Cheng W, Kvilekval K V, Abumrad N A
Department of Surgery, State University of New York at Stony Brook 11794, USA.
Am J Physiol. 1995 Oct;269(4 Pt 1):E642-8. doi: 10.1152/ajpendo.1995.269.4.E642.
The effects of dexamethasone on lipid accumulation by human monocyte-derived macrophages were investigated. Preincubation of macrophages with dexamethasone for a period of 16-20 h resulted in a reproducible increase (3.5-fold) in the incorporation of oleate into cholesteryl esters. The effect was specific because no alterations were observed in oleate incorporation into triglycerides or phospholipids. Measurement of cellular cholesteryl esters indicated a fourfold increase after preincubation with dexamethasone. This increase was mediated by opposite effects on synthesis and breakdown of these lipids. Dexamethasone produced a 60% increase in activity of the enzyme acyl-CoA: cholesterol O-acyltransferase (ACAT), active in synthesis of cholesteryl esters, and a 40% decrease in that of neutral cholesteryl esterase, active in cholesteryl ester breakdown. The increased ACAT activity appeared to reflect increased mRNA for the enzyme. The effects of dexamethasone on cholesteryl ester accumulation by macrophages reached statistical significance at a concentration of 100 nM. They were dose dependent, and saturation was observed at around 1 microM. The effects were significant at low concentrations of cholesterol in the medium. At high-medium cholesterol, there was a large cholesterol-induced increase in ACAT activity that obscured most of the effect of dexamethasone. In general, the data suggest that high glucocorticoid levels enhance lipid accumulation by macrophages and thus would have an atherogenic action that is independent of serum cholesterol.
研究了地塞米松对人单核细胞衍生巨噬细胞脂质积累的影响。巨噬细胞与地塞米松预孵育16 - 20小时，可使油酸掺入胆固醇酯的量出现可重复的增加（3.5倍）。该效应具有特异性，因为在油酸掺入甘油三酯或磷脂的过程中未观察到变化。细胞胆固醇酯的测量表明，与地塞米松预孵育后增加了四倍。这种增加是由对这些脂质合成和分解的相反作用介导的。地塞米松使参与胆固醇酯合成的酰基辅酶A：胆固醇O - 酰基转移酶（ACAT）的活性增加60%，而参与胆固醇酯分解的中性胆固醇酯酶的活性降低40%。ACAT活性的增加似乎反映了该酶mRNA的增加。地塞米松对巨噬细胞胆固醇酯积累的影响在浓度为100 nM时具有统计学意义。它们呈剂量依赖性，在约1 microM时达到饱和。在培养基中胆固醇浓度较低时，这些效应很显著。在中高胆固醇水平时，胆固醇诱导的ACAT活性大幅增加，掩盖了地塞米松的大部分作用。总体而言，数据表明高糖皮质激素水平会增强巨噬细胞的脂质积累，因此具有独立于血清胆固醇的致动脉粥样硬化作用。
