The GR-gp78 Pathway is Involved in Hepatic Lipid Accumulation

57 Glucocorticoids are essential participants in the regulation of lipid metabolism. On a tissue58 specific level, glucocorticoid signal is controlled by 11β-Hydroxysteroid dehydrogenase 1 59 (11β-HSD1). Up-regulation of 11β-HSD1 expression during non-alcoholic fatty liver disease 60 (NAFLD) has been previously shown, while 11β-HSD1 inhibition has conversely been 61 shown to reduce hepatic lipids in NAFLD, although the underlying mechanisms remain 62 unclear. Here, in this study, we created in vitro cell culture and in vivo transgenic hepatocyte63 specific 11β-HSD1 mouse models of NAFLD to determine the regulatory mechanisms of 64 11β-HSD1 during lipid metabolism dysfunction. We found that 11β-HSD1 overexpression 65 activated glucocorticoid receptors and promoted their nuclear translocation, thus stimulating 66 gp78. The induction of gp78 sharply reduced expression of Insig2, but not Insig1, which led 67 to up-regulation of lipogenesis regulatory proteins including SREBP1, FAS, SCD1, and 68