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5 alpha-Reductase Type 1 Deficiency or Inhibition Predisposes to Insulin Resistance, Hepatic Steatosis, and Liver Fibrosis in Rodents

Research output: Contribution to journalArticle

Original languageEnglish
Pages (from-to)447-458
Number of pages12
JournalDiabetes
Volume64
Issue number2
Early online date19 Sep 2014
DOIs
Publication statusPublished - 22 Jan 2015

Abstract

5 alpha-Reductase type 1 (5 alpha R1) catalyses A-ring reduction of androgens and glucocorticoids in liver, potentially influencing hepatic manifestations of the metabolic syndrome. Male mice, homozygous for a disrupted 5aR1 allele (5aR1 knockout [KO] mice), were studied after metabolic (high-fat diet) and fibrotic (carbon tetrachloride [CCI4]) challenge. The effect of the 5 alpha-reductase inhibitor finasteride on metabolism was investigated in male obese Zucker rats. While eating a high-fat diet, male 5 alpha R1-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 mu mol . g(-1)). mRNA transcript profiles in liver were consistent with decreased fatty acid beta-oxidation and increased triglyceride storage. 5 alpha R1-KO male mice were more susceptible to fibrosis after CCI4 administration (37% increase in collagen staining). The nonselective 5a-reductase inhibitor finasteride induced hyperinsulinemia and hepatic steatosis (10.6 +/- 1.2 vs. 7.0 +/- 1.0 mu mol . g(-1)) in obese male Zucker rats, both intact and castrated. 5aR1 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 5 alpha R1 activity in obesity and with nonselective 5 alpha-reductase inhibition in men with prostate disease may have important 447 consequences for the onset and progression of metabolic liver disease.

    Research areas

  • 5-alpha Reductase Inhibitors, Animals, Cholestenone 5 alpha-Reductase, Dietary Fats, Enzyme Assays, Fatty Liver, Finasteride, Insulin Resistance, Liver Cirrhosis, Male, Mice, Mice, Knockout, RNA, Messenger, Rats, Weight Gain

ID: 18929174