title: Hepatic overexpression of methionine sulfoxide reductase A reduces atherosclerosis in apolipoprotein E-deficient mice.
abstract: Methionine sulfoxide reductase A (MsrA), a specific enzyme that converts methionine-S-sulfoxide to methionine, plays an important role in the regulation of protein function and the maintenance of redox homeostasis. In this study, we examined the impact of hepatic MsrA overexpression on lipid metabolism and atherosclerosis in apoE-deficient (apoE(-/-)) mice. In vitro study showed that in HepG2 cells, lentivirus-mediated human MsrA (hMsrA) overexpression upregulated the expression levels of several key lipoprotein-metabolism-related genes such as liver X receptor α, scavenger receptor class B type I, and ABCA1. ApoE(-/-) mice were intravenously injected with lentivirus to achieve high-level hMsrA expression predominantly in the liver. We found that hepatic hMsrA expression significantly reduced plasma VLDL/LDL levels, improved plasma superoxide dismutase, and paraoxonase-1 activities, and decreased plasma serum amyloid A level in apoE(-/-) mice fed a Western diet, by significantly altering the expression of several genes in the liver involving cholesterol selective uptake, conversion and excretion into bile, TG biosynthesis, and inflammation. Moreover, overexpression of hMsrA resulted in reduced hepatic steatosis and aortic atherosclerosis. These results suggest that hepatic MsrA may be an effective therapeutic target for ameliorating dyslipidemia and reducing atherosclerosis-related cardiovascular diseases.
authors: Department of Biochemistry and Molecular Biology Wuhan University School of Basic Medical Sciences, Wuhan, China.
authors: Yan-Yong
authors: YY
authors: Xu
authors: Department of Biochemistry and Molecular Biology Wuhan University School of Basic Medical Sciences, Wuhan, China Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University School of Basic Medical Sciences, Wuhan, China Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, SC.
authors: Fen
authors: F
authors: Du
authors: Department of Biochemistry and Molecular Biology Wuhan University School of Basic Medical Sciences, Wuhan, China.
authors: Bing
authors: B
authors: Meng
authors: Department of Biochemistry and Molecular Biology Wuhan University School of Basic Medical Sciences, Wuhan, China.
authors: Guang-Hui
authors: GH
authors: Xie
authors: Department of Biochemistry and Molecular Biology Wuhan University School of Basic Medical Sciences, Wuhan, China.
authors: Jia
authors: J
authors: Cao
authors: Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, SC.
authors: Daping
authors: D
authors: Fan
authors: Department of Biochemistry and Molecular Biology Wuhan University School of Basic Medical Sciences, Wuhan, China Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University School of Basic Medical Sciences, Wuhan, China.
authors: Hong
authors: H
authors: Yu
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000201:enzymology / Q000378:metabolism*; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051150:Methionine Sulfoxide Reductases / Q000096:biosynthesis* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D011973:Receptors, LDL; D002784:Cholesterol; D051150:Methionine Sulfoxide Reductases
keywords: antioxidants; cholesterol efflux; cholesterol elimination; inflammation; lipoprotein metabolism; lipoprotein receptors; paraoxonase-1