Testosterone suppresses the expression of regulatory enzymes of fatty acid synthesis and protects against hepatic steatosis in cholesterol-fed androgen deficient mice.
AIMS
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.


MAIN 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.


KEY FINDINGS
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.


SIGNIFICANCE
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.
['Kelly|Daniel M|DM|', 'Nettleship|Joanne E|JE|', 'Akhtar|Samia|S|', 'Muraleedharan|Vakkat|V|', 'Sellers|Donna J|DJ|', 'Brooke|Jonathan C|JC|', 'McLaren|David S|DS|', 'Channer|Kevin S|KS|', 'Jones|T Hugh|TH|']
D000818:Animals D002784:Cholesterol D015536:Down-Regulation D005227:Fatty Acids D005234:Fatty Liver D006801:Humans D050155:Lipogenesis D008099:Liver D008297:Male D051379:Mice D009154:Mutation D011944:Receptors, Androgen D013739:Testosterone
Testosterone Fatty liver Androgen receptor Lipid deposition Lipogenesis