Pandak W M, Heuman D M, Redford K, Stravitz R T, Chiang J Y, Hylemon P B, Vlahcevic Z R
Department of Medicine, Veterans Affairs Medical Center and Medical College of Virginia, Virginia Commonwealth University, Richmond 23298, USA.
J Lipid Res. 1997 Dec;38(12):2483-91.
In primary cultures of rat hepatocytes, transcription of the cholesterol 7alpha-hydroxylase gene is induced synergistically by glucocorticoid and thyroid hormones. The objective of the present study was to evaluate the role of endogenous glucocorticoid and thyroid hormones in the maintenance of cholesterol 7alpha-hydroxylase gene expression in vivo. Male Sprague-Dawley rats underwent adrenalectomy (A), thyroidectomy (T), adrenalectomy + thyroidectomy (A + T), hypophysectomy (H), or sham surgery (paired controls). Ten days post surgery, livers were harvested and choles terol 7alpha-hydroxylase specific activity, steady-state mRNA levels, and transcriptional activity were determined. Serum corticosterone levels were <2% of paired controls in A, A + T, and H rats. Free thyroxine index was <32% of paired controls in rats with T and H. When compared to sham-operated controls, A + T and H led to decreases in cholesterol 7alpha-hydroxylase specific activities of 44 +/- 8% and 57 +/- 3%, respectively (P < 0.03 and < 0.05). Similar changes were observed in cholesterol 7alpha-hydroxylase steady-state mRNA levels, which decreased by 43 +/- 10% (P < 0.001) and 56 +/- 19% (P < 0.05), respectively. Cholesterol 7alpha-hydroxylase transcriptional activity in A + T and H rats decreased by 34 +/- 11% (P < 0.01) and 61 +/- 4% (P < 0.001), respectively. The observed decreases were greater after H than after A + T, suggesting the possibility that another pituitary hormone plays a role in regulation of cholesterol 7alpha-hydroxylase. Thyroidectomy alone led to a decrease in cholesterol 7alpha-hydroxylase specific activity of 37 +/- 7% (P < 0.05) and a trend toward decreased steady-state mRNA levels (21 +/- 12%; P = ns). Adrenalectomy did not significantly decrease cholesterol 7alpha-hydroxylase specific activity or mRNA levels. Neither thyroidectomy nor adrenalectomy alone affected transcriptional activity. We conclude that under physiologic circumstances, full expression of the cholesterol 7alpha-hydroxylase gene requires synergistic action of glucocorticoids and thyroid hormone.
在大鼠肝细胞原代培养物中，糖皮质激素和甲状腺激素可协同诱导胆固醇7α-羟化酶基因的转录。本研究的目的是评估内源性糖皮质激素和甲状腺激素在体内维持胆固醇7α-羟化酶基因表达中的作用。雄性Sprague-Dawley大鼠接受肾上腺切除术（A）、甲状腺切除术（T）、肾上腺切除术 + 甲状腺切除术（A + T）、垂体切除术（H）或假手术（配对对照）。术后10天，采集肝脏并测定胆固醇7α-羟化酶的比活性、稳态mRNA水平和转录活性。A、A + T和H组大鼠的血清皮质酮水平低于配对对照组的2%。T组和H组大鼠的游离甲状腺素指数低于配对对照组的32%。与假手术对照组相比，A + T组和H组大鼠的胆固醇7α-羟化酶比活性分别降低了44±8%和57±3%（P < 0.03和< 0.05）。胆固醇7α-羟化酶稳态mRNA水平也有类似变化，分别降低了43±10%（P < 0.001）和56±19%（P < 0.05）。A + T组和H组大鼠的胆固醇7α-羟化酶转录活性分别降低了34±11%（P < 0.01）和61±4%（P < 0.001）。观察到的降低在H组比A + T组更大，提示可能有另一种垂体激素参与胆固醇7α-羟化酶的调节。单独甲状腺切除术导致胆固醇7α-羟化酶比活性降低37±7%（P < 0.05），稳态mRNA水平有降低趋势（21±12%；P = 无显著性差异）。肾上腺切除术未显著降低胆固醇7α-羟化酶比活性或mRNA水平。单独甲状腺切除术和肾上腺切除术均未影响转录活性。我们得出结论，在生理情况下，胆固醇7α-羟化酶基因的充分表达需要糖皮质激素和甲状腺激素的协同作用。
