Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1993 Aug;92(2):750–757. doi: 10.1172/JCI116646

Macrophage colony-stimulating factor regulates both activities of neutral and acidic cholesteryl ester hydrolases in human monocyte-derived macrophages.

T Inaba 1, H Shimano 1, T Gotoda 1, K Harada 1, M Shimada 1, M Kawamura 1, Y Yazaki 1, N Yamada 1
PMCID: PMC294910  PMID: 8394386

Abstract

Macrophage colony-stimulating factor (M-CSF) regulates cholesterol metabolism in vivo and in vitro. We studied the effects of M-CSF on enzyme activities of acidic cholesteryl ester (CE) hydrolase, neutral CE hydrolase, and acyl-coenzyme A:cholesterol acyltransferase (ACAT), all of which are involved in cellular cholesterol metabolism in macrophages. During the differentiation of monocytes to macrophages, these enzyme activities were induced and further enhanced in response to M-CSF. M-CSF (100 ng/ml) enhanced acidic and neutral CE hydrolase and ACAT activities by 3.2-, 4-, and 2.3-fold, respectively, in the presence of acetyl LDL. The presence of acetyl LDL influenced these enzyme activities. ACAT and acidic CE hydrolase activities were increased and neutral CE hydrolase activity was decreased, indicating that these enzymes are regulated by intracellular cholesterol enrichment. M-CSF increased the ratios of acidic CE hydrolase to ACAT activity and of neutral CE hydrolase to ACAT activity. The results suggest that M-CSF enhances net hydrolysis of CE by stimulating the two CE hydrolases to a greater extent than ACAT, and M-CSF may reduce the rate of atherogenesis.

