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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:2573.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Apolipoprotein A-V Deficiency Results in Marked Hypertriglyceridemia Attributable to Decreased Lipolysis of Triglyceride-Rich Lipoproteins and Removal of Their Remnants

Itamar Grosskopf; Nadine Baroukh; Sung-Joon Lee; Yehuda Kamari; Dror Harats; Edward M. Rubin; Len A. Pennacchio; Allen D. Cooper

From the Department of Medicine (I.G., A.D.C.), School of Medicine, Stanford University, Calif; the Research Institute (I.G., A.D.C.), Palo Alto Medical Foundation, Calififornia; the Department of Medicine (I.G.), Tel Aviv-Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, 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; the Institute of Lipid and Atherosclerosis Research (Y.K., D.H.), Sheba Medical Center, Tel Hashomer, Israel.

Correspondence to Itamar Grosskopf, Department of Medicine, Tel Aviv Sourasky Medical Center, 6 Weizmann St, Tel Aviv 64239, Israel. 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.

Absence of apoAV in mice slows lipolysis of triglyceride-rich lipoproteins and the removal of their remnants by regulating their apoproteins. In humans decreased apoAV could be atherogenic by increasing remnant residence time in the circulation. As this is elucidated the potential of apoAV as a therapeutic target will be clarified.

Key Words: Apoa5 • hypertriglyceridemia • knockout • lipolysis • triglyceride-rich lipoproteins

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