Patients with familial hypercholesterolemia (FH) have increased LDL levels because they do not clear LDL from the circulation efficiently. In addition to the clearance defect, many FH patients overproduce apoB-containing lipoproteins. Until recently, there has been no direct mechanism for explaining the relationship between loss of the LDL receptor and lipoprotein overproduction. We have identified a novel role for the LDL receptor. We showed that early in the secretory pathway, the presence of the LDL receptor can target newly-synthesized apoB for degradation, thus reducing the amount of apoB that is secreted. In addition to this pathway, we have confirmed work of others showing that the LDL receptor can also participate in reuptake of newly-secreted VLDL particles. We hypothesize that the LDL receptor retains apoB within the secretory pathway to enable its assembly with neutral lipids and phospholipids into a mature lipoprotein particle. With the accretion of the lipids, the particle is released and secreted. The experiments in this proposal will test this hypothesis with mice deficient in triglyceride and cholesterol synthesis as a consequence of a mutation in stearoyI-CoA desaturase. We will also use transgenic mice with various mutations in the apoB molecule to identify the segments of apoB that are critical for the interaction with the receptor within the secretory pathway. Finally, we will study various LDL receptor mutations that affect trafficking of the receptor within the cell. This will enable us to differentiate between an interaction with apoB early in the secretory pathway and an interaction that occurs after apoB secretion leading to re-uptake of the lipoprotein particles.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL056593-05
Application #
6572600
Study Section
Metabolism Study Section (MET)
Program Officer
Wassef, Momtaz K
Project Start
1998-05-01
Project End
2006-11-30
Budget Start
2002-12-18
Budget End
2003-11-30
Support Year
5
Fiscal Year
2003
Total Cost
$291,000
Indirect Cost
Name
University of Wisconsin Madison
Department
Biochemistry
Type
Schools of Earth Sciences/Natur
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Blasiole, Daniel A; Oler, Angie T; Attie, Alan D (2008) Regulation of ApoB secretion by the low density lipoprotein receptor requires exit from the endoplasmic reticulum and interaction with ApoE or ApoB. J Biol Chem 283:11374-81
Attie, Alan D; Flowers, Matthew T; Flowers, Jessica B et al. (2007) Stearoyl-CoA desaturase deficiency, hypercholesterolaemia, cholestasis and diabetes. Novartis Found Symp 286:47-53;discussion 54-7, 162-3, 1
Blasiole, Daniel A; Davis, Roger A; Attie, Alan D (2007) The physiological and molecular regulation of lipoprotein assembly and secretion. Mol Biosyst 3:608-19
Flowers, Jessica B; Rabaglia, Mary E; Schueler, Kathryn L et al. (2007) Loss of stearoyl-CoA desaturase-1 improves insulin sensitivity in lean mice but worsens diabetes in leptin-deficient obese mice. Diabetes 56:1228-39
Attie, Alan D; Flowers, Matthew T; Flowers, Jessica B et al. (2007) Stearoyl-CoA desaturase deficiency, hypercholesterolemia, cholestasis, and diabetes. Nutr Rev 65:S35-8
Nassoury, Nasha; Blasiole, Daniel A; Tebon Oler, Angie et al. (2007) The cellular trafficking of the secretory proprotein convertase PCSK9 and its dependence on the LDLR. Traffic 8:718-32
Yi, Nengjun; Shriner, Daniel; Banerjee, Samprit et al. (2007) An efficient Bayesian model selection approach for interacting quantitative trait loci models with many effects. Genetics 176:1865-77
Flowers, Matthew T; Groen, Albert K; Oler, Angie Tebon et al. (2006) Cholestasis and hypercholesterolemia in SCD1-deficient mice fed a low-fat, high-carbohydrate diet. J Lipid Res 47:2668-80
Lan, Hong; Chen, Meng; Flowers, Jessica B et al. (2006) Combined expression trait correlations and expression quantitative trait locus mapping. PLoS Genet 2:e6
Benjannet, Suzanne; Rhainds, David; Essalmani, Rachid et al. (2004) NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol. J Biol Chem 279:48865-75

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