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Loss of 5α-reductase type 1 accelerates the development of hepatic steatosis but protects against hepatocellular carcinoma in male mice.
Dowman, Joanna K; Hopkins, Laurence J; Reynolds, Gary M; Armstrong, Matthew J; Nasiri, Maryam; Nikolaou, Nikolaos; van Houten, E Leonie A F; Visser, Jenny A; Morgan, Stuart A; Lavery, Gareth G; Oprescu, Andrei; Hübscher, Stefan G; Newsome, Philip N; Tomlinson, Jeremy W.
Afiliação
  • Dowman JK; PhD, FRCP, Centre for Endocrinology, Diabetes, and Metabolism, School of Clinical and Experimental Medicine, Institute of Biomedical Research, University of Birmingham, Queen Elizabeth Hospital, Birmingham B15 2TT, United Kingdom. J.W.Tomlinson@bham.ac.uk.
Endocrinology ; 154(12): 4536-47, 2013 Dec.
Article em En | MEDLINE | ID: mdl-24080367
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: 3-Oxo-5-alfa-Esteroide 4-Desidrogenase / Regulação Enzimológica da Expressão Gênica / Carcinoma Hepatocelular / Fígado Gorduroso / Neoplasias Hepáticas Limite: Animals / Humans / Male Idioma: En Revista: Endocrinology Ano de publicação: 2013 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: 3-Oxo-5-alfa-Esteroide 4-Desidrogenase / Regulação Enzimológica da Expressão Gênica / Carcinoma Hepatocelular / Fígado Gorduroso / Neoplasias Hepáticas Limite: Animals / Humans / Male Idioma: En Revista: Endocrinology Ano de publicação: 2013 Tipo de documento: Article