Department of Human Metabolism, Medical School, Universiy of Sheffield, Sheffield, UK.
Department of Human Metabolism, Medical School, Universiy of Sheffield, Sheffield, UK.
Life Sci. 2014 Jul 30;109(2):95-103. doi: 10.1016/j.lfs.2014.06.007. Epub 2014 Jun 20.
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.
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.
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.
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.
非酒精性脂肪性肝病及其前体肝脂肪变性在肥胖和 2 型糖尿病中很常见，并且与心血管疾病（CVD）有关。患有 2 型糖尿病和/或 CVD 的男性睾酮缺乏症的患病率很高。睾酮替代治疗可改善关键心血管危险因素。睾酮对肝脂肪变性的影响尚不完全清楚。
使用睾丸女性化（Tfm）小鼠，其雄激素受体（AR）无功能，血清睾酮水平极低，研究睾酮对高胆固醇饮食诱导的肝脂肪变性的影响。
与具有正常雄激素生理功能的完整野生型同窝对照相比，Tfm 小鼠和去势野生型同窝对照的肝脂质沉积增加。与安慰剂治疗相比，接受睾酮治疗的 Tfm 小鼠的脂质沉积减少。雌激素受体阻断显著但仅部分降低了睾酮治疗对肝脂质蓄积的有益作用。关键脂肪酸合成调节酶的表达，乙酰辅酶 A 羧化酶α（ACACA）和脂肪酸合酶（FASN）在安慰剂治疗的 Tfm 小鼠中均高于安慰剂治疗的同窝对照和接受睾酮治疗的 Tfm 小鼠。正常饮食的 Tfm 小鼠的脂质蓄积比同窝对照增加，但明显低于胆固醇喂养的 Tfm 小鼠，并表现出激素敏感脂肪酶、硬脂酰辅酶 A 去饱和酶-1 和过氧化物酶体增殖物激活受体-γ的基因表达增加，但 FASN 和 ACACA 没有改变。
提示存在一种独立于经典 AR 的睾酮对肝脂质沉积的作用。睾酮可能部分通过对关键调节脂肪生成酶的作用来防止肝脂肪变性。
