Adenosine monophosphate-activated protein kinase induces cholesterol efflux from macrophage-derived foam cells and alleviates atherosclerosis in apolipoprotein E-deficient mice.
Increasing evidence suggests that adenosine monophosphate-activated protein kinase (AMPK) exerts protective effects for cardiovascular diseases apart from the regulation of energy homeostasis. However, the role of AMPK and its underlying mechanism on macrophage foam cell formation are poorly understood. In this study, we sought to investigate the potential effects of AMPK in modulating cholesterol deposition by using murine macrophage-derived foam cells. Incubation with 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) markedly attenuated the cholesterol ester accumulation in oxidized low density lipoprotein-loaded macrophages. Notably, AICAR treatment significantly increased ATP-binding cassette transporters G1 (Abcg1) mRNA and protein levels without affecting mRNA and protein expression of ABCA1, scavenger receptors, including scavenger receptor-A, CD36, and scavenger receptor-BI (SR-BI), and cholesterol synthesis-related genes. The up-regulation of Abcg1 by AICAR was independent of the liver X receptor/retinoid X receptor pathway but dependent on ERK activation. AICAR elevates Abcg1 expression through a post-transcriptional mechanism that stabilizes the mRNA. Using a heterologous system with luciferase as a reporter, we further identify the Abcg1 mRNA 3'-UTR responsible for the regulatory effect of AICAR. Prevention of ABCG1 expression by small interfering RNA abolished the AICAR-mediated attenuation on foam cell formation. Furthermore, increased ABCG1 expression and reduced lipid accumulation were demonstrated in AICAR-treated macrophages isolated from apolipoprotein E-deficient mice (apoE(-/-) mice). AICAR treatment also inhibited atherosclerotic plaque formation in apoE(-/-) mice. Our findings elucidate a precise mechanism involved in the prevention of atherogenesis by AMPK.
Li
Dan
D
From the Guangdong Provincial Key Laboratory of Food, Nutrition, and Health, Guangzhou, Guangdong Province 510080, China; Department of Nutrition, School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province 510080, China.
Wang
Duan
D
Department of Nutrition, School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province 510080, China.
Wang
Yun
Y
Department of Nutrition, School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province 510080, China.
Ling
Wenhua
W
From the Guangdong Provincial Key Laboratory of Food, Nutrition, and Health, Guangzhou, Guangdong Province 510080, China; Department of Nutrition, School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province 510080, China.
Feng
Xiang
X
From the Guangdong Provincial Key Laboratory of Food, Nutrition, and Health, Guangzhou, Guangdong Province 510080, China; Department of Nutrition, School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province 510080, China.
Xia
Min
M
From the Guangdong Provincial Key Laboratory of Food, Nutrition, and Health, Guangzhou, Guangdong Province 510080, China; Department of Nutrition, School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province 510080, China. Electronic address: xiamin@mail.sysu.edu.cn.
D020413:3' Untranslated Regions / Q000235:genetics; D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001057:Apolipoproteins E; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D018955:CD36 Antigens / Q000096:biosynthesis / Q000235:genetics; D002460:Cell Line; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism*; D005487:Foam Cells / Q000378:metabolism* / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008074:Lipoproteins / Q000096:biosynthesis / Q000235:genetics; D017737:Macrophages, Peritoneal / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D012265:Ribonucleotides / Q000494:pharmacology
D020413:3' Untranslated Regions; C577836:ABCA1 protein, human; C419353:ABCG1 protein, human; C487540:ABCG1 protein, mouse; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D001057:Apolipoproteins E; D018955:CD36 Antigens; D007004:Hypoglycemic Agents; D008074:Lipoproteins; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D002784:Cholesterol; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide