| First Author | Livingstone DE | Year | 2015 |
| Journal | Diabetes | Volume | 64 |
| Issue | 2 | Pages | 447-58 |
| PubMed ID | 25239636 | Mgi Jnum | J:246166 |
| Mgi Id | MGI:5922282 | Doi | 10.2337/db14-0249 |
| Citation | Livingstone DE, et al. (2015) 5alpha-Reductase type 1 deficiency or inhibition predisposes to insulin resistance, hepatic steatosis, and liver fibrosis in rodents. Diabetes 64(2):447-58 |
| abstractText | 5alpha-Reductase type 1 (5alphaR1) catalyses A-ring reduction of androgens and glucocorticoids in liver, potentially influencing hepatic manifestations of the metabolic syndrome. Male mice, homozygous for a disrupted 5alphaR1 allele (5alphaR1 knockout [KO] mice), were studied after metabolic (high-fat diet) and fibrotic (carbon tetrachloride [CCl4]) challenge. The effect of the 5alpha-reductase inhibitor finasteride on metabolism was investigated in male obese Zucker rats. While eating a high-fat diet, male 5alphaR1-KO mice demonstrated greater mean weight gain (21.6 +/- 1.4 vs 16.2 +/- 2.4 g), hyperinsulinemia (insulin area under the curve during glucose tolerance test 609 +/- 103 vs. 313 +/- 66 ng mL(-1) min), and hepatic steatosis (liver triglycerides 136.1 +/- 17.0 vs. 89.3 +/- 12.1 mumol g(-1)). mRNA transcript profiles in liver were consistent with decreased fatty acid beta-oxidation and increased triglyceride storage. 5alphaR1-KO male mice were more susceptible to fibrosis after CCl4 administration (37% increase in collagen staining). The nonselective 5alpha-reductase inhibitor finasteride induced hyperinsulinemia and hepatic steatosis (10.6 +/- 1.2 vs. 7.0 +/- 1.0 mumol g(-1)) in obese male Zucker rats, both intact and castrated. 5alphaR1 deficiency induces insulin resistance and hepatic steatosis, consistent with the intrahepatic accumulation of glucocorticoids, and predisposes to hepatic fibrosis. Hepatic steatosis is independent of androgens in rats. Variations in 5alphaR1 activity in obesity and with nonselective 5alpha-reductase inhibition in men with prostate disease may have important consequences for the onset and progression of metabolic liver disease. |
