Session: SAT 1-25-Glucocorticoid Actions & HPA Axis
Poster Board SAT-13
Method: Liver fibrotic responses were studied at intervals for up to 8 days after a 12 week period of twice weekly intraperitoneal carbon tetrachloride (CCL4) administration in male C57Bl6 mice with or without global 11βHSD1 deletion (KO) or administration (in food) of the selective murine 11βHSD1 inhibitor, UE2316. Immunohistochemistry, qPCR, Western blot and flow cytometry were conducted in liver. The fibrotic response of mouse HSCs to glucocorticoid treatment and 11βHSD1 inhibition was studied in in vitro.
Results: 11βHSD1 KO mice were protected from CCl4-induced hepatocyte injury (with lower serum transaminases), and had a similar inflammatory response to injury (macrophage counts and cytokine transcripts), yet had more profound fibrosis, with higher fibrillar collagen staining (A.U. of picrosirus red staining: KO 1.3±0.1 v.s. wild type 1.0 ±0.1 p=0.048 and A.U. of Collagen 1 staining: KO 1.2 ±0.1 v.s. wild type 1.0 ±0.1, p=0.039) and increased pro-fibrotic gene transcripts (aSMA 4-fold, p<0.04; Col1 ~2-fold, p<0.03; Timp1 8-fold, p<0.02) compared with wild type controls. Similar results were obtained in mice treated with the 11βHSD1 inhibitor UE2316 from the start of CCl4 administration. However, administration of UE2316 only during the 8 day recovery phase showed no effects on fibrosis, indicating that loss of 11βHSD1 during liver injury is important. In HSCs in vitro, both corticosterone and DHC inhibited aSMA, Col1 and MMP expression, with effects of DHC prevented by UE2316. HSCs from 11βHSD1 KO mice were prone to activation in vitro.
Conclusion: 11βHSD1 deficiency causes increased activation of HSCs following chemical injury and promotes liver fibrosis. Effects of 11βHSD1 inhibition, a potential therapy in metabolic syndrome, on tissue repair appear context-specific, with beneficial anti-fibrotic effects in adipose, anti-inflammatory effects in atherosclerosis, and improved tissue repair after myocardial infarction perhaps being offset by adverse outcomes in liver.
Nothing to Disclose: XZ, AP, PR, RA, MC, AM, SW, JI, BRW, ZM
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