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


RESULTS
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.


CONCLUSIONS
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.
INSERM, UMR 1048, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse 31432, France.|Université de Toulouse III, UMR 1048, Toulouse 31300, France.
Laeticia
L
Lichtenstein
INSERM, UMR 1048, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse 31432, France.|Université de Toulouse III, UMR 1048, Toulouse 31300, France.
Nizar
N
Serhan
Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
Wijtske
W
Annema
INSERM, UMR 1048, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse 31432, France.|Université de Toulouse III, UMR 1048, Toulouse 31300, France.
Guillaume
G
Combes
Institute of Interdisciplinary Research, IRIBHM, Université Libre de Bruxelles, Gosselies, Belgium.
Bernard
B
Robaye
Institute of Interdisciplinary Research, IRIBHM, Université Libre de Bruxelles, Gosselies, Belgium.
Jean-Marie
JM
Boeynaems
INSERM, UMR 1048, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse 31432, France.|CHU de Toulouse, Hôpital Purpan, Toulouse, France.
Bertrand
B
Perret
Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
Uwe J F
UJF
Tietge
INSERM, UMR 1048, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse 31432, France.|Université de Toulouse III, UMR 1048, Toulouse 31300, France.
Muriel
M
Laffargue
INSERM, UMR 1048, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse 31432, France.|Université de Toulouse III, UMR 1048, Toulouse 31300, France.|CHU de Toulouse, Hôpital Purpan, Toulouse, France.
Laurent O
LO
Martinez