阿托伐他汀钙和非诺贝特酸对2型糖尿病患者泡沫细胞胆固醇外流的影响

The effects of atorvastatin and fenofibrate on macrophage cholesterol efflux in patients with type-2 diabetes

目的了解巨噬细胞对胆固醇处理能力的改变在糖尿病泡沫细胞形成中的作用,以及调脂药物治疗对细胞内胆固醇(IC)外流的影响。方法选择2型糖尿病合并动脉粥样硬化(AS)患者8例(Ⅰ组)、非糖尿病AS患者8例(Ⅱ组)和非糖尿病非AS患者6例(Ⅲ组)。外周血单核细胞经乙酰化低密度脂蛋白(LDL)诱导成泡沫细胞。采用免疫细胞化学和细胞酶联免疫吸附法测定阿托伐他汀钙和非诺贝特酸处理后泡沫细胞过氧化物酶体增殖物激活受体(PPAR)α和三磷酸腺苷结合盒转运体A1(ABCA1)的表达。高效液相色谱法测定药物处理前后IC和胆固醇酯(CE)转运率。结果Ⅰ组患者巨噬细胞对乙酰化LDL有很强的吞噬能力。乙酰化LDL显著抑制细胞PPARα和ABCA1的表达。非诺贝特酸明显上调细胞PPARα和ABCA1的表达,并在Ⅰ组显著促进IC外流。两药均可抑制巨噬细胞对脂质的吞噬和脂质引起的细胞损伤,并加速泡沫细胞IC和CE的外流。结论糖尿病巨噬细胞对胆固醇处理能力的改变与细胞内脂质沉积相关,调脂药物对细胞损伤具有保护作用,并促进IC外流。

Objective To understand the effect of atorvastatin and fenofibric acid on macrophage cholesterol efflux in diabetic patients.Methods Patients with diabetes and atherosclerosis （group Ⅰ , 8 pts. ）, patients with atherosclerosis without diabetes （group Ⅱ , 8 pts. ） and patients without diabetes or atherosclerosis （group Ⅲ, 6 pts） were enrolled in this study. Macrophages derived from monocytes of these patients were cultured in vitro , and induced to form foam ceils by the introduction of Acl-LDL. The expression of PPAR-α and ABCA1 in foam ceils was determined by cellular ELISA assay. Ⅰ ntracellular cholesterol was measured by HPLC, and cellular cholesterol efflux rates were calculated. The effects of atorvastatin and fenofibric acid on phagotrophic ability of macrophages and on cellular cholesterol efflux were observed. Results Monocyte-derived macrophages in group Ⅰ had more vigorous phagotrophic ability than those in groups Ⅱ and Ⅲ, even before the inducement by Acl-LDL. Acl-LDL inhibited the expression of PPAR-α and ABCA1 in foam ceils significantly in all three groups, which was more pronounced in group Ⅰ . Atorvastatin and fenofibric acid could prevent macrophages from phagocytosis of Acl-LDL and protect cells from damage caused by Acl-LDL. Both drugs could accelerate the efflux of cellular cholesterol and cholesterol ester. Fenofibric acid caused more potent expression of PPARα and ABCA1 in macrophages （ P 〈 0.05）, and more cholesterol efflux than atorvastatin did in group Ⅰ . Conclusion The changes of ability of macrophages to handle cholesterol in diabetes relate to the deposition of intracellular lipid. Lipid-lowering drugs can protect ceils from damage caused by lipid and promote the efflux of intracellular cholesterol.