Abstract
High-density lipoprotein (HDL) is known to protect against atherosclerosis by promoting the reverse cholesterol transport. A new pathway for the regulation of HDL-cholesterol (HDL-c) removal involving F1-ATPase and P2Y13 receptor (P2Y13R) was described in vitro, and recently in mice. However, the physiological role of F1-ATPase/P2Y13R pathway in the modulation of vascular pathology i.e. in the development of atherosclerotic plaques is still unknown. We designed a specific novel agonist (CT1007900) of the P2Y13R that caused stimulation of bile acid secretion associated with an increased uptake of HDL-c in the liver after single dosing in mice. Repeated dose administration in mice, for 2 weeks, stimulated the apoA-I synthesis and formation of small HDL particles. Plasma samples from the agonist-treated mice had high efflux capacity for mobilization of cholesterol in vitro compared to placebo group. In apoE−/− mice this agonist induced a decrease of atherosclerotic plaques in aortas and carotids. The specificity of P2Y13R pathway in those mice was assessed using adenovirus encoding P2Y13R-shRNA. These results demonstrate that P2Y13R plays a pivotal role in the HDL metabolism and could also be a useful therapeutic agent to decrease atherosclerosis. In this study, the up-regulation of HDL-c metabolism via activation of the P2Y13R using agonists could promote reverse cholesterol transport and promote inhibition of atherosclerosis progression in mice.
Highlights
The protective effect of high density lipoprotein (HDL) against atherosclerosis is in large part attributed to its ability to mobilize cholesterol from the vessel wall, in particular from lipid-rich atherosclerotic plaques, and transport it to the liver where it is excreted from the body in the form of bile acids or free cholesterol, in a process called reverse cholesterol transport [1,2]
Since P2Y13 receptor (P2Y13R) is highly expressed in liver as compared to other tissues [18,19], we hypothesized that administration of P2Y13R agonists in animals would increase the reverse cholesterol transport, i.e. the HDL-c uptake by the liver and subsequently the bile acid and bile cholesterol secretions
An increase in liver bile acid content at 30 mg/kg of P2Y13R agonist (Figure 1D) as well as an increase of CYP7A1 mRNA expression (1.760.4 fold, p,0.05, 1 h post oral gavage – data not shown) was clearly demonstrated which is in agreement with the stimulation of HDL-c uptake by the liver that results in an increase in the bile acid synthesis
Summary
The protective effect of high density lipoprotein (HDL) against atherosclerosis is in large part attributed to its ability to mobilize cholesterol from the vessel wall, in particular from lipid-rich atherosclerotic plaques, and transport it to the liver where it is excreted from the body in the form of bile acids or free cholesterol, in a process called reverse cholesterol transport [1,2]. These measures do not indicate if the lipoprotein particles are functional and actively transferring cholesterol for elimination Both LDL particles (LDL-p) and HDL particles (HDL-p) vary in their content of cholesterol, and determining the concentration of lipoprotein particles may be more predictive rather than estimating the cholesterol concentration in assessing the cardiovascular risk. This hypothesis was supported by the data from the Framingham offspring study on LDL-c [8] and more recently for HDL-c in the MESA (MultiEthnic Study of Atherosclerosis) trial [9]. Feces from individual mouse were collected for 6 h and extracted for cholesterol (empty bars) and bile acid content (grey bars) and the radioactivity was determined by scintillation counting. *p,0.05. doi:10.1371/journal.pone.0095807.g001 evaluate novel HDL-directed therapies which could modulate such lipoprotein particles metabolism [10]
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