A selective estrogen receptor α agonist ameliorates hepatic steatosis in the male aromatase knockout mouse
A selective estrogen receptor α agonist ameliorates hepatic steatosis in the male aromatase knockout mouse
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DOI：
10.1530/joe-10-0462
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发表时间：
2011-09-01
影响因子：
4
通讯作者：
Boon, Wah Chin
中科院分区：
文献类型：
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作者：
Chow, Jenny D. Y.;Jones, Margaret E. E.;Boon, Wah Chin
雄性芳香酶基因敲除小鼠(ARKO；雌激素缺乏模型)出现男性特有的肝脏脂肪变性，经17β-雌二醇替代后可逆转。本研究旨在阐明雌激素受体(ER)亚型，ERα或ERβ，参与调节肝脏甘油三酯(TG)的动态平衡。9月龄雄性Arko小鼠通过皮下注射Vehicle、ERα或ERβ特异性激动剂。每日注射，连续6周。用ERα激动剂处理的雄性ARKO小鼠与赋形剂处理的ARKO小鼠相比，肝脏组织学和TG含量正常；大网膜(性腺)和肾下(内脏)脂肪垫重量与赋形剂处理的野生型(WT)小鼠的体重正常化。相反，ERβ激动剂治疗并没有导致这些Arko表型的类似逆转。在赋形剂治疗的ARKO小鼠中，肝脏脂肪酸合成酶(FASN)和硬脂酰辅酶A脱饱和酶1的转录表达显著高于赋形剂治疗的WT，但经ERα激动剂处理后仅FASN的表达降至WT水平。肉碱棕榈酰转移酶1(将FA残基转移到线粒体进行β-氧化所必需的)和固醇调节元件结合因子1c(从头合成FA的上游调节因子)的转录水平没有显著变化。我们还通过RT-PCR证实，只有ERα在小鼠肝脏中表达。在所有治疗组中，肝雄激素受体转录水平没有变化。我们的数据表明，雌激素通过ERα调节Arko肝脏中的甘油三酯稳态。由于肝脏、脂肪组织和弓状核主要表达ERα，雌激素可通过外周和中枢途径调节肝功能。内分泌学杂志(2011)210,323-334
Male aromatase knockout mice (ArKO; an estrogen-deficient model) present with male-specific hepatic steatosis that is reversible upon 17 beta-estradiol replacement. This study aims to elucidate which estrogen receptor (ER) subtype, ER alpha or ER beta, is involved in the regulation of triglyceride (TG) homeostasis in the liver. Nine-month-old male ArKO mice were treated with vehicle, ER alpha- or ER beta-specific agonists via s.c. injection, daily for 6 weeks. Male ArKO mice treated with ER alpha agonist had normal liver histology and TG contents compared with vehicle-treated ArKO; omental (gonadal) and infra-renal (visceral) fat pad weights were normalized to those of vehicle-treated wild-type (WT). In contrast, ER beta agonist treatment did not result in the similar reversal of these ArKO phenotypes. In vehicle-treated ArKO mice, hepatic transcript expression of fatty acid synthase (Fasn) and stearoyl-coenzyme A desaturase 1 (key enzymes in de novo FA synthesis) were significantly elevated compared with vehicle-treated WT, but only Fasn expression was lowered to WT level after ER alpha agonist treatment. There were no significant changes in the transcript levels of carnitine palmitoyl transferase 1 (required for transfer of FA residues into the mitochondria for beta-oxidation) and sterol regulatory element-binding factor 1c (the upstream regulator of de novo FA synthesis). We also confirmed by RT-PCR that only ER alpha is expressed in the mouse liver. There were no changes in hepatic androgen receptor transcript level across all treatment groups. Our data suggest that estrogens act via ER alpha to regulate TG homeostasis in the ArKO liver. Since the liver, adipose tissue and arcuate nucleus express mainly ER alpha, estrogens could regulate hepatic functions via peripheral and central pathways. Journal of Endocrinology (2011) 210, 323-334