Mitochondrial function and regulation of macrophage sterol metabolism and inflammatory responses

Abstract

The aim of this review is to explore the role of mitochondria in regulating macrophage sterol homeostasis and inflammatory responses within the aetiology of atherosclerosis. Macrophage generation of oxysterol activators of liver X receptors (LXRs), via sterol 27-hydroxylase, is regulated by the rate of flux of cholesterol to the inner mitochondrial membrane, via a complex of cholesterol trafficking proteins. Oxysterols are key signalling molecules, regulating the transcriptional activity of LXRs which coordinate macrophage sterol metabolism and cytokine production, key features influencing the impact of these cells within atherosclerotic lesions. The precise identity of the complex of proteins mediating mitochondrial cholesterol trafficking in macrophages remains a matter of debate, but may include steroidogenic acute regulatory protein and translocator protein. There is clear evidence that targeting either of these proteins enhances removal of cholesterol via LXRα-dependent induction of ATP binding cassette transporters (ABCA1, ABCG1) and limits the production of inflammatory cytokines; interventions which influence mitochondrial structure and bioenergetics also impact on removal of cholesterol from macrophages. Thus, molecules which can sustain or improve mitochondrial structure, the function of the electron transport chain, or increase the activity of components of the protein complex involved in cholesterol transfer, may therefore have utility in limiting or regressing atheroma development, reducing the incidence of coronary heart disease and myocardial infarction.

Keywords: Atherosclerosis, Macrophage, Cholesterol, High density lipoproteins, Apolipoproteins, ATP binding cassette transporters, Scavenger receptor B1, Mitochondria (dys)function, Sterol 27-hydroxylase, Liver X receptors

Core tip: Mitochondrial cholesterol trafficking to CYP27A1 located on the inner mitochondrial membrane regulates the formation of oxysterol ligands for liver X receptors (LXRs) in sterol-laden macrophage “foam” cells. In turn, ligation of LXRα has profound implications for sterol removal and inflammatory responses in macrophage “foam” cells, both factors which may contribute to the effective resolution of atherosclerotic lesions and reductions in the incidence of coronary heart disease and its sequelae.