Inhibition of 11β-hydroxysteroid dehydrogenase 1 relieves fibrosis through depolarizing of hepatic stellate cell in NASH

11 beta-hydroxysteroid dehydrogenase type 1 (11 beta HSD1) is a key enzyme that catalyzes the intracellular conversion of cortisone to physiologically active cortisol. Although 11 beta HSD1 has been implicated in numerous metabolic syndromes, such as obesity and diabetes, the functional roles of 11 beta HSD1 during progression of nonalcoholic steatohepatitis (NASH) and consequent fibrosis have not been fully elucidated. We found that pharmacological and genetic inhibition of 11 beta HSD1 resulted in reprogramming of hepatic stellate cell (HSC) activation via inhibition of p-SMAD3, alpha-SMA, Snail, and Col1A1 in a fibrotic environment and in multicellular hepatic spheroids (MCHSs). We also determined that 11 beta HSD1 contributes to the maintenance of NF-kappa B signaling through modulation of TNF, TLR7, ITGB3, and TWIST, as well as regulating PPAR alpha signaling and extracellular matrix accumulation in activated HSCs during advanced fibrogenesis in MCHSs. Of great interest, the 11 beta HSD1 inhibitor J2H-1702 significantly attenuated hepatic lipid accumulation and ameliorated liver fibrosis in diet- and toxicity-induced NASH mouse models. Together, our data indicate that J2H-1702 is a promising new clinical candidate for the treatment of NASH.