Cholesteryl ester transfer protein (CETP) increases postprandial triglyceridaemia and delays triacylglycerol plasma clearance in transgenic mice.
The CETP (cholesteryl ester transfer protein) is a plasma protein synthesized in several tissues, mainly in the liver; CETP reduces plasma HDL (high-density lipoprotein) cholesterol and increases the risk of atherosclerosis. The effect of CETP levels on postprandial intravascular metabolism of TAGs (triacylglycerols) is an often-overlooked aspect of the relationship between CETP and lipoprotein metabolism. Here, we tested the hypothesis that CETP delays the plasma clearance of TAG-rich lipoprotein by comparing human CETP expressing Tg (transgenic) and non-Tg mice. After an oral fat load, the postprandial triglyceridaemia curve was markedly increased in CETP-Tg compared with non-Tg mice (280+/-30 versus 190+/-20 mg/dl per 6 h respectively, P<0.02). No differences in intestinal fat absorption and VLDL (very-low-density lipoprotein) secretion rates were observed. Kinetic studies of double-labelled chylomicron-like EMs (emulsions) showed that both [(3)H]triolein and [(14)C]cholesteryl oleate FCRs (fractional clearance rates) were significantly reduced ( approximately 20%) in CETP-Tg mice. Furthermore, TAG from lipid EM pre-incubated with CETP-Tg plasma had plasma clearance and liver uptake significantly lower than the non-Tg plasma-treated lipid EM. In addition, reductions in post-heparin plasma LPL (lipoprotein lipase) activity (50%) and adipose tissue mRNA abundance (39%) were verified in CETP-Tg mice. Therefore we conclude that CETP expression in Tg mice delays plasma clearance and liver uptake of TAG-rich lipoproteins by two mechanisms: (i) transferring TAG to HDLs and increasing CE content of the remnant particles and (ii) by diminishing LPL expression. These findings show that the level of CETP expression can influence the responsiveness to dietary fat and may lead to fat intolerance.
Salerno
Alessandro G
AG
Departamento Fisiologia e Biofísica, Instituto de Biologia, UNICAMP (Universidade Estadual de Campinas), Campinas, SP, Brazil.
Patrício
Patrícia R
PR
Berti
Jairo A
JA
Oliveira
Helena C F
HC
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D053480:Cholesterol Ester Transfer Proteins / Q000378:metabolism*; D015243:Cholesterol, VLDL / Q000378:metabolism; D002914:Chylomicrons / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology; D004655:Emulsions; D005215:Fasting / Q000097:blood; D005260:Female; D006949:Hyperlipidemias / Q000097:blood*; D007408:Intestinal Absorption / Q000187:drug effects; D026502:LDL-Receptor Related Proteins / Q000378:metabolism; D008071:Lipoprotein Lipase / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009929:Organ Size / Q000187:drug effects; D019518:Postprandial Period / Q000187:drug effects; D014280:Triglycerides / Q000097:blood*
D001786:Blood Glucose; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D015243:Cholesterol, VLDL; D002914:Chylomicrons; D004041:Dietary Fats; D004655:Emulsions; D026502:LDL-Receptor Related Proteins; D014280:Triglycerides; D008071:Lipoprotein Lipase