on September 15, 2005
Published online before print September 15, 2005, doi: 10.1161/01.ATV.0000186189.26141.12
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Submitted on January 20, 2005
Accepted on September 1, 2005
Apolipoprotein A-V Deficiency Results in Marked Hypertriglyceridemia Attributable to Decreased Lipolysis of Triglyceride-Rich Lipoproteins and Removal of Their Remnants
Itamar Grosskopf *;
From the Department of Medicine (I.G., A.D.C.), School of Medicine, Stanford University, Stanford, Calif; the Research Institute (I.G., A.D.C.), Palo Alto Medical Foundation, Palo Alto, Calif; the Department of Medicine (I.G.), Tel Aviv-Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; the Department of Genome Sciences (N.B., E.M.R., L.A.P.), Lawrence Berkeley National Laboratory, Berkeley, Calif and DOE Joint Genome Institute, Walnut Creek, Calif; the Division of Food Sciences (S.-J.L.), Korea University, Seoul, Korea; the Institute of Lipid and Atherosclerosis Research (Y.K., D.H.), and the Sheba Medical Center, Tel Hashomer, Israel.
* To whom correspondence should be addressed. E-mail: itamarg{at}stanford.edu.
Objective--ApoAV, a newly discovered apoprotein, affects plasma triglyceride level. To determine how this occurs, we studied triglyceride-rich lipoprotein (TRL) metabolism in mice deficient in apoAV.
Methods and Results--No significant difference in triglyceride production rate was found between apoa5-/- mice and controls. The presence or absence of apoAV affected TRL catabolism. After the injection of 14C-palmitate and 3H-cholesterol labeled chylomicrons and 125I-labeled chylomicron remnants, the disappearance of 14C, 3H, and 125I was significantly slower in apoa5-/- mice relative to controls. This was because of diminished lipolysis of TRL and the reduced rate of uptake of their remnants in apoa5-/- mice. Observed elevated cholesterol level was caused by increased high-density lipoprotein (HDL) cholesterol in apoa5-/- mice. VLDL from apoa5-/- mice were poor substrate for lipoprotein lipase, and did not bind to the low-density lipoprotein (LDL) receptor as well as normal very-low-density lipoprotein (VLDL). LDL receptor levels were slightly elevated in apoa5-/- mice consistent with lower remnant uptake rates. These alterations may be the result of the lower apoE-to-apoC ratio found in VLDL isolated from apoa5-/- mice.
Conclusions--These results support the hypothesis that the absence of apoAV slows lipolysis of TRL and the removal of their remnants by regulating their apoproteins content after secretion.
Key words: Apoa5 • hypertriglyceridemia • knockout • lipolysis • triglyceride-rich lipoproteins
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