Lack of P2Y13 in mice fed a high cholesterol diet results in decreased hepatic cholesterol content, biliary lipid secretion and reverse cholesterol transport

Nutrition & Metabolism

Laurent O Martinez⁴  Muriel Laffargue¹  Uwe J F Tietge²  Bertrand Perret⁴  Jean-Marie Boeynaems³  Bernard Robaye³  Guillaume Combes¹  Wijtske Annema²  Nizar Serhan¹  Laeticia Lichtenstein¹ 

[1] Université de Toulouse III, UMR 1048, Toulouse 31300, France;Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands;Institute of Interdisciplinary Research, IRIBHM, Université Libre de Bruxelles, Gosselies, Belgium;CHU de Toulouse, Hôpital Purpan, Toulouse, France

关键词: ATP synthase;    Liver;    Cholesterol metabolism;    Reverse cholesterol transport;    Bile lipid secretions;    High cholesterol diet;    HDL-uptake;    HDL;    P2Y₁₃;   

Others  :  803099
DOI  :  10.1186/1743-7075-10-67

 received in 2013-07-24, accepted in 2013-10-30,  发布年份 2013

【 摘 要 】

Background

The protective effect of HDL is mostly attributed to their metabolic function in reverse cholesterol transport (RCT), a process whereby excess cellular cholesterol is taken up from peripheral cells, processed in HDL particles, and later delivered to the liver for further metabolism and biliary secretion. Mechanistically, the purinergic P2Y₁₃ ADP-receptor is involved in hepatic HDL endocytosis (i.e., uptake of both HDL protein + lipid moieties), which is considered an important step of RCT. Accordingly, chow-fed P2Y₁₃ knockout (P2Y₁₃^-/-) mice exhibit lower hepatic HDL uptake, which translates into a decrease of hepatic free cholesterol content and biliary cholesterol and phospholipid secretion.

Findings

The aim of this study was to determine the effect of high cholesterol diet (HCD) in P2Y₁₃^-/- mice, in order to mimic high dietary cholesterol intake, which is a major cause of dyslipidemia in humans. As previously reported with chow-diet, HCD did not affect plasma lipid levels in P2Y₁₃^-/- compared with control mice but decreased hepatic free and esterified cholesterol content (p < 0.05, P2Y₁₃^-/- versus control). Interestingly, biliary lipid secretion and macrophages-to-feces RCT were more dramatically impaired in P2Y₁₃^-/- mice fed a HCD than chow-diet. HCD did not enhance atherosclerosis in P2Y₁₃^-/- compared with control mice.

Conclusion

This study demonstrates that high dietary cholesterol intake accentuated the metabolic phenotype of P2Y₁₃^-/- mice, with impaired hepatobiliary RCT. Although other animal models might be required to further evaluate the role of P2Y₁₃ receptor in atherosclerosis, P2Y₁₃ appears a promising target for therapeutic intervention aiming to stimulate RCT, particularly in individuals with lipid-rich diet.

【 授权许可】

   
2013 Lichtenstein et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Pöss J, Custodis F, Werner C, Weingärtner O, Böhm MLU: Cardiovascular disease and dyslipidemia: beyond LDL. Curr Pharm Des 2011, 17:861-870.
• [2]DeGoma EM, DeGoma RL, Rader DJ: Beyond high-density lipoprotein cholesterol levels evaluating high-density lipoprotein function as influenced by novel therapeutic approaches. J Am Coll Cardiol 2008, 51:2199-2211.
• [3]Martinez LO, Jacquet S, Esteve JP, Rolland C, Cabezon E, Champagne E, et al.: Ectopic beta-chain of ATP synthase is an apolipoprotein A-I receptor in hepatic HDL endocytosis. Nature 2003, 421:75-79.
• [4]Fabre AC, Malaval C, Ben Addi A, Verdier C, Pons V, Serhan N, et al.: P2Y13 receptor is critical for reverse cholesterol transport. Hepatology 2010, 52:1477-1483.
• [5]Serhan N, Cabou C, Verdier C, Lichtenstein L, Malet N, Perret B, et al.: Chronic pharmacological activation of P2Y13 receptor in mice decreases HDL-cholesterol level by increasing hepatic HDL uptake and bile acid secretion. Biochim Biophys Acta 2013, 1831:719-725.
• [6]Dullaart RPF, Annema W, de Boer JF, Tietge UJF: Pancreatic β-cell function relates positively to HDL functionality in well-controlled type 2 diabetes mellitus. Atherosclerosis 2012, 222:567-573.
• [7]Nijstad N, de Boer JF, Lagor WR, Toelle M, Usher D, Annema W, et al.: Overexpression of apolipoprotein O does not impact on plasma HDL levels or functionality in human apolipoprotein A-I transgenic mice. Biochim Biophys Acta 2011, 1811:294-299.
• [8]Paigen B, Morrow A, Holmes PA, Mitchell DWR: Quantitative assessment of atherosclerotic lesions in mice. Atherosclerosis 1987, 68:231-240.
• [9]Nijstad N, Gautier T, Briand F, Rader DJ, Tietge UJF: Biliary sterol secretion is required for functional in vivo reverse cholesterol transport in mice. Gastroenterology 2011, 140:1043-1051.
• [10]Naik SU, Wang X, Da Silva JS, Jaye M, Macphee CH, Reilly MP, et al.: Pharmacological activation of liver X receptors promotes reverse cholesterol transport in vivo. Circulation 2006, 113:90-97.
• [11]Jacquet S, Malaval C, Martinez LO, Sak K, Rolland C, Perez C, et al.: The nucleotide receptor P2Y13 is a key regulator of hepatic high-density lipoprotein (HDL) endocytosis. Cell Mol Life Sci 2005, 62:2508-2515.
• [12]François B, Snehal U, Naik Llia F, John S, Millar C, Colin M, Max W, Jeffrey B, George Rothblat DJ: Both the Peroxisome Proliferator-Activated Receptor δ Agonist, GW0742, and Ezetimibe Promote Reverse Cholesterol Transport in Mice by Reducing Intestinal Reabsorption of HDL-Derived Cholesterol. Clin Transl Sci 2009, 2:127-133.
• [13]Dikkers A, Freak De Boer J, Annema W, Groen AK, Tietge UJF: Scavenger receptor BI and ABCG5/G8 differentially impact biliary sterol secretion and reverse cholesterol transport in mice. Hepatology 2013, 58:293-303.
• [14]Röhrl C, Pagler TA, Ellinger A, Pavelka M, Meisslitzer-ruppitsch C: Europe PMC Funders Group Characterization of endocytic compartments after holo-high density lipoprotein particle uptake in HepG2 cells. Histochem Cell Biol 2011, 133:261-272.
• [15]Haghpassand M, Bourassa PK, Francone OL, Aiello RJ: Monocyte/macrophage expression of ABCA1 has minimal contribution to plasma HDL levels. J Clin Invest 2001, 108:1315-1320.
• [16]Communi D, Gonzalez NS, Detheux M, Brezillon S, Lannoy V, Parmentier M, et al.: Identification of a novel human ADP receptor coupled to G(i). J Biol Chem 2001, 276:41479-41485.