Glucocorticoids are essential participants in the regulation of lipid metabolism. On a tissue-specific level, glucocorticoid signal is controlled by 11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1). Up-regulation of 11β-HSD1 expression during non-alcoholic fatty liver disease (NAFLD) has been previously shown, while 11β-HSD1 inhibition has been shown to reduce hepatic lipids in NAFLD, but the underlying mechanisms remain unclear. Here, in this study, we created in vitro cell culture and in vivo transgenic hepatocyte-specific 11β-HSD1 mouse models of NAFLD to determine the regulatory mechanisms of 11β-HSD1 during lipid metabolism dysfunction. We found that 11β-HSD1 overexpression activated glucocorticoid receptors and promoted their nuclear translocation, and then stimulating gp78. The induction of gp78 sharply reduced expression of Insig2, but not Insig1, which led to up-regulation of lipogenesis regulatory proteins including SREBP1, FAS, SCD1, and ACC1. Our results suggested that overexpression of 11β-HSD1 induced lipid accumulation, at least partially through the GR/gp78/Insig2/SREBP1 pathway, which may serve as a potential diagnostic and therapeutic target for treatment of NAFLD.
Keywords: 11β-HSD1; Insig2/SREBP1; glucocorticoid receptor; gp78; non-alcoholic fatty liver disease..
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