
BACKGROUND: The activation of hepatic stellate cells (HSCs) plays a crucial role in liver fibrosis, however the role of HSCs is less understood in hepatic insulin resistance. Since in the liver cGMP-dependent protein kinase I (cGKI) was detected in HSC but not in hepatocytes, and cGKI-deficient mice that express cGKI selectively in smooth muscle but not in other cell types (cGKI-SM mice) displayed hepatic insulin resistance, we hypothesized that cGKI modulates HSC activation and insulin sensitivity. MATERIALS AND METHODS: To study stellate cell activation in cGKI-SM mice, retinol storage and gene expression were studied. Moreover, in the human stellate cell line LX2, the consequences of cGKI-silencing on gene expression were investigated. Finally, cGKI expression was examined in human liver biopsies covering a wide range of liver fat content. RESULTS: Retinyl-ester concentrations in the liver of cGKI-SM mice were lower compared to wild-type animals, which was associated with disturbed expression of genes involved in retinol metabolism and inflammation. cGKI-silenced LX2 cells showed an mRNA expression profile of stellate cell activation, altered matrix degradation and activated chemokine expression. On the other hand, activation of LX2 cells suppressed cGKI expression. In accordance with this finding, in human liver biopsies, we observed a negative correlation between cGKI mRNA and liver fat content. CONCLUSIONS: These results suggest that the lack of cGKI possibly leads to stellate cell activation, which stimulates chemokine expression and activates inflammatory processes, which could disturb hepatic insulin sensitivity.
BACKGROUND: The activation of hepatic stellate cells (HSCs) plays a crucial role in liver fibrosis, however the role of HSCs is less understood in hepatic insulin resistance. Since in the liver cGMP-dependent protein kinase I (cGKI) was detected in HSC but not in hepatocytes, and cGKI-deficient mice that express cGKI selectively in smooth muscle but not in other cell types (cGKI-SM mice) displayed hepatic insulin resistance, we hypothesized that cGKI modulates HSC activation and insulin sensitivity. MATERIALS AND METHODS: To study stellate cell activation in cGKI-SM mice, retinol storage and gene expression were studied. Moreover, in the human stellate cell line LX2, the consequences of cGKI-silencing on gene expression were investigated. Finally, cGKI expression was examined in human liver biopsies covering a wide range of liver fat content. RESULTS:Retinyl-ester concentrations in the liver of cGKI-SM mice were lower compared to wild-type animals, which was associated with disturbed expression of genes involved in retinol metabolism and inflammation. cGKI-silenced LX2 cells showed an mRNA expression profile of stellate cell activation, altered matrix degradation and activated chemokine expression. On the other hand, activation of LX2 cells suppressed cGKI expression. In accordance with this finding, in human liver biopsies, we observed a negative correlation between cGKI mRNA and liver fat content. CONCLUSIONS: These results suggest that the lack of cGKI possibly leads to stellate cell activation, which stimulates chemokine expression and activates inflammatory processes, which could disturb hepatic insulin sensitivity.
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