Macrophage cholesterol metabolism

Tdrdcsik, D., A. Szanto, and L. Nagy. 2009. Oxysterol signaling links cholesterol metabolism and inflammation via the liver X receptor in macrophages. 30... 

Fig. 2. Cholesterol metabolism in macrophages. AcLDL, Acetyl LDL EC = esterified cholesterol UC = unesterified cholesterol RER, SER, rough, smooth endoplasmic reticulum...

In another study, hesperetin enhanced ApoA-l-mediated cholesterol efflux in THP-1 macrophages, probably due to a greater transcription of ABCAl gene, which is critical for cholesterol metabolism. The effect of hesperetin on ABCAl-dependent cholesterol efflux may be explained in part by its LXRa and PPARy agonist action. These results indicates the potential of this flavonoid in the prevention and treatment of atherosclerosis [61]. 

Brown, M.S. and Goldstein, J.L. (1983). Lipxsprotein metabolism in the macrophage implications fiar cholesterol dep>o-sition in atherosclerosis. Ann. Rev. Biochem. 52, 223-261. 

Beauveriolides I (19) and III (20), two fungal (Beauveria Spp) metabolites, have been found to be specific inhibitors of lipid droplet formation in mouse macrophages. It has been recently observed that the metabolisms of A[3 proteins and cholesterol esters are closely linked. One of the... 

Macrophages and cytokines can also influence lipoprotein metabolism [139], Grove et al. indicated that macrophages can secrete several proteins, including 27-oxygenated metabolites of cholesterol, that upregulate LDL receptors in HepG2 cells [140], This mechanism was compared with the classical HDL-dependent reverse cholesterol transport. With albumin as extracellular acceptor, the major secreted product was 3-/3-hydroxy-5-cholestenoic acid with HDL as acceptor, 27-hydroxycholesterol was the major secreted product [140, 141]. 

In an extracellular location in the arterial intima the lipids must be regarded as comprising a largely inert metabolic pool. Its subsequent removal or clearance from the intima can be accomplished only after the phagocytotic uptake by macrophages, a process which will convert the cholesterol to a metabolically active intracellular pool, thus permitting the HDL-mediated reverse cholesterol transport. 

Brown MS, Goldstein JL. Lipoprotein metabolism in the macrophage implications for cholesterol deposition in atherosclerosis. Annu Rev Biochem 1983 52 223-61. 

Tabas 1 (2000) Cholesterol and phospholipid metabolism in macrophages. Biochim Biophys Acta 1529 164-174... 

In earlier sections of this chapter we focused on the distribution and physical properties of CE and on several intra- and extracellular enzymes and proteins that mediate CE formation, hydrolysis, and transfer. We turn now to a discussion of the major pathways of CE metabolism in plasma, and in cells such as fibroblasts, steroid hormone-forming cells, macrophages, and hepatocytes. These pathways seem to be integrated in such a way as to effect not only the transport and storage of cholesterol, but possibly also the transport of essential fatty acids. It can be argued in addition that the pathways of CE metabolism in plasma and in tissues provide a critical mechanism for buffering the content of UC in cell membranes and maintaining cholesterol homeostasis in the body (see Chapter 2). 

Excess cholesterol can also be metabolized to CE. ACAT is the ER enzyme that catalyzes the esterification of cellular sterols with fatty acids. In vivo, ACAT plays an important physiological role in intestinal absorption of dietary cholesterol, in intestinal and hepatic lipoprotein assembly, in transformation of macrophages into CE laden foam cells, and in control of the cellular free cholesterol pool that serves as substrate for bile acid and steroid hormone formation. ACAT is an allosteric enzyme, thought to be regulated by an ER cholesterol pool that is in equilibrium with the pool that regulates cholesterol biosynthesis. ACAT is activated more effectively by oxysterols than by cholesterol itself, likely due to differences in their solubility. As the fatty acyl donor, ACAT prefers endogenously synthesized, monounsaturated fatty acyl-CoA. 

---