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: Yan-Yong Xu, Fen Du, Bing Meng, Guang-Hui Xie, Jia Cao, Daping Fan, Hong Yu
• Journal: Journal of lipid research (J Lipid Res) Vol. 56 Issue 10 Pg. 1891-900 (Oct 2015) ISSN: 1539-7262 [Electronic] United States
• PMID: 26318157 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 by the American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Apolipoproteins E
• Receptors, LDL
• Cholesterol
• Methionine Sulfoxide Reductases

Topics

• Animals
• Apolipoproteins E (deficiency, genetics, metabolism)
• Atherosclerosis (enzymology, metabolism)
• Cells, Cultured
• Cholesterol (metabolism)
• Hep G2 Cells
• Humans
• Lipid Metabolism
• Liver (metabolism)
• Male
• Methionine Sulfoxide Reductases (biosynthesis, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Receptors, LDL (metabolism)