Cholesterol loading

Wang N, Tabas I, Winchester R, Ravalli S, Rabbani LE, Tall A. Interleukin 8 is induced by cholesterol loading of macrophages and expressed by macrophage foam cells in human atheroma. J Biol Chem 1996 271(15) 8837-8842. 

Moreau M, Brocheriou I, Petit L, Ninio E, Chapman MJ, Rouis M. Interleukin-8 mediates downregulation of tissue inhibitor of metalloproteinase-1 expression in cholesterol-loaded human macrophages relevance to stability of atherosclerotic plaque. Circulation 1999 99(3) 420-426. 

Shiffman D et al. Large scale gene expression analysis of cholesterol-loaded macrophages. J Biol Chem 2000 275 37324-37332. 

Li, Y., Ge, M., Ciani, L., Kuriakose, G., Westover, E.J., Dura, M., Covey, D.F., Freed, J.H., Maxfield, F.R., Lytton, J., and Tabas, I., 2004, Enrichment of endoplasmic reticulum with cholesterol inhibits sarcoplasmic-endoplasmic reticulum calcium ATPase-2b activity in parallel with increased order of membrane lipids implications for depletion of endoplasmic reticulum calcium stores and apoptosis in cholesterol-loaded macrophages../. Biol. Chem. 279, 37030—37039 Lin, P., Yao, Y., Hofmeister, R., Tsien, R.Y., and Farquhar, M.G., 1999, Overexpression of CALNUC (nucleobindin) increases agonist and thapsigargin releasable Ca2+ storage in the Golgi. J. Cell Biol. 145, 279-289... 

Macrophages appear to do more than simply bind and take up remnant particles. Cultured macrophages secrete lipoprotein lipase into the culture medium (C6, K12, M7, W3), and the consequent depletion of chylomicron triglyceride appears to accelerate the uptake of chylomicron remnants and the accumulation of eholesteryl esters by macrophages (010). Macrophages also can produce apoE (B17) perhaps this may be a mechanism for removing cholesterol from a cholesterol-loaded cell. 

N4. Nestel, P., Tada, N., Billington, T., Huff, M., and Fidge, N., Changes in very low density lipoproteins with cholesterol loading in man. Metabolism 31, 398-405 (1982). 

Unwanted deposits of cholesterol occur because cholesterol, being a lipid with no water-soluble end, needs help to be transported around in the bloodstream. The transporters are called low-density lipids. They form little bubbles around the cholesterol, not unlike soap solvates dirt, using their oily hydrocarbon ends to connect with the cholesterol and their organic-acid ends to connect with the watery fluid of blood. The structure of the low-density lipids (abbreviated LDL) helps them deposit their cholesterol load when they reach the cells where it is needed, but, unfortunately, their structure also facilitates the dumping of excess cholesterol on blood vessel walls when the cells have all they need. When we speak of... 

Zager RA, Johnson AC, Lund S, Endotoxin tolerance TNF-a hyper-reactivity and tubular cytoresistance in a renal cholesterol loading state. Kidney Int, 2007, 71 496-503. 

Tabas, L, Marathe, S., Keesler, G. A., Beatini, N., and Shiratori, Y. (1996). Evidence that the initial up-regulation of phosphatidylcholine biosynthesis in free cholesterol-loaded macrophages is an adaptive response that prevents cholesterol-induced cellular necrosis. /. Biol. Chem. 271, 22773-22781. 

Engel T, Lueken A, Bode G, et al. (2004) ADP-ribosylation factor (ARF)-like 7 (ARL7) is induced by cholesterol loading and participates in apolipoprotein Al-dependent cholesterol export. FEBS Lett 566 241-246... 

Fu X, Menke JG, Chen Y, et al. (2001) 27-hydroxycholesterol is an endogenous ligand for liver X receptor in cholesterol-loaded cells. J Biol Chem 276 38378-38387... 

Garner B, Mellor HR, Butters TD, et al. (2002) Modulation of THP-1 macrophage and cholesterol-loaded foam cell apolipoprotein E levels by glycosphingolipids. Biochem Biophys Res Commun 290 1361-1367... 

Oram JF, Mendez AJ, Slotte JP, et al. (1991) High density lipoprotein apolipoproteins mediate removal of sterol from intracellular pools but not from plasma membranes of cholesterol-loaded fibroblasts. Arterioscler Thromb 11 403 14... 

