title: Leptin modulates ACAT1 expression and cholesterol efflux from human macrophages.
abstract: Leptin is an adipose tissue-derived hormone implicated in atherosclerosis and macrophage foam cell formation. The current study was conducted to examine the effect of leptin on cholesteryl ester accumulation in human monocytes/macrophages. Exogenously added leptin at 5 nM during differentiation of monocytes into macrophages for 7 days accelerated acetylated LDL (acetyl-LDL)-induced cholesteryl ester accumulation by 30-50%. Leptin did not affect endocytic uptake of acetyl-LDL; however, it increased ACAT activity 1.8-fold and ACAT-1 protein expression 1.9-fold. Among the four ACAT-1 mRNA transcripts, two shorter transcripts (2.8 and 3.6 kb) were upregulated approximately 1.7-fold upon leptin treatment. The enhanced expression of ACAT-1 protein by leptin was suppressed by inhibitors of Janus-activated kinase2 (JAK2) and phosphatidylinositol 3-kinase (PI3K). HDL-mediated cholesterol efflux was suppressed by leptin, which was canceled by K-604, an ACAT-1 inhibitor. Expression of long form of leptin receptor was upregulated during monocytic differentiation into macrophages and sustained after differentiation. Thus, the results suggest that leptin accelerates cholesteryl ester accumulation in human monocyte-derived macrophages by increasing ACAT-1 expression via JAK2 and PI3K, thereby suppressing cholesterol efflux.
authors.affiliation: Department of Biochemistry, Showa University School of Medicine, Tokyo, Japan. shongo@med.showa-u.ac.jp
authors.forename: Shigeki
authors.initials: S
authors.lastname: Hongo
authors.forename: Takuya
authors.initials: T
authors.lastname: Watanabe
authors.forename: Shigeko
authors.initials: S
authors.lastname: Arita
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kanome
authors.forename: Haruaki
authors.initials: H
authors.lastname: Kageyama
authors.forename: Seiji
authors.initials: S
authors.lastname: Shioda
authors.forename: Akira
authors.initials: A
authors.lastname: Miyazaki
mesh_terms: D000101:Acetyl-CoA C-Acetyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D001562:Benzimidazoles / Q000494:pharmacology; D001693:Biological Transport, Active / Q000187:drug effects; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D002788:Cholesterol Esters / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D020738:Leptin / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D009000:Monocytes / Q000378:metabolism / Q000502:physiology; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism
chemical_list: C520671:(2-(4-(2-benzimidazol-2ylthio)ethyl)piperazin-1yl)-N-(2,4-bis(methylthio)-6-methyl-3-pyridyl)acetamide; D001562:Benzimidazoles; D002788:Cholesterol Esters; D004791:Enzyme Inhibitors; C515448:LEPR protein, human; D020738:Leptin; D054411:Receptors, Leptin; D002784:Cholesterol; C506639:ACAT1 protein, human; D000101:Acetyl-CoA C-Acetyltransferase