Ursolic acid enhances macrophage autophagy and attenuates atherogenesis

Shuilong Leng, Stephen Iwanowycz, Fatma Saaoud, Junfeng Wang, Yuzhen Wang, Ismail Sergin, Babak Razani, Daping Fan

Research output: Contribution to journalArticle

21 Scopus citations

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 cholesterolloaded 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.

Original languageEnglish
Pages (from-to)1006-1016
Number of pages11
JournalJournal of lipid research
Volume57
Issue number6
DOIs
StatePublished - Jun 2016

Keywords

  • Atherosclerosis
  • Cholesterol efflux
  • Inflammation
  • Lipophagy

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    Leng, S., Iwanowycz, S., Saaoud, F., Wang, J., Wang, Y., Sergin, I., Razani, B., & Fan, D. (2016). Ursolic acid enhances macrophage autophagy and attenuates atherogenesis. Journal of lipid research, 57(6), 1006-1016. https://doi.org/10.1194/jlr.M065888