title: LDL Receptor-Related Protein-1 (LRP1) Regulates Cholesterol Accumulation in Macrophages.
abstract: Within the circulation, cholesterol is transported by lipoprotein particles and is taken up by cells when these particles associate with cellular receptors. In macrophages, excessive lipoprotein particle uptake leads to foam cell formation, which is an early event in the development of atherosclerosis. Currently, mechanisms responsible for foam cell formation are incompletely understood. To date, several macrophage receptors have been identified that contribute to the uptake of modified forms of lipoproteins leading to foam cell formation, but the in vivo contribution of the LDL receptor-related protein 1 (LRP1) to this process is not known [corrected]. To investigate the role of LRP1 in cholesterol accumulation in macrophages, we generated mice with a selective deletion of LRP1 in macrophages on an LDL receptor (LDLR)-deficient background (macLRP1-/-). After feeding mice a high fat diet for 11 weeks, peritoneal macrophages isolated from Lrp+/+ mice contained significantly higher levels of total cholesterol than those from macLRP1-/- mice. Further analysis revealed that this was due to increased levels of cholesterol esters. Interestingly, macLRP1-/- mice displayed elevated plasma cholesterol and triglyceride levels resulting from accumulation of large, triglyceride-rich lipoprotein particles in the circulation. This increase did not result from an increase in hepatic VLDL biosynthesis, but rather results from a defect in catabolism of triglyceride-rich lipoprotein particles in macLRP1-/- mice. These studies reveal an important in vivo contribution of macrophage LRP1 to cholesterol homeostasis.
authors.affiliation: Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, United States of America; Department of Pathology, Duke University Medical Center, Durham, NC 27710, United States of America.
authors.forename: Anna P
authors.initials: AP
authors.lastname: Lillis
authors.affiliation: Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, United States of America; Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, United States of America.
authors.forename: Selen Catania
authors.initials: SC
authors.lastname: Muratoglu
authors.affiliation: Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, United States of America.
authors.forename: Dianaly T
authors.initials: DT
authors.lastname: Au
authors.affiliation: Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, United States of America; Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, United States of America.
authors.forename: Mary
authors.initials: M
authors.lastname: Migliorini
authors.affiliation: Department of Medicine, Section of Endocrinology, Diabetes and Nutrition, Boston University School of Medicine, Boston, MA 02118, United States of America.
authors.forename: Mi-Jeong
authors.initials: MJ
authors.lastname: Lee
authors.affiliation: Department of Medicine, Section of Endocrinology, Diabetes and Nutrition, Boston University School of Medicine, Boston, MA 02118, United States of America.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Fried
authors.affiliation: Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, United States of America; Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, United States of America.
authors.forename: Irina
authors.initials: I
authors.lastname: Mikhailenko
authors.affiliation: Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, United States of America; Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, United States of America; Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, United States of America.
authors.forename: Dudley K
authors.initials: DK
authors.lastname: Strickland
mesh_terms: D000273:Adipose Tissue / Q000201:enzymology; D000818:Animals; D002784:Cholesterol / Q000378:metabolism*; D017353:Gene Deletion; D007728:Kupffer Cells / Q000378:metabolism*; D008049:Lipase / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051379:Mice; D008822:Mice, Transgenic; D009132:Muscles / Q000201:enzymology; D011973:Receptors, LDL / Q000235:genetics / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins; D002784:Cholesterol; D008049:Lipase