Abstract
Background
While the role of insulin in glucose uptake and its aberration in diabetes are well
established, the effect of insulin on lipoprotein clearance in the postprandial phase
is not yet fully understood. The dietary lipids are carried in chylomicron remnants
(CR) which are taken up into the liver mainly via LDLR-related protein 1 (LRP1). In
this study, the effect of insulin on LRP1-mediated hepatic CR uptake was investigated.
Methods
The study was based on determining the subcellular localisation of LRP1 by subcellular
fractionation and immunofluorescence microscopy and correlating those findings with
the hepatic uptake of fluorescently or radioactively labelled LRP1-specific ligands
and CR in hepatoma cells, primary hepatocytes and mouse models.
Results and conclusion
In vitro and in vivo, insulin stimulated the translocation of hepatic LRP1 from intracellular vesicles
to the plasma membrane, which correlates with an increased uptake of LRP1-specific
ligands. In wild-type mice, a glucose-induced insulin response increased the hepatic
uptake of LRP1 ligands while in leptin-deficient obese mice (ob/ob), which are characterised by hepatic insulin resistance, insulin-inducible LRP1 ligand
uptake was abolished. Finally, upon hepatic LRP1 knockdown, insulin no longer significantly
enhanced CR uptake into the liver. The insulin-induced LRP1-mediated CR uptake, as
demonstrated here, suggests that impaired hepatic LRP1 translocation can contribute
to the postprandial lipaemia in insulin resistance.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to AtherosclerosisAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
Reference
- Hepatic catabolism of remnant lipoproteins: where the action is.Arterioscler Thromb Vasc Biol. 2004; 24: 213-215
- Apolipoprotein E recycling: implications for dyslipidemia and atherosclerosis.Arterioscler Thromb Vasc Biol. 2006; 26: 442-448
- Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia). Questions, quandaries, and paradoxes.J Lipid Res. 1999; 40: 1933-1949
- Liver heparan sulfate proteoglycans mediate clearance of triglyceride-rich lipoproteins independently of LDL receptor family members.J Clin Invest. 2007; 117: 153-164
- Scavenger receptor BI plays a role in facilitating chylomicron metabolism.J Biol Chem. 2004; 279: 18401-18406
- Inducible inactivation of hepatic LRP gene by cre-mediated recombination confirms role of LRP in clearance of chylomicron remnants.J Clin Invest. 1998; 101: 689-695
- Lipoprotein clearance mechanisms in LDL receptor-deficient “Apo-B48-only” and “Apo-B100-only” mice.J Clin Invest. 1998; 102: 1559-1568
- The LDL-receptor-related protein, LRP, is an apolipoprotein E-binding protein.Nature. 1989; 341: 162-164
- Low density lipoprotein receptor-related protein mediates uptake of cholesteryl esters derived from apoprotein E-enriched lipoproteins.Proc Natl Acad Sci USA. 1989; 86: 5810-5814
- Lipoprotein lipase enhances the binding of chylomicrons to low density lipoprotein receptor-related protein.Proc Natl Acad Sci USA. 1991; 88: 8342-8346
- The alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein binds lipoprotein lipase and beta-migrating very low density lipoprotein associated with the lipase.J Biol Chem. 1993; 268: 15048-15055
- Endothelial-derived lipoprotein lipase is bound to postprandial triglyceride-rich lipoproteins and mediates their hepatic clearance in vivo.J Mol Med. 2002; 80: 576-584
- The low-density-lipoprotein receptor-related protein (LRP) is processed by furin in vivo and in vitro.Biochem J. 1996; 313: 71-76
- Functional expression of low density lipoprotein receptor-related protein is controlled by receptor-associated protein in vivo.Proc Natl Acad Sci USA. 1995; 92: 4537-4541
- Postprandial lipoprotein metabolism and atherosclerosis.J Intern Med. 1999; 246: 341-355
- Elevated triglyceride-rich lipoproteins in diabetes. A study of apolipoprotein B-48.Acta Diabetol. 1996; 33: 205-210
- Overproduction of VLDL1 driven by hyperglycemia is a dominant feature of diabetic dyslipidemia.Arterioscler Thromb Vasc Biol. 2005; 25: 1697-1703
- Adipocyte signaling and lipid homeostasis: sequelae of insulin-resistant adipose tissue.Circ Res. 2005; 96: 1042-1052
- Changes in matrix proteoglycans induced by insulin and fatty acids in hepatic cells may contribute to dyslipidemia of insulin resistance.Diabetes. 2001; 50: 2126-2132
- Fatty acid-induced atherogenic changes in extracellular matrix proteoglycans.Curr Opin Lipidol. 2007; 18: 546-553
- GeneQuest Investigators. Large scale association analysis for identification of genes underlying premature coronary heart disease: cumulative perspective from analysis of 111 candidate genes.J Med Genet. 2004; 41: 334-341
- Influence of exonic polymorphisms in the gene for LDL receptor-related protein (LRP) on risk of coronary artery disease.Atherosclerosis. 2003; 168: 115-121
- LRP: a multifunctional scavenger and signaling receptor.J Clin Invest. 2001; 108: 779-784
Herz J, Clouthier DE, Hammer RE. LDL receptor-related protein internalizes and degrades uPA-PAI-1 complexes and is essential for embryo implantation. Cell 1992; 71:411–21 [erratum 1993;73:428].
- Insulin increases the cell surface concentration of alpha 2-macroglobulin receptors in 3T3-L1 adipocytes. Altered transit of the receptor among intracellular endocytic compartments.J Biol Chem. 1989; 264: 10133-10138
- Insulin stimulates receptor-mediated uptake of apoE-enriched lipoproteins and activated alpha 2-macroglobulin in adipocytes