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

Laeticia Lichtenstein (1) , Nizar Serhan (1) , Wijtske Annema (2) , Guillaume Combes (1) , Bernard Robaye (3) , Jean-Marie Boeynaems (3) , Bertrand Perret (4) , Uwe J. F. Tietge (2) , Muriel Laffargue (1) , Laurent O. Martinez (1, 4)

1 I2MC - Institut des Maladies Métaboliques et Cardiovasculaires
2 Department of Pediatrics
3 IRIBHM - Institute of Interdisciplinary Research
4 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse

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.

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

Domaines: Biologie cellulaire

Laeticia Lichtenstein, Nizar Serhan, Wijtske Annema, Guillaume Combes, Bernard Robaye, et al.. Lack of P2Y13 in mice fed a high cholesterol diet results in decreased hepatic cholesterol content, biliary lipid secretion and reverse cholesterol transport.. Nutr Metab (Lond), 2013, 10 (1), pp.67. ⟨10.1186/1743-7075-10-67⟩. ⟨inserm-01055313⟩