Apo-E (chylomicron remnant) Liver Chylomicron remnants HDL-with apo-E (HDL ) Apo-E Not subject to marked down-regulation Uptake of chylomicron remnants and cholesterol-loaded HDL-with-apo-E Delivery of cholesterol to the liver for excretion... 

Phosphatidylcholine is the major phospholipid of lesional cells and, as mentioned above, serves both structural and signaling functions (Chapter 8). In terms of cellular membrane structure, the cholesteroLphospholipid ratio in lesional cells must be kept within a certain limit in order for the proper functioning of membrane proteins [14]. Cholesterol-rich foam cells isolated from atherosclerotic lesions have intracellular phospholipid whorl-like structures, and phosphatidylcholine biosynthesis is increased in lesional areas of the arterial wall (Fig. 8). Cell-culture studies have revealed that cholesterol loading of macrophages directly leads to the activation of CTPrphospho-choline cytidylyltransferase and an increase in phosphatidylcholine biosynthesis and mass. Proof that this is an adaptive response to FC excess came from a study in which the cytidylyltransferase-a gene was disrupted in macrophages, which resulted in... 

Fig. 8. Phospholipid whorls in cholesterol-loaded macrophages. (A) Electron micrograph showing a membrane whorl in the cytoplasm of a foam cell. The cell was isolated from an advanced aortic atherosclerotic lesion in a cholesterol-fed rabbit. From [34]. Lab. Invest. 41 160-167. (B) Electron micrograph showing a membrane whorl in the cytoplasm of a cholesterol-loaded J774 macrophage. The cell was in the adaptive stage, i.e., before the onset of unesterified cholesterol-induced death. From Shiratori et al. (1994). J. Biol. Chem. 269 11337-11348. Reproduced with permission from the publisher.

The promotion of cholesterol efflux from cells could be the first step in reverse cholesterol transport. In their experiments using cholesterol-loaded human skin fibroblasts, Stein and colleagues [31] showed a significant enhancement of cholesterol efflux by Apo A-IV/phospholipid complexes. It is not yet fully understood how apoproteins promote cellular cholesterol efflux. Evidence is accumulating that a specific receptor-mediated process is involved. Thus far, it has been shown that Apo A-IV binds to cells and membrane preparations from different species. Ghiselli et al. [14] concluded from their experiments that rat Apo A-IV/DMPC complexes bound specifically in a saturable manner to rat liver membranes. Along the same line, Dvorin... 

Both the HDL-dependent and the HDL-independent pathway protect the macrophage and maybe other cholesterol-loaded cells from overaccumulation of cholesterol and foam cell formation. Cholesterol accumulation and inflammatory activation trigger the macrophage to synthesize and secrete a large variety of secretory products including enzymes, proteins, and growth factors for fibroblasts, endothelial cells, and smooth muscle cells which enhance the atherosclerotic process. 

Phospholipid transfer protein (PLTP) (carrier protein that shuttles between lipoproteins to redistribute lipids) deficiency in mice is associated with decreased atherosclerosis despite decreased HDL levels. Two mechanisms are involved decreased Apo B-containing lipoprotein production and levels, and increased antioxidation potential. Human studies indicated that PLTP activity positively correlated with aging, obesity, DM, and CAD (reviewed in ref. 429). PLTP mRNA protein expression and activity was increased by cholesterol loading of macrophages. PLTP increased HDL binding to biglycan, suggesting a role in lipoprotein retention on ECM (430). 

Feng B, Tabas I. ABCAl-mediated cholesterol efflux is defective in free cholesterol-loaded macrophages. Mechanism involves enhanced ABCAl degradation in a process requiring full NPCl activity. J Biol Chem 2002 277 43,271-43,280. 

Li Y, Ge M, Ciani L et al. (2004) Enrichment of endoplasmic reticulum with cholesterol inhibits sarcoplasmic-endoplasmic reticulum calcium AT-Pase-2b activity in parallel with increased order of membrane lipids implications for depletion of endoplasmic reticulum calcium stores and apoptosis in cholesterol-loaded macrophages. J Biol Chem 279, 37030-37039. 

Sixty years have passed since Anitschkow succeeded in producing an atheroma in his experiment by "cholesterol loading" in rabbits. Until the author (1972)(31,33) the mechanism of a athero-genesis remained unresolved as a long time enigma. 

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