Very low density lipoprotein (VLDL) receptor-deficient mice have reduced lipoprotein lipase activity. Possible causes of hypertriglyceridemia and reduced body mass with VLDL receptor deficiency.
Although very low density lipoprotein (VLDL) receptor (VLDLr) knockout mice have been reported to have no lipoprotein abnormalities, they develop less adipose tissue than control mice when fed a high calorie diet. Mice that are deficient in adipose tissue expression of lipoprotein lipase (LpL) also have less fat, but only when crossed with ob/ob mice. We hypothesized that the VLDLr, a protein that will bind and transport LpL, is required for optimal LpL actions in vivo and that hypertriglyceridemia due to VLDLr deficiency is exacerbated by either LpL deficiency or VLDL overproduction. Fasted VLDLr knockout (VLDLr0) mice were more hypertriglyceridemic than controls (2-fold greater triglyceride levels). The hypertriglyceridemia due to VLDLr0 was even more evident when VLDLr0 mice were crossed with heterozygous LpL-deficient (LpL1) and human apolipoprotein B (apoB) transgenic mice. This was due to an increase in apoB48-containing VLDL. [(3)H]VLDL turnover studies showed that VLDL-triglyceride clearance in VLDLr0/LpL1 mice was impaired by 50% compared with LpL1 mice. VLDLr0/LpL1 mice had less LpL activity in postheparin plasma, heart, and skeletal muscle. Infection of mice with an adenovirus-expressing receptor-associated protein, an inhibitor of the VLDLr, reduced LpL activity in wild type but not VLDLr0 mice. Therefore, the VLDLr is required for normal LpL regulation in vivo, and the disruption of VLDLr results in hypertriglyceridemia associated with decreased LpL activity.
Yagyu
Hiroaki
H
Department of Medicine, Columbia University, New York, New York 10032, USA.
Lutz
E Peer
EP
Kako
Yuko
Y
Marks
Steven
S
Hu
Yunying
Y
Choi
Sungshin Y
SY
Bensadoun
Andre
A
Goldberg
Ira J
IJ
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism; D001161:Arteriosclerosis / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D015152:Blotting, Northern; D001835:Body Weight; D002851:Chromatography, High Pressure Liquid; D005838:Genotype; D005947:Glucose / Q000378:metabolism; D015228:Hypertriglyceridemia / Q000235:genetics; D015151:Immunoblotting; D007700:Kinetics; D026563:LDL-Receptor Related Protein-Associated Protein / Q000235:genetics / Q000378:metabolism; D008071:Lipoprotein Lipase / Q000097:blood / Q000378:metabolism*; D008074:Lipoproteins / Q000097:blood; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009132:Muscles / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011973:Receptors, LDL / Q000235:genetics* / Q000502:physiology*; D013997:Time Factors; D014018:Tissue Distribution
D001055:Apolipoproteins B; D001786:Blood Glucose; D026563:LDL-Receptor Related Protein-Associated Protein; D008074:Lipoproteins; D011973:Receptors, LDL; C036053:VLDL receptor; D008071:Lipoprotein Lipase; D005947:Glucose