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

JK Dowman, LJ Hopkins, GM Reynolds, MJ Armstrong, M Nasiri, N Nikolaou, Leonie Houten, Jenny Visser, SA Morgan, GG Lavery, A Oprescu, SG Hubscher, PN Newsome, JW Tomlinson

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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 5 alpha-reductase (5 alpha R) has a critical role in androgen and glucocorticoid action. We hypothesize that 5 alpha R 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, 5 alpha R1(-/-), 5 alpha R2(-/-) , 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. 5 alpha R1 and -2 were highly expressed in human liver, and 5 alpha R1 protein expression increased with severity of NAFLD. 5 alpha R1(-/-) (but not 5 alpha R2(-/-)) 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 5 alpha R2(-/-) and 0% of 5 alpha R1(-/-) mice (P < .05). 5 alpha R1 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.
Original languageUndefined/Unknown
Pages (from-to)4536-4547
Number of pages12
Issue number12
Publication statusPublished - 2013

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  • EMC MM-01-39-04

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