CHOLESTEROL-SYNTHESIS BY HUMAN-FETAL HEPATOCYTES - EFFECTS OF HORMONES
CHOLESTEROL-SYNTHESIS BY HUMAN-FETAL HEPATOCYTES - EFFECTS OF HORMONES
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DOI：
10.1210/jcem-58-6-1111
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发表时间：
1984-01-01
影响因子：
5.8
通讯作者：
SIMPSON, ER
中科院分区：
文献类型：
--
作者：
CARR, BR;SIMPSON, ER
在以前的研究中，发现人胎肝组织中胆固醇合成率很高，仅次于胎儿肾上腺组织中的胆固醇合成率。之前对来自母体隔室的胎儿胆固醇含量的估计在20%的范围内。肝脏可能是人类胎儿循环脂蛋白的主要来源，人类成年人也是如此。低密度脂蛋白是胎儿肾上腺类固醇合成的主要胆固醇来源；因此，人胎肝中调节胆固醇合成的因子可能间接控制肾上腺皮质类固醇的分泌速度。本研究的目的是确定激素，特别是那些由胎儿-胎盘单位产生的激素，是否可能有助于刺激人类胚胎肝脏的胆固醇合成。通过测定培养的肝细胞中[~3H]水掺入[~3H]胆固醇的速率或测定人胎肝微粒体内3-羟基-3-甲基戊二酰辅酶A还原酶的比活力来测定胆固醇的生物合成速率。加入地塞米松(10-10-10-6M)，在暴露的第2天和第6天之间，刺激胆固醇合成高达2-4倍。当人胎肝细胞在地塞米松(10-7M)存在时，微体组分中3-羟基-3-甲基戊二酰辅酶A还原酶的活性比对照细胞高4倍。皮质醇还以浓度依赖的方式刺激胆固醇的生物合成。在培养上清液中加入17β-雌二醇(E_2)，从10~(-10)~10~(-7)M起呈浓度依赖性地刺激胆固醇的生物合成，当有E_2存在时(10~(-7)M)，胆固醇合成速率是未处理细胞的4倍。在与E2孵育的2-7天期间，E2对胆固醇合成的刺激作用保持不变。雌酮、雌三醇和雌二醇(10-6M)引起人胎肝细胞胆固醇合成速率相似的增加(3-4倍)。最后，浓度大于10-6M的孕酮显著刺激人胎肝细胞胆固醇的合成。而胰岛素、胰升糖素、催乳素、生长激素、脱氢表雄酮及其硫酸盐、表皮生长因子、成纤维细胞生长因子、T_3[三碘甲状腺原氨酸](Bu)_2cAMP和霍乱毒素等激素和因子对人胎肝细胞胆固醇合成无明显影响。总而言之，由胎儿-胎盘单位产生的雌激素、糖皮质激素和黄体酮刺激人胎肝细胞胆固醇合成的速度。
In previous investigations, high rates of cholesterol synthesis were found in human fetal liver tissue, second only to rates in fetal adrenal tissue. Previous estimates of the amount of cholesterol in the fetus derived from the maternal compartment are in the range of 20%. The liver may be the principal source of circulating lipoproteins in the human fetus, as is true in the human adult. Low density lipoprotein is the major source of cholesterol used for fetal adrenal steroidogenesis; therefore, it follows that factors regulating cholesterol synthesis in the human fetal liver may indirectly control the rate of steroid secretion by the adrenal cortex. The purpose of the present investigation was to determine if hormones, particularly those produced by the fetal-placental unit, might serve to stimulate cholesterol synthesis in the human fetal liver. The rate of cholesterol biosynthesis was determined by measuring the rate of incorporation of [3H] water into [3H]cholesterol in hepatocytes maintained in culture or by determination of the specific activity of 3-hydroxy-3-methylglutaryl CoA reductase in microsomal preparations from human fetal liver. The addition of dexamethasone (10-10-10-6 M) stimulated cholesterol synthesis up to 2- to 4-fold between days 2 and 6 of exposure. When human fetal liver cells were maintained in the presence of dexamethasone (10-7 M), the activity of 3-hydroxy-3-methylglutaryl CoA reductase in microsomal fractions was stimulated 4-fold compared to that in control cells. Cortisol also stimulated cholesterol biosynthesis in a concentration-dependent manner. The addition of 17.beta.-estradiol (E2) to the culture medium resulted in stimulation of cholesterol biosynthesis in a concentration-dependent manner from 10-10-10-7 M. The rate of cholesterol synthesis when E2 was present (10-7 M) was 4-fold greater than that in untreated cells. Stimulation of cholesterol synthesis by E2 was maintained between 2-7 days of incubation with E2. Estrone, estriol and E2 (10-6 M) caused similar increases (3- to 4-fold) in the rates of cholesterol synthesis in human fetal hepatocytes. Finally, progesterone in concentrations greater than 10-6 M significantly stimulated cholesterol synthesis in human fetal liver cells. In contrast, other hormones and factors, including insulin, glucagon, PRL [prolactin], GH [growth hormone], dehydroepiandrosterone and it sulfate, epidermal growth factor, fibroblast growth factor, T3 [triiodothyronine] (Bu)2cAMP and cholera toxin, had no effect on the rate of cholesterol synthesis in human fetal liver cells. In summary, estrogens, glucocorticoids and progesterone produced by the fetal-placental unit stimulate the rate of cholesterol synthesis in human fetal liver cells.