Oxysterols present in atherosclerotic tissue decrease the expression of lipoprotein lipase messenger RNA in human monocyte-derived macrophages.

Abstract

The presence of oxysterols in macrophages isolated from atherosclerotic tissue and the effect of oxysterols on the regulation of lipoprotein lipase (LPL) mRNA were studied. Both rabbit and human macrophages, freshly isolated from atherosclerotic aorta, show about the same distribution of oxysterols, analyzed by isotope dilution mass spectrometry, except that all three preparations of human arterial-derived macrophages contained high levels of 27-hydroxycholesterol, which was not found in rabbit macrophages. To determine if oxysterols regulate LPL expression, human monocyte-derived macrophages were incubated with different oxysterols. Incubation with 7 ␤ -hydroxycholesterol and 25-hydroxycholesterol resulted in a 70-75% reduction of LPL mRNA, analyzed by quantitative RT-PCR. Cholesterol and other tested oxysterols showed no effect on macrophage LPL mRNA expression compared with control. LPL activity in the medium was also reduced after exposure of the macrophages to 7 ␤ -hydroxycholesterol and 25-hydroxycholesterol. In conclusion, we have demonstrated accumulation of oxysterols in macrophage-derived foam cells isolated from atherosclerotic aorta. There was suppression of LPL mRNA in human monocyte-derived macrophages after incubation with 7 ␤ -hydroxycholesterol and 25-hydroxycholesterol. It is tempting to suggest that an exposure to oxysterols may explain our earlier observation of a low level of LPL mRNA in arterial foam cells. ( J. Clin. Invest. 1996. 97:461-468.)

Oxidized LDL Can Induce Macrophage Survival, DNA Synthesis, and Enhanced Proliferative Response to CSF-1 and GM-CSF

“…28 Interestingly, the oxysterol-to-cholesterol ratio in foam cell macrophages isolated from plaques is even higher than in the bulk tissue of the lesion. 46 It is therefore possible that such molecules may stimulate macrophage DNA synthesis in vitro and in atherosclerotic plaques. Another possibility is that lysophosphatidylcholine in ox-LDL is also contributing.…”

Caveolin mRNA levels are up-regulated by free cholesterol and down-regulated by oxysterols in fibroblast monolayers

“…7K-C is a major oxysterol of human atherosclerotic plaques (16,31). It was recently identified as an inhibitor of FC efflux from macrophages (17).…”

Retinoid X receptors: X-ploring their (patho)physiological functions

“…172 This enzyme is expressed in macrophages in atherosclerotic lesions. [172][173][174] A mutation in this enzyme leads to a human disease -cerebrotendinous xanthomatosis, a rare sterol storage disease characterized by xanthomas in tendons and also in the CNS leading to ataxia, spinal cord paresis, neurological dysfuntions, normolipidemic xanthomatosis and accelerated atherosclerosis. [175][176][177] In the context of atherosclerosis macrophages' cholesterol metabolism is only one question besides the other main problem: the control of the absorption and metabolism of cholesterol in the liver and its distribution to peripheral tissues.…”