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5α-Reductase type 1 deficiency or inhibition predisposes to insulin resistance, hepatic steatosis, and liver fibrosis in rodents

Lookup NU author(s): Professor Brian Walker

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Abstract

© 2015 by the American Diabetes Association.5α-Reductase type 1 (5αR1) catalyses A-ring reduction of androgens and glucocorticoids in liver, potentially influencing hepatic manifestations of the metabolic syndrome. Male mice, homozygous for a disrupted 5αR1 allele (5αR1 knockout [KO] mice), were studied after metabolic (high-fat diet) and fibrotic (carbon tetrachloride [CCl4]) challenge. The effect of the 5α-reductase inhibitor finasteride on metabolism was investigated in male obese Zucker rats. While eating a high-fat diet, male 5αR1-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 mmol $ g-1). mRNA transcript profiles in liver were consistent with decreased fatty acid β-oxidation and increased triglyceride storage. 5αR1-KO male mice were more susceptible to fibrosis after CCl4 administration (37% increase in collagen staining). The nonselective 5α-reductase inhibitor finasteride induced hyperinsulinemia and hepatic steatosis (10.6 ± 1.2 vs. 7.0 ± 1.0 mmol $ g-1) in obese male Zucker rats, both intact and castrated. 5αR1 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 5αR1 activity in obesity and with nonselective 5α-reductase inhibition in men with prostate disease may have important consequences for the onset and progression of metabolic liver disease. Acknowledgments. The authors thank Dr. Mala Mahendroo (University of Texas Southwestern Medical Center, Dallas, TX) for her support. The authors also thank the Wellcome Trust and British Heart Foundation for their financial support; Carolynn Cairns, Scott Denham, Karen French, Jill Harrison, Sanjay Kothiya, and Rachel McDonnell (University of Edinburgh) for excellent technical support; the staff of the Genetic Screening and Intervention Technologies, University of Edinburgh, for rederivation services; the Histology Shared University Research Facilities, University of Edinburgh, for histology services; and the Wellcome Trust Clinical Research Facility Mass Spectrometry Core Laboratory (University of Edinburgh) for analytical support.


Publication metadata

Author(s): Livingstone DEW, Barat P, Di Rollo EM, Rees GA, Weldin BA, Rog-Zielinska EA, Macfarlane DP, Walker BR, Andrew R

Publication type: Article

Publication status: Published

Journal: Diabetes

Year: 2015

Volume: 64

Issue: 2

Pages: 447-458

Print publication date: 01/02/2015

Online publication date: 22/01/2015

Acceptance date: 29/08/2014

ISSN (print): 0012-1797

ISSN (electronic): 1939-327X

Publisher: American Diabetes Association Inc.

URL: https://doi.org/10.2337/db14-0249

DOI: 10.2337/db14-0249

PubMed id: 25239636


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