Hepatic overexpression of methionine sulfoxide reductase A reduces atherosclerosis in apolipoprotein E-deficient mice

Yan-Yong Xu,Fen Du,Bing Meng,Guang-Hui Xie,Jia Cao,Daping Fan,Hong Yu

doi:10.1194/jlr.m058776

Yan-Yong Xu, Fen Du + Show 5 more

Open Access

https://doi.org/10.1194/jlr.m058776

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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.

Highlights

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
The results showed that overexpression of human MsrA (hMsrA) in HepG2 cells significantly increased the expression levels of LXR␣, ABCA1, and scavenger receptor class B type I (SR-BI), but not that of low density lipoprotein receptor (LDLR) (Fig. 1)
The data presented here provide the first evidence that high-level hepatic expression of hMsrA, achieved by lentiviral injection, resulted in diminished hepatic steatosis and attenuated atherosclerosis in Western-diet-fed apoEϪ/Ϫ mice

Summary

Introduction

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. 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 ␣, scavenger receptor class B type I, and ABCA1. Overexpression of hMsrA resulted in reduced hepatic steatosis and aortic atherosclerosis. Yu. Hepatic overexpression of methionine sulfoxide reductase A reduces atherosclerosis in apolipoprotein E-deficient mice. The liver plays a critical metabolic role in regulating lipid and redox homeostasis through many processes including synthesis of cholesterol, VLDL secretion, the uptake of cholesterol from the peripheral tissues, and its excretion into bile by a process called reverse cholesterol transport (RCT).

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