Ursolic acid enhances macrophage autophagy and attenuates atherogenesis

Abstract

This article is available online at http://www.jlr.org recycled for downstream metabolism (1). Among the three major kinds of autophagy, macroautophagy, microautophagy, and chaperone-mediated autophagy, macroautophagy is the most prevalent form and, thus, commonly referred to as autophagy (2, 3). Over the past decade, research efforts regarding this ancient biological process have been revived due to the realization that alterations in autophagy play crucial pathological roles in many diseases (4, 5) for which current therapeutic means are limited. While many basic aspects of autophagy have been unraveled, little has been translated into clinical benefit, and no autophagy-modulating therapies have been approved for clinical use.The autophagy process starts with the formation of a double-membrane autophagosome, which engulfs cytoplasmic materials. Autophagosomes are targeted to the lysosomal compartment and single-membrane autolysosomes are generated in which the sequestered cargos are degraded in the highly acidic environment and the resulting simple products are reused (6, 7). There are many molecules involved in autophagy, including Beclin-1 (involved in vesicle nucleation); Atg5, Atg7, and Atg16L1 (involved in vesicle elongation); and LC3 (involved in the expansion of autophagosome membrane and autophagosome-lysosome fusion) (8). Autophagy occurs in almost all cell types, including macrophages. Macrophages primarily use phagocytosis as the first line of defense against exogenous pathogens and endogenous waste products. They adopt autophagy to process bulky materials (e.g., damaged mitochondria and excessive lipids) in unfavorable microenvironments, thus mitigating cytotoxicity. Recently, autophagy has been shown to play a critical role in inflammatory responses in macrophages by interacting with inflammasomes or directly targeting pro-interleukin 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)-1 protein levels and mature IL-1 secretion in macrophages in response to lipopolysaccharide (LPS), without reducing IL-1 mRNA expression. Confocal microscopy showed that in LPS-treated macrophages, UA increased LC3 protein levels and LC3 appeared to colocalize with IL-1. 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 atherogenesi...

Luteolin Attenuates Foam Cell Formation and Apoptosis in Ox-LDL-Stimulated Macrophages by Enhancing Autophagy

“…Several observations have demonstrated that autophagy facilitates intracellular lipid droplet degradation and cholesterol efflux to impede foam cell formation [30,31]. Thus, current experimental evidence supports a role for autophagy-mediated efflux that favors ABCA1 expression [32,33]. These observations are consistent with the possibility that autophagy plays a major role in the expression of ABCA1.…”

Inactivation of Beclin‐1‐dependent autophagy promotes ursolic acid‐induced apoptosis in hypertrophic scar fibroblasts

“…Autophagy is induced by UA in various cells. UA has been demonstrated to promote macrophage autophagy and thereby suppresses IL‐1β secretion, promotes cholesterol efflux and attenuates atherosclerosis in mice . UA also activates autophagy and, hence, has been shown to induce cytotoxicity and reduce tumor growth in the cervical cancer cell line TC‐1 in a concentration‐dependent manner .…”

“…UA has been demonstrated to promote macrophage autophagy and thereby suppresses IL-1β secretion, promotes cholesterol efflux and attenuates atherosclerosis in mice. [25] UA also activates autophagy and, hence, has been shown to induce cytotoxicity and reduce tumor growth in the cervical cancer cell line TC-1 in a concentration-dependent manner. [19] In the present study, we first demonstrated that UA induced HSFB autophagy in a dose-and timedependent manner (Figure 2).…”

Supercritical CO2 extraction of steroidal sapogenins from fenugreek (Trigonella foenum-graecum L.)seed

“…other steroidal sapogenins, namely sarsapogenin and protodioscin, detected in fenugreek possessed significant anticancer, hypocholesterolemic, and antidepressant activities [6][7][8][9][10][11][12], exhibited the beneficial effects on the cardiovascular system [10], and might take a part in the regulation of glycemia and high blood pressure [8][9]13]. Besides, oleanolic and ursolic acids are known for different biological activities, their ability to reduce blood pressure, to regulate cholesterol level, and to induce the apoptosis of cancer cells [14][15][16][17][18][19][20]. Interestingly, ursolic acid represents one of the most important constituents of fenugreek seed.…”

“…Interestingly, ursolic acid represents one of the most important constituents of fenugreek seed. In the literature so far, it was reported to be present only in its ethanol-aqueous extract [16][17][18][19][20][21][22]. The concurrent presence of oleanolic acid and ursolic acid, its isomer, in plant material might be responsible for their possible synergistic effect on several health impairments [23][24][25].…”