Endocrine Abstracts

5α-Reductase 1 (5aR1) catalyses A-ring reduction of glucocorticoids and androgens, predominantly in liver and modulates steroid hormone action. We previously demonstrated transgenic disruption of 5aR1 predisposes mice to developing fatty liver. Here we tested whether 5aR1 disruption increases susceptibility to the development of liver injury, using the carbon tetrachloride induced liver fibrosis model.

Male 5aR1−/− (KO) mice and wild-type controls (WT) were studied aged 4–5 months following 6 weeks of twice-weekly injection of carbon tetrachloride (CCl−₄; 0.3 μl/g) or vehicle (olive oil); n=4−8/group. Liver fibrosis was assessed by picrosirius red staining (PSR) of collagen in fixed liver sections and quantified by pixel counting. Plasma and liver triglycerides were measured colourimetrically and liver RNA transcripts quantified by real-time PCR. Data are mean±S.E.M.; *P<0.05.

Body weight was not different between WT and KO mice, and was not altered by 6 weeks CCl−₄ treatment. However, collagen deposition stimulated by CCl−₄ treatment was more marked in KO than WT (6575±873 vs 4776±398 pixels*). Liver weight was not different between WT and KO, but triglyceride content was higher in KO (24.5±2.3 vs 16.1±1.6 nmol/mg*). CCl−₄ did not alter liver weight or triglyceride content in WT, but reduced liver weight (19%*) and depleted liver triglyceride (60%*) in KO. Plasma triglyceride concentration was correspondingly increased in CCl−₄ treated KO (80% vs KO-vehicle* and 43% vs WT- CCl₄*). CCl−₄ increased RNA for pro-fibrotic α-SMA and TIMP-1 (12-* and 3-fold* respectively), but there was no differential effect between WT and KO.

In summary, disruption of 5aR1 is associated with fatty liver and increased susceptibility to liver injury in the CCl4 induced liver fibrosis model. This more severe injury is associated with depletion of liver triglycerides coupled with a rise in circulating triglycerides. The mechanism underpinning the increased injury is not clear, but may have important implications for patients being treated with 5aR inhibitors.

Declaration of funding

This work was supported by the British Heart Foundation.