title: Testosterone suppresses the expression of regulatory enzymes of fatty acid synthesis and protects against hepatic steatosis in cholesterol-fed androgen deficient mice.
abstract: OBJECTIVE
  Non-alcoholic fatty liver disease and its precursor hepatic steatosis is common in obesity and type-2 diabetes and is associated with cardiovascular disease (CVD). Men with type-2 diabetes and/or CVD have a high prevalence of testosterone deficiency. Testosterone replacement improves key cardiovascular risk factors. The effects of testosterone on hepatic steatosis are not fully understood.
  
  
  METHODS
  Testicular feminised (Tfm) mice, which have a non-functional androgen receptor (AR) and very low serum testosterone levels, were used to investigate testosterone effects on high-cholesterol diet-induced hepatic steatosis.
  
  
  RESULTS
  Hepatic lipid deposition was increased in Tfm mice and orchidectomised wild-type littermates versus intact wild-type littermate controls with normal androgen physiology. Lipid deposition was reduced in Tfm mice receiving testosterone treatment compared to placebo. Oestrogen receptor blockade significantly, but only partially, reduced the beneficial effects of testosterone treatment on hepatic lipid accumulation. Expression of key regulatory enzymes of fatty acid synthesis, acetyl-CoA carboxylase alpha (ACACA) and fatty acid synthase (FASN) were elevated in placebo-treated Tfm mice versus placebo-treated littermates and Tfm mice receiving testosterone treatment. Tfm mice on normal diet had increased lipid accumulation compared to littermates but significantly less than cholesterol-fed Tfm mice and demonstrated increased gene expression of hormone sensitive lipase, stearyl-CoA desaturase-1 and peroxisome proliferator-activated receptor-gamma but FASN and ACACA were not altered.
  
  
  CONCLUSIONS
  An action of testosterone on hepatic lipid deposition which is independent of the classic AR is implicated. Testosterone may act in part via an effect on the key regulatory lipogenic enzymes to protect against hepatic steatosis.
authors: Department of Human Metabolism, Medical School, Universiy of Sheffield, Sheffield, UK. Electronic address: daniel.kelly@sheffield.ac.uk.
authors: Daniel M
authors: DM
authors: Kelly
authors: Department of Human Metabolism, Medical School, Universiy of Sheffield, Sheffield, UK.
authors: Joanne E
authors: JE
authors: Nettleship
authors: Department of Human Metabolism, Medical School, Universiy of Sheffield, Sheffield, UK.
authors: Samia
authors: S
authors: Akhtar
authors: Department of Human Metabolism, Medical School, Universiy of Sheffield, Sheffield, UK; Centre for Diabetes and Endocrinology, Barnsley Hospital NHS Foundation Trust, Barnsley, UK.
authors: Vakkat
authors: V
authors: Muraleedharan
authors: Biomedical Research Centre, Sheffield Hallam University, Sheffield S1 1WB, UK.
authors: Donna J
authors: DJ
authors: Sellers
authors: Department of Human Metabolism, Medical School, Universiy of Sheffield, Sheffield, UK.
authors: Jonathan C
authors: JC
authors: Brooke
authors: Department of Human Metabolism, Medical School, Universiy of Sheffield, Sheffield, UK.
authors: David S
authors: DS
authors: McLaren
authors: Biomedical Research Centre, Sheffield Hallam University, Sheffield S1 1WB, UK; Department of Cardiology, Royal Hallamshire Hospital, Sheffield, UK.
authors: Kevin S
authors: KS
authors: Channer
authors: Department of Human Metabolism, Medical School, Universiy of Sheffield, Sheffield, UK; Centre for Diabetes and Endocrinology, Barnsley Hospital NHS Foundation Trust, Barnsley, UK.
authors: T Hugh
authors: TH
authors: Jones
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects*; D005227:Fatty Acids / Q000378:metabolism*; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D050155:Lipogenesis / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009154:Mutation; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: D005227:Fatty Acids; D011944:Receptors, Androgen; D013739:Testosterone; D002784:Cholesterol
keywords: Androgen receptor; Fatty liver; Lipid deposition; Lipogenesis; Testosterone