ATP Synthase β-Chain Overexpression in SR-BI Knockout Mice Increases HDL Uptake and Reduces Plasma HDL Level.

Guoqing Liu,Peng Yang,Shen Qu,Kexiu Song,Yingchun Han,Linhua Zhang,Xiaoyun Cheng,Le Bu,Hui Sheng

doi:10.1155/2014/356432

Guoqing Liu, Peng Yang + Show 7 more

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https://doi.org/10.1155/2014/356432

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Abstract

HDL cholesterol is known to be inversely correlated with cardiovascular disease due to its diverse antiatherogenic functions. SR-BI mediates the selective uptake of HDL-C. SR-BI knockout diminishes but does not completely block the transport of HDL; other receptors may be involved. Ectopic ATP synthase β-chain in hepatocytes has been previously characterized as an apoA-I receptor, triggering HDL internalization. This study was undertaken to identify the overexpression of ectopic ATP synthase β-chain on DIL-HDL uptake in primary hepatocytes in vitro and on plasma HDL levels in SR-BI knockout mice. Human ATP synthase β-chain cDNA was delivered to the mouse liver by adenovirus and GFP adenovirus as control. The adenovirus-mediated overexpression of β-chain was identified at both mRNA and protein levels on mice liver and validated by its increasing of DiL-HDL uptake in primary hepatocytes. In response to hepatic overexpression of β-chain, plasma HDL-C levels and cholesterol were reduced in SR-BI knockout mice, compared with the control. The present data suggest that ATP synthase β-chain can serve as the endocytic receptor of HDL, and its overexpression can reduce plasma HDL-C.

Highlights

Both epidemiological and clinical studies have demonstrated that the serum levels of high-density lipoprotein (HDL) cholesterol are inversely correlated with the risk of atherosclerosis [1,2,3]
We set out to determine whether overexpression of ATPase-B1 affects plasma lipoprotein levels and whether this effect is mediated by scavenger receptor class B type I (SR-BI)
A previous study showed that the surface β-chain is an apoA-I/HDL receptor [21], and the complex has been found on the cell surface of endothelial cells, adipocytes, hepatocytes, and tumor cells by immunofluorescence or after biotinylation of the cell surface [24,25,26,27,28]

Summary

Introduction

Both epidemiological and clinical studies have demonstrated that the serum levels of high-density lipoprotein (HDL) cholesterol are inversely correlated with the risk of atherosclerosis [1,2,3]. HDL protects against atherosclerosis and cardiovascular disease by mediating reverse cholesterol transport, protecting vascular endothelium, and exerting antioxidant, anti-inflammatory, and antithrombotic effects [4, 5]. Clinical trials have shown that HDL could be an important therapeutic target [7]. Therapy with the HDL mimetic apoAI phospholipid may result in regression of atherosclerosis [7], and these mimetic peptides may influence the vascular biology of the vessel wall and protect against other acute and chronic inflammatory diseases [8]. Functional integrity of HDL is important for its antiatherogenic properties, as one study showed that patients with normal or elevated but functionally abnormal HDL suffered from atherosclerosis [9]

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