Mice lacking prostaglandin E receptor subtype 4 manifest disrupted lipid metabolism attributable to impaired triglyceride clearance.
Upon high-fat feeding, prostaglandin E receptor subtype 4 (EP4)-knockout mice gain less body weight than their EP4(+/+) littermates. We investigated the cause of the lean phenotype. The mice showed a 68.8% reduction in weight gain with diminished fat mass that was not attributable to reduced food intake, fat malabsorption, or increased energy expenditure. Plasma triglycerides in the mice were elevated by 244.9%. The increase in plasma triglycerides was independent of changes in hepatic very low density lipoprotein (VLDL)-triglyceride production or intestinal chylomicron-triglyceride synthesis. However, VLDL-triglyceride clearance was drastically impaired in the EP4-knockout mice. The absence of EP4 in mice compromised the activation of lipoprotein lipase (LPL), the key enzyme responsible for trafficking of plasma triglycerides into peripheral tissues. Deficiency in EP4 reduced hepatic mRNA expression of the transcriptional factor cAMP response element binding protein H (by 36.8%) and LPL activators, including apolipoprotein (Apo)a5 (by 40.2%) and Apoc2 (by 61.3%). In summary, the lean phenotype of EP4-deficient mice resulted from reduction in adipose tissue and accretion of other peripheral organs caused by impaired triglyceride clearance. The findings identify a new metabolic dimension in the physiologic role played by endogenous EP4.
*Department of Pharmacology and Pharmacy, Department of Medicine, Department of Physiology, and the State Key Laboratory of Pharmaceutical Biotechnology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
Yin
Y
Cai
*Department of Pharmacology and Pharmacy, Department of Medicine, Department of Physiology, and the State Key Laboratory of Pharmaceutical Biotechnology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
Fan
F
Ying
*Department of Pharmacology and Pharmacy, Department of Medicine, Department of Physiology, and the State Key Laboratory of Pharmaceutical Biotechnology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
Erfei
E
Song
*Department of Pharmacology and Pharmacy, Department of Medicine, Department of Physiology, and the State Key Laboratory of Pharmaceutical Biotechnology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
Yu
Y
Wang
*Department of Pharmacology and Pharmacy, Department of Medicine, Department of Physiology, and the State Key Laboratory of Pharmaceutical Biotechnology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
Aimin
A
Xu
*Department of Pharmacology and Pharmacy, Department of Medicine, Department of Physiology, and the State Key Laboratory of Pharmaceutical Biotechnology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
Paul M
PM
Vanhoutte
*Department of Pharmacology and Pharmacy, Department of Medicine, Department of Physiology, and the State Key Laboratory of Pharmaceutical Biotechnology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China evatang1@hku.hk.
Eva Hoi-Ching
EH
Tang
D000818:Animals; D001823:Body Composition; D001835:Body Weight; D006706:Homeostasis; D006937:Hypercholesterolemia / Q000235:genetics; D015228:Hypertriglyceridemia / Q000235:genetics; D050356:Lipid Metabolism / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D010805:Physical Conditioning, Animal; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000235:genetics*; D014280:Triglycerides / Q000097:blood*; D015431:Weight Loss
C545651:Ptger4 protein, mouse; D058309:Receptors, Prostaglandin E, EP4 Subtype; D014280:Triglycerides
Creb-h; apolipoprotein; high-fat diet; hypertriglyceridemia; lipoprotein lipase