Altered expression of fatty acid-metabolizing enzymes in aromatase-deficient mice
Altered expression of fatty acid-metabolizing enzymes in aromatase-deficient mice
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DOI：
10.1172/jci9575
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发表时间：
2000-06-01
影响因子：
15.9
通讯作者：
Shizuta, Y
中科院分区：
文献类型：
--
作者：
Nemoto, Y;Toda, K;Shizuta, Y
肝脏脂肪变性是非肥胖乳腺癌患者接受他莫昔芬治疗的常见并发症，他莫昔芬是一种强有力的雌激素拮抗剂。此外，在缺乏内在雌激素产生的芳香酶缺陷(ARKO)小鼠中，肝脏脂肪变性变得明显。这些临床和实验室观察表明，雌激素有助于维持结构性脂代谢。为了阐明这一假设，Me描述了参与过氧化物酶和线粒体脂肪酸β-氧化的酶在Arko小鼠肝脏中的表达和活性。Northern分析显示，超长脂肪酰辅酶A合成酶、过氧化物型脂肪酰辅酶A氧化酶和中链脂肪酰辅酶A脱氢酶的mRNAs表达减少，这是脂肪酸β氧化所需的酶。以极长链脂肪酸(C24：0)、长链脂肪酸(C16：0)或中等链脂肪酸(C12：0)为底物的脂肪酸β氧化活性的体外测定证实，相应的活性也降低了。脂肪酸β-氧化受损的基因表达和酶活性恢复到野生型水平，17β-雌二醇治疗的动物肝脏脂肪变性显著减轻。野生型和ARKO小鼠的肝细胞核提取物与过氧化物酶增殖物反应元件的结合活性没有差异。这些发现表明，雌激素在支持与脂质β-氧化相关的基因在肝脏的结构性表达以及在维持肝脏脂质平衡方面起着关键作用。
Hepatic steatosis is a frequent complication in nonobese patients with breast cancer treated with tamoxifen, a potent antagonist of estrogen. In addition, hepatic steatosis became evident spontaneously in the aromatase-deficient (ArKO) mouse, which lacks intrinsic estrogen production. These clinical and laboratory observations suggest that estrogen helps to maintain constitutive lipid metabolism. To clarify this hypothesis, me characterized the expression and activity in ArKO mouse liver of enzymes involved in peroxisomal and mitochondrial fatty acid beta-oxidation. Northern analysis showed reduced expression of mRNAs for very long fatty acyl-CoA synthetase, peroxisomal fatty acyl-CoA oxidase, and medium-chain acyl-CoA dehydrogenase, enzymes required in fatty acid beta-oxidation. In vitro assays of fatty acid beta-oxidation activity using very long (C24:0), long (C16:0), or medium (C12:0) chain fatty acids as the substrates confirmed that the corresponding activities are also diminished. Impaired gene expression and enzyme activities of fatty acid beta-oxidation were restored to the wild-type levels, and hepatic steatosis was substantially diminished in animals treated with 17 beta-estradiol. Wild-type and ArKO mice showed no difference in the binding activities of the hepatic nuclear extracts to a peroxisome proliferator response element. These findings demonstrate the pivotal role of estrogen in supporting constitutive hepatic expression of genes involved in lipid beta-oxidation and in maintaining hepatic lipid homeostasis.