Mitochondrial regulation of macrophage cholesterol homeostasis.
Mitochondrial regulation of macrophage cholesterol homeostasis.
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DOI：
10.1016/j.freeradbiomed.2015.08.010
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发表时间：
2015-12-01
影响因子：
7.4
通讯作者：
Graham, Annette
中科院分区：
文献类型：
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作者：
Graham, Annette
这篇综述探讨了线粒体结构与巨噬细胞胆固醇代谢调节功能之间的关系，并提出线粒体功能障碍导致通常将细胞固醇水平维持在限定范围内的优雅稳态机制的丧失。线粒体固醇27-羟化酶（CYP 27 A1）可产生肝X受体的氧固醇激活剂，其与类维生素A X受体异二聚化，增强ATP结合盒转运蛋白（ABCA 1、ABCG 1和ABCG 4）的转录，其可通过外排至载脂蛋白A-1、E和高密度脂蛋白来清除过量胆固醇，并抑制炎症。CYP 27 A1的活性由胆固醇底物供应到线粒体内膜的速率调节，由蛋白质复合物介导。这种动态复合物的确切身份仍然存在争议，即使在类固醇生成组织中，但可能包括类固醇生成急性调节蛋白和18 kDa转运蛋白，以及电压依赖性阴离子通道，ATP酶AAA结构域包含蛋白3A，视神经萎缩1型蛋白。当然，星星和TSPO蛋白的过表达可以增强巨噬细胞胆固醇流出至apoA-I和/或HDL，而线粒体功能的扰动或线粒体融合蛋白表达的变化改变胆固醇流出的效率。可以维持或改善线粒体功能或增加参与胆固醇转移的蛋白质复合物的活性的分子可以用于解决巨噬细胞胆固醇稳态失调的问题，巨噬细胞胆固醇稳态失调是一种可能导致炎症、动脉粥样硬化、非酒精性脂肪性肝炎、成骨细胞骨吸收和中枢神经系统的一些疾病的病症。
This review explores the relationship between mitochondrial structure and function in the regulation of macrophage cholesterol metabolism and proposes that mitochondrial dysfunction contributes to loss of the elegant homeostatic mechanisms which normally maintain cellular sterol levels within defined limits. Mitochondrial sterol 27-hydroxylase (CYP27A1) can generate oxysterol activators of liver X receptors which heterodimerise with retinoid X receptors, enhancing the transcription of ATP binding cassette transporters (ABCA1, ABCG1, and ABCG4), that can remove excess cholesterol via efflux to apolipoproteins A-1, E, and high density lipoprotein, and inhibit inflammation. The activity of CYP27A1 is regulated by the rate of supply of cholesterol substrate to the inner mitochondrial membrane, mediated by a complex of proteins. The precise identity of this dynamic complex remains controversial, even in steroidogenic tissues, but may include steroidogenic acute regulatory protein and the 18 kDa translocator protein, together with voltage-dependent anion channels, ATPase AAA domain containing protein 3A, and optic atrophy type 1 proteins. Certainly, overexpression of StAR and TSPO proteins can enhance macrophage cholesterol efflux to apoA-I and/or HDL, while perturbations in mitochondrial function, or changes in the expression of mitochondrial fusion proteins, alter the efficiency of cholesterol efflux. Molecules which can sustain or improve mitochondrial function or increase the activity of the protein complex involved in cholesterol transfer may have utility in resolving the problem of dysregulated macrophage cholesterol homeostasis, a condition which may contribute to inflammation, atherosclerosis, nonalcoholic steatohepatitis, osteoblastic bone resorption, and some disorders of the central nervous system.