Altered lipoprotein metabolism in P2Y(13) knockout mice.
The purinergic receptor P2Y(13) has been shown to play a role in the uptake of holo-HDL particles in in vitro hepatocyte experiments. In order to determine the role of P2Y(13) in lipoprotein metabolism in vivo, we ablated the expression of this gene in mice. Here we show that P2Y(13) knockout mice have lower fecal concentrations of neutral sterols (-27%±2.1% in males) as well as small decreases in plasma HDL (-13.1%±3.2% in males; -17.5%±4.0% in females) levels. In addition, significant decreases were detected in serum levels of fatty acids and glycerol in female P2Y(13) knockout mice. Hepatic mRNA profiling analyses showed increased expression of SREBP-regulated cholesterol and fatty acid biosynthesis genes, while fatty acid β-oxidation genes were significantly decreased. Liver gene signatures also identified changes in PPARα-regulated transcript levels. With the exception of a small increase in bone area, P2Y(13) knockout mice do not show any additional major abnormalities, and display normal body weight, fat mass and lean body mass. No changes in insulin sensitivity and oral glucose tolerance could be detected. Taken together, our experiments assess a role for the purinergic receptor P2Y(13) in the regulation of lipoprotein metabolism and demonstrate that modulating its activity could be of benefit to the treatment of dyslipidemia in people.
Blom
Daniël
D
Department of Cardiovascular Diseases, Merck & Co, Inc., Rahway, NJ 07065, USA. daniel_blom@merck.com
Yamin
Ting-Ting
TT
Champy
Marie-France
MF
Selloum
Mohammed
M
Bedu
Elodie
E
Carballo-Jane
Ester
E
Gerckens
Lynn
L
Luell
Silvi
S
Meurer
Roger
R
Chin
Jayne
J
Mudgett
John
J
Puig
Oscar
O
D000818:Animals; D005260:Female; D020869:Gene Expression Profiling; D008074:Lipoproteins / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000502:physiology*
D008074:Lipoproteins; C486689:P2ry13 protein, mouse; D012333:RNA, Messenger; D018048:Receptors, Purinergic P2