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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)-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 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-1? secretion, promotes cholesterol efflux, and attenuates atherosclerosis in mice.

SUBMITTER: Leng S

PROVIDER: S-EPMC4878185 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Ursolic acid enhances macrophage autophagy and attenuates atherogenesis.

Leng Shuilong S Iwanowycz Stephen S Saaoud Fatma F Wang Junfeng J Wang Yuzhen Y Sergin Ismail I Razani Babak B Fan Daping D

Journal of lipid research 20160410 6

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 ...[more]

PMID: 27063951

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Project description:Catharanthus roseus (C. roseus) and ursolic acid (UA) are ayurvedic medicines with multiple pharmacological activities including antidiabetic activity, but till date, no study is available on their combination. This study documented the antidiabetic efficacy of the combination of C. roseus and UA in rats. Rats were divided into six groups. All groups were given a single dose of Streptozotocin (STZ) at a dose of 50?mg/kg by intraperitoneal route for induction of diabetes, except the normal control group. Group 1 was treated as a normal control (NC) group and fed with saline water, Group 2 as a Diabetes Control group, Group 3 as a STZ+C. roseus ethanolic extract (CREE) group at 50?mg/kg p.o., Group 4 as a STZ+UA group orally at 50?mg/kg, Group 5 as a STZ+CREE (25?mg/kg p.o.)+UA (25?mg/kg p.o.) group, and Group 6 as a STZ+Glimepiride (0.1?mg/kg) group. Diabetes was confirmed after 72 hours by estimation of blood glucose level, and then treatment was given for the next 28 days. During the course of treatment, plasma insulin and blood glucose were measured regularly at the interval of 7 days. At the end of the protocol, blood was collected and animals were sacrificed. The glucose level, insulin level, liver glycogen storage level, and antioxidant enzymes (LPO, CAT, SOD, GPx, GST) were measured. The blood glucose level in Group 5 significantly (P < 0.001) reduced to 98.35 ± 2.45?mg/dl in comparison with that in Group 2 (321.75 ± 5.46?mg/dl). The level of plasma insulin in Group 5 increased (13.65 ± 0.10??U/ml) significantly (P < 0.01) as compared with that in Group 2 (05.93 ± 0.31??U/ml). In Group 5, the level of glycogen in liver was significantly (P < 0.01) increased as compared with that in Group 2 rats. The level of antioxidant enzymes in Group 5 restored toward normal values significantly (P < 0.01; P < 0.001) as compared with that in Group 2 animals. These findings suggest that low-dose combination of CREE and UA is effective in the treatment of diabetes.

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Ursolic acid enhances macrophage autophagy and attenuates atherogenesis.

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Ursolic acid enhances macrophage autophagy and attenuates atherogenesis.

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