Loss of 5α-Reductase Type 1 Accelerates the Development of Hepatic Steatosis but Protects Against Hepatocellular Carcinoma in Male Mice

Abstract

Nonalcoholic fatty liver disease (NAFLD) has been associated with glucocorticoid excess and androgen deficiency, yet in the majority of patients with steatohepatitis, circulating cortisol and androgen levels are normal. The enzyme 5α-reductase (5αR) has a critical role in androgen and glucocorticoid action. We hypothesize that 5αR has an important role in the pathogenesis of steatohepatitis through regulation of intracrine/paracrine hormone availability. Human liver samples from patients with NAFLD and normal donor tissue were used for gene expression and immunohistochemical analysis. NAFLD samples were scored using the Kleiner classification. In addition, 5αR1−/−, 5αR2−/−, and wild-type (WT) mice were fed normal chow or American lifestyle-induced obesity syndrome (ALIOS) diet for 6 or 12 months. Liver histology was graded and staged. Hepatic and circulating free fatty acid and triglyceride levels were quantified, and gene and protein expression was measured by real-time PCR and immunohistochemistry. 5αR1 and -2 were highly expressed in human liver, and 5αR1 protein expression increased with severity of NAFLD. 5αR1−/− (but not 5αR2−/−) mice fed an ALIOS diet developed greater hepatic steatosis than WT mice, and hepatic mRNA expression of genes involved in insulin signaling was decreased. Furthermore, 60% of WT mice developed focal hepatocellular lesions consistent with hepatocellular carcinoma after 12 months of the ALIOS diet, compared with 20% of 5αR2−/− and 0% of 5αR1−/− mice (P < .05). 5αR1 deletion accelerates the development of hepatic steatosis but may protect against the development of NAFLD-related hepatocellular neoplasia and therefore has potential as a therapeutic target.

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

“…However, the drive to accumulate lipid was still evident in the transcriptional profile, with downregulation of Ppara and its regulator Pgc1a typical of less oxidation and increased fatty acid synthase. Markers of hepatic stellate cell activation increased to the same extent in WT and 5aR1-KO mice, similar to the findings of Dowman et al (19). The development of liver fibrosis represents a balance between matrix deposition and collagen synthesis and resorption.…”

“…Some enzymes involved with collagen cross-linking were suppressed in 5aR1-KO mice, which may have influence on protein stability and solubility. These data are complementary to those of Dowman et al (19), who found that in mice fed an ALIOS diet hepatic triglycerides accumulated over a 6-month period, but that at a later stage, when fibrosis had developed, the excess lipid was depleted, although we did not assess liver histology in 5aR1-KO mice being fed a high-fat diet.…”

“…Others have reported recently that the 5aR1-KO mice are more susceptible to hepatocellular carcinoma after prolonged feeding (12 months) on the American lifestyle-induced obesity syndrome (ALIOS) diet (19), and that liver transcript changes in 5aR1-KO mice overlap with those induced by the administration of glucocorticoids rather than androgens (19). Given that we have demonstrated impaired hepatic metabolic clearance of corticosterone in 5aR1-KO mice (11) and persistence of the effect of finasteride in GDX rats, we conclude that local glucocorticoid excess is the most likely mechanism underpinning hepatic steatosis in 5aR1 deficiency or inhibition; combined alterations in androgen and/or glucocorticoid signaling may contribute to other aspects of the adverse metabolic phenotype.…”

“…Importantly, these transcript profile changes with 5aR1 deficiency do not support increased lipogenesis, contrasting with the hepatic androgen receptor KO mouse (39), emphasizing that our findings are inconsistent with the effects of 5aR1 being mediated solely through local androgen deficiency. While the disruption of 5aR1 in mice was associated with a constellation of exaggerated features of the metabolic syndrome, it is worth noting that from the age of 5 months control mice on the mixed C57BL6/SvEv/129 background were starting to increase adipose tissue and become insulin resistant; and, indeed, mice on this genetic background appear relatively resistant to metabolic challenge (19). Accordingly, some of the changes in the WT mice brought about by high-fat feeding during the period of study were modest, perhaps indicating the resistance of this strain to ad libitum high-fat feeding.…”

“…We have previously demonstrated that mice deficient in 5aR1 accumulate excess glucocorticoid in liver and adipose (11), which may have direct consequences for glucocorticoid receptor activation. A recent report (19) shows that mice lacking 5aR1 are more prone to hepatic steatosis, but with no apparent differences in body fat distribution or insulin sensitivity and with protection from hepatocellular carcinoma; the mechanisms remain unclear, in particular the independent roles of glucocorticoid and androgen metabolism. However, they are important to elucidate as the finding that deficiency in 5aR1 adversely affects metabolism translates into human health.…”