title: Mitochondrial regulation of macrophage cholesterol homeostasis.
abstract: 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.
authors.affiliation: Department of Life Sciences, School of Health and Life Sciences, and Institute for Applied Health Research, Glasgow Caledonian University, 70 Cowcaddens Road, Glasgow G4 0BA, United Kingdom. Electronic address: Ann.Graham@gcu.ac.uk.
authors.forename: Annette
authors.initials: A
authors.lastname: Graham
mesh_terms: D000818:Animals; D001692:Biological Transport; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*
keywords: ATP binding cassette transporter; Cholesterol; Liver X receptor; Macrophage; Mitochondria; Sterol 27-hydroxylase