title: Ursolic acid enhances macrophage autophagy and attenuates atherogenesis.
abstract: Macrophage autophagy has been shown to be protective against atherosclerosis. We previously discovered that ursolic acid (UA) promoted cancer cell autophagy. In the present study, we aimed to examine whether UA enhances macrophage autophagy in the context of atherogenesis. Cell culture study showed that UA enhanced autophagy of macrophages by increasing the expression of Atg5 and Atg16l1, which led to altered macrophage function. UA reduced pro-interleukin (IL)-1β protein levels and mature IL-1β secretion in macrophages in response to lipopolysaccharide (LPS), without reducing IL-1β mRNA expression. Confocal microscopy showed that in LPS-treated macrophages, UA increased LC3 protein levels and LC3 appeared to colocalize with IL-1β. In cholesterol-loaded macrophages, UA increased cholesterol efflux to apoAI, although it did not alter mRNA or protein levels of ABCA1 and ABCG1. Electron microscopy showed that UA induced lipophagy in acetylated LDL-loaded macrophages, which may result in increased cholesterol ester hydrolysis in autophagolysosomes and presentation of free cholesterol to the cell membrane. In LDLR(-/-) mice fed a Western diet to induce atherogenesis, UA treatment significantly reduced atherosclerotic lesion size, accompanied by increased macrophage autophagy. In conclusion, the data suggest that UA promotes macrophage autophagy and, thereby, suppresses IL-1β secretion, promotes cholesterol efflux, and attenuates atherosclerosis in mice.
authors.affiliation: Department of Human Anatomy, School of Basic Science, Guangzhou Medical University, Guangzhou, Guangdong 510182, People's Republic of China Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29209 shuilongleng@hotmail.com daping.fan@uscmed.sc.edu.
authors.forename: Shuilong
authors.initials: S
authors.lastname: Leng
authors.affiliation: Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29209.
authors.forename: Stephen
authors.initials: S
authors.lastname: Iwanowycz
authors.affiliation: Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29209.
authors.forename: Fatma
authors.initials: F
authors.lastname: Saaoud
authors.affiliation: Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29209.
authors.forename: Junfeng
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29209.
authors.forename: Yuzhen
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Cardiovascular Division, Departments of Medicine and Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Ismail
authors.initials: I
authors.lastname: Sergin
authors.affiliation: Cardiovascular Division, Departments of Medicine and Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Babak
authors.initials: B
authors.lastname: Razani
authors.affiliation: Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29209 shuilongleng@hotmail.com daping.fan@uscmed.sc.edu.
authors.forename: Daping
authors.initials: D
authors.lastname: Fan
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1 / Q000378:metabolism; D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001343:Autophagy / Q000187:drug effects; D000071187:Autophagy-Related Protein 5 / Q000235:genetics; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000235:genetics; D002784:Cholesterol / Q000378:metabolism*; D066273:Diet, Western; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000188:drug therapy* / Q000473:pathology; D053583:Interleukin-1beta / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D000067996:RAW 264.7 Cells; D011973:Receptors, LDL / Q000235:genetics; D014315:Triterpenes / Q000008:administration & dosage*; D000097245:Ursolic Acid
chemical_list: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D000071187:Autophagy-Related Protein 5; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D002784:Cholesterol; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D011973:Receptors, LDL; D014315:Triterpenes; D000097245:Ursolic Acid; C487540:ABCG1 protein, mouse; C532820:Atg16l1 protein, mouse; C495773:Atg5 protein, mouse
keywords: atherosclerosis; cholesterol efflux; inflammation; lipophagy