Full text

PDF
750

Images in this article

753Image
on p.753
753Image
on p.753
753Image
on p.753
753Image
on p.753

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anderson R. A., Sando G. N. Cloning and expression of cDNA encoding human lysosomal acid lipase/cholesteryl ester hydrolase. Similarities to gastric and lingual lipases. J Biol Chem. 1991 Nov 25;266(33):22479–22484. [PubMed] [Google Scholar]
  2. Basu S. K., Goldstein J. L., Brown M. S. Independent pathways for secretion of cholesterol and apolipoprotein E by macrophages. Science. 1983 Feb 18;219(4586):871–873. doi: 10.1126/science.6823554. [DOI] [PubMed] [Google Scholar]
  3. Behrman H. R., Amstrong D. T. Cholesterol esterase stimulation by luteinizing hormone in luteinized rat ovaries. Endocrinology. 1969 Sep;85(3):474–480. doi: 10.1210/endo-85-3-474. [DOI] [PubMed] [Google Scholar]
  4. Brecher P., Pyun H. Y., Chobanian A. V. Effect of atherosclerosis on lysosomal cholesterol esterase activity in rabbit aorta. J Lipid Res. 1977 Mar;18(2):154–163. [PubMed] [Google Scholar]
  5. Brown M. S., Goldstein J. L., Krieger M., Ho Y. K., Anderson R. G. Reversible accumulation of cholesteryl esters in macrophages incubated with acetylated lipoproteins. J Cell Biol. 1979 Sep;82(3):597–613. doi: 10.1083/jcb.82.3.597. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Brown M. S., Ho Y. K., Goldstein J. L. The cholesteryl ester cycle in macrophage foam cells. Continual hydrolysis and re-esterification of cytoplasmic cholesteryl esters. J Biol Chem. 1980 Oct 10;255(19):9344–9352. [PubMed] [Google Scholar]
  7. Clark S. C., Kamen R. The human hematopoietic colony-stimulating factors. Science. 1987 Jun 5;236(4806):1229–1237. doi: 10.1126/science.3296190. [DOI] [PubMed] [Google Scholar]
  8. Fogelman A. M., Shechter I., Seager J., Hokom M., Child J. S., Edwards P. A. Malondialdehyde alteration of low density lipoproteins leads to cholesteryl ester accumulation in human monocyte-macrophages. Proc Natl Acad Sci U S A. 1980 Apr;77(4):2214–2218. doi: 10.1073/pnas.77.4.2214. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gotoda T., Yamada N., Kawamura M., Kozaki K., Mori N., Ishibashi S., Shimano H., Takaku F., Yazaki Y., Furuichi Y. Heterogeneous mutations in the human lipoprotein lipase gene in patients with familial lipoprotein lipase deficiency. J Clin Invest. 1991 Dec;88(6):1856–1864. doi: 10.1172/JCI115507. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hajjar D. P., Minick C. R., Fowler S. Arterial neutral cholesteryl esterase. A hormone-sensitive enzyme distinct from lysosomal cholesteryl esterase. J Biol Chem. 1983 Jan 10;258(1):192–198. [PubMed] [Google Scholar]
  11. Haley N. J., Fowler S., de Duve C. Lysosomal acid cholesteryl esterase activity in normal and lipid-laden aortic cells. J Lipid Res. 1980 Nov;21(8):961–969. [PubMed] [Google Scholar]
  12. Hara H., Yokoyama S. Interaction of free apolipoproteins with macrophages. Formation of high density lipoprotein-like lipoproteins and reduction of cellular cholesterol. J Biol Chem. 1991 Feb 15;266(5):3080–3086. [PubMed] [Google Scholar]
  13. Inaba T., Yamada N., Gotoda T., Shimano H., Shimada M., Momomura K., Kadowaki T., Motoyoshi K., Tsukada T., Morisaki N. Expression of M-CSF receptor encoded by c-fms on smooth muscle cells derived from arteriosclerotic lesion. J Biol Chem. 1992 Mar 15;267(8):5693–5699. [PubMed] [Google Scholar]
  14. Inoue I., Inaba T., Motoyoshi K., Harada K., Shimano H., Kawamura M., Gotoda T., Oka T., Shiomi M., Watanabe Y. Macrophage colony stimulating factor prevents the progression of atherosclerosis in Watanabe heritable hyperlipidemic rabbits. Atherosclerosis. 1992 Apr;93(3):245–254. doi: 10.1016/0021-9150(92)90261-e. [DOI] [PubMed] [Google Scholar]
  15. Ishibashi S., Inaba T., Shimano H., Harada K., Inoue I., Mokuno H., Mori N., Gotoda T., Takaku F., Yamada N. Monocyte colony-stimulating factor enhances uptake and degradation of acetylated low density lipoproteins and cholesterol esterification in human monocyte-derived macrophages. J Biol Chem. 1990 Aug 25;265(24):14109–14117. [PubMed] [Google Scholar]
  16. Ishibashi S., Yamada N., Shimano H., Mori N., Mokuno H., Gotohda T., Kawakami M., Murase T., Takaku F. Apolipoprotein E and lipoprotein lipase secreted from human monocyte-derived macrophages modulate very low density lipoprotein uptake. J Biol Chem. 1990 Feb 25;265(6):3040–3047. [PubMed] [Google Scholar]
