Endocrine Abstracts

Background: Liver fibrosis in cirrhosis is characterized by accumulation of extracellular matrix from activated hepatic stellate cells (HSCs). Glucocorticoids (GCs) limit HSC activation in vitro. Local GC levels are regulated by 11β-hydroxysteroid dehydrogenase-1 (11βHSD1) which converts inactive GCs (11-dehydrocorticosterone) into active GCs (corticosterone). In this study we hypothesized that 11βHSD1 could potentially inhibit liver fibrosis.

Method: 11βHSD1 levels in mouse models of liver injury were investigated. We studied liver fibrotic responses to carbon tetrachloride in mice with global 11βHSD1 deletion (KO) or with administration of a selective murine 11βHSD1 inhibitor, UE2316. Immunohistochemistry, qPCR, western blot and flow cytometry were used to analyse the liver response. Primary mouse HSCs were cultured in vitro to investigate the effect of 11βHSD1.

Results: 11βHSD1 mRNA and protein levels were decreased concurrently with peak fibrosis and later recovered in liver injury models. Despite lower indices of hepatocyte injury, 11βHSD1 KO mice had exaggerated fibrosis with increased collagen deposition (Col I) and HSC activation (aSMA+). The fibrotic response persisted after injury. An array of profibrotic genes (Col1, aSMA, Tgfb) and genes involved in ECM remodelling (MMP2, MMP9, Timp1) were highly up-regulated in the 11βHSD1 KO mice. In the resolution phase 11βHSD1 KO mice showed an impairment in ‘resolving macrophages’ populations (decreased F4/80^int cd11b^hi ly6C^lo macrophage ratio). Findings were similar after UE2316 administration during injury. In vitro studies showed 11βHSD1 deficient HSCs were more activated than wild type after 8 days in culture and this activation was inhibited by 11-dehydrocorticosterone and corticosterone.

Conclusion: Loss of GCs regenerated within the liver by 11βHSD1 may contribute to unrestrained activation of HSCs following chemical injury and promote liver fibrosis. This contrasts with anti-fibrotic effects of 11βHSD1 deficiency in adipose. Context-specific effects of 11βHSD1 inhibitors on inflammation and repair deserve careful further scrutiny.

Declaration of funding: British Heart Foundation(BHF); Translational Medicine Research Initiative (TMRI); Medical Research Council (MRC); China Scholarship Council (CSC).