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

Abstract

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 μmol ⋅ 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 μmol ⋅ 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.

Adverse effects of 5α-reductase inhibitors: What do we know, don’t know, and need to know?

“…The marked increase in susceptibility to steatosis increased the susceptibility to fibrotic liver injury. These observations suggest that 5α-R type 1 deficiency or inhibition may contributed to enhanced progression of non-alcoholic fatty liver disease [151,152]. Thus, it can be hypothesized that the inhibition of the aforementioned regulatory enzymes may result in an imbalance in steroid metabolism and clearance rates, ultimately purtrubing physiological processes.…”

“…Since impaired insulin sensitivity predicts future risk of type 2 diabetes mellitus [150], the authors pointed out that in older men with already impaired insulin sensitivity might be more susceptible to the metabolic consequences of 5α-Rs inhibition. A recent preclinical study in 5α-R type 1deficient mice, demonstrated that this enzyme plays a key role in predisposition to metabolic disease, modulating hepatic steatosis and body fat distribution and insulin sensitivity [151,152]. The marked increase in susceptibility to steatosis increased the susceptibility to fibrotic liver injury.…”

Glucocorticoids and non-alcoholic fatty liver disease

“…Interestingly, these animals were also entirely protected from the development of NAFLD associated hepatocellular carcinoma, although the mechanisms that underpin these observations have not been elucidated. Additional studies using differing dietary interventions as well as pharmacological inhibition have also demonstrated hepatic steatosis and increased fibrosis in 5αR1 KO mice (122). It remains to be determined whether these effects are mediated exclusively by actions upon GC availability, or whether modulation of androgen availability has an additional role to play.…”

5α-Reductase inhibitors alter steroid metabolism and may contribute to insulin resistance, diabetes, metabolic syndrome and vascular disease: a medical hypothesis

“…Recent studies demonstrated that 5αR type 1 deficiency induces insulin resistance and hepatic steatosis and predisposes to hepatic fibrosis [54]. We speculate that finasteride and dutasteride interfere with androgen and GC metabolism and may contribute to alterations in carbohydrate metabolism, insulin sensitivity, diabetes, and their vascular sequelae.…”