  17. Khoo J. C., Mahoney E. M., Steinberg D. Neutral cholesterol esterase activity in macrophages and its enhancement by cAMP-dependent protein kinase. J Biol Chem. 1981 Dec 25;256(24):12659–12661. [PubMed] [Google Scholar]
  18. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  19. Magee D. M., Wing E. J., Ampel N. M., Waheed A., Shadduck R. K. Macrophage colony-stimulating factor enhances the expression of Fc receptors on murine peritoneal macrophages. Immunology. 1987 Nov;62(3):373–378. [PMC free article] [PubMed] [Google Scholar]
  20. Mori N., Gotoda T., Ishibashi S., Shimano H., Harada K., Inaba T., Takaku F., Yazaki Y., Yamada N. Effects of human recombinant macrophage colony-stimulating factor on the secretion of lipoprotein lipase from macrophages. Arterioscler Thromb. 1991 Sep-Oct;11(5):1315–1321. doi: 10.1161/01.atv.11.5.1315. [DOI] [PubMed] [Google Scholar]
  21. Motoyoshi K., Yoshida K., Hatake K., Saito M., Miura Y., Yanai N., Yamada M., Kawashima T., Wong G. G., Temple P. A. Recombinant and native human urinary colony-stimulating factor directly augments granulocytic and granulocyte-macrophage colony-stimulating factor production of human peripheral blood monocytes. Exp Hematol. 1989 Jan;17(1):68–71. [PubMed] [Google Scholar]
  22. Munn D. H., Cheung N. K. Antibody-dependent antitumor cytotoxicity by human monocytes cultured with recombinant macrophage colony-stimulating factor. Induction of efficient antibody-mediated antitumor cytotoxicity not detected by isotope release assays. J Exp Med. 1989 Aug 1;170(2):511–526. doi: 10.1084/jem.170.2.511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Oram J. F. Effects of high density lipoprotein subfractions on cholesterol homeostasis in human fibroblasts and arterial smooth muscle cells. Arteriosclerosis. 1983 Sep-Oct;3(5):420–432. doi: 10.1161/01.atv.3.5.420. [DOI] [PubMed] [Google Scholar]
  24. Pomerantz K. B., Hajjar D. P. High-density-lipoprotein-induced cholesterol efflux from arterial smooth muscle cell derived foam cells: functional relationship of the cholesteryl ester cycle and eicosanoid biosynthesis. Biochemistry. 1990 Feb 20;29(7):1892–1899. doi: 10.1021/bi00459a033. [DOI] [PubMed] [Google Scholar]
  25. Shimano H., Yamada N., Ishibashi S., Harada K., Matsumoto A., Mori N., Inaba T., Motoyoshi K., Itakura H., Takaku F. Human monocyte colony-stimulating factor enhances the clearance of lipoproteins containing apolipoprotein B-100 via both low density lipoprotein receptor-dependent and -independent pathways in rabbits. J Biol Chem. 1990 Aug 5;265(22):12869–12875. [PubMed] [Google Scholar]
  26. Shimano H., Yamada N., Motoyoshi K., Matsumoto A., Ishibashi S., Mori N., Takaku F. Plasma cholesterol-lowering activity of monocyte colony-stimulating factor (M-CSF). Ann N Y Acad Sci. 1990;587:362–370. doi: 10.1111/j.1749-6632.1990.tb00177.x. [DOI] [PubMed] [Google Scholar]
  27. Stanley E. R., Heard P. M. Factors regulating macrophage production and growth. Purification and some properties of the colony stimulating factor from medium conditioned by mouse L cells. J Biol Chem. 1977 Jun 25;252(12):4305–4312. [PubMed] [Google Scholar]
  28. Steinberg D., Parthasarathy S., Carew T. E., Khoo J. C., Witztum J. L. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med. 1989 Apr 6;320(14):915–924. doi: 10.1056/NEJM198904063201407. [DOI] [PubMed] [Google Scholar]
  29. Takano T., Black W. J., Peters T. J., de Duve C. Assay, kinetics, and lysosomal localization of an acid cholesteryl esterase in rabbit aortic smooth muscle cells. J Biol Chem. 1974 Nov 10;249(21):6732–6737. [PubMed] [Google Scholar]
  30. Warren M. K., Ralph P. Macrophage growth factor CSF-1 stimulates human monocyte production of interferon, tumor necrosis factor, and colony stimulating activity. J Immunol. 1986 Oct 1;137(7):2281–2285. [PubMed] [Google Scholar]
  31. Wong G. G., Temple P. A., Leary A. C., Witek-Giannotti J. S., Yang Y. C., Ciarletta A. B., Chung M., Murtha P., Kriz R., Kaufman R. J. Human CSF-1: molecular cloning and expression of 4-kb cDNA encoding the human urinary protein. Science. 1987 Mar 20;235(4795):1504–1508. doi: 10.1126/science.3493529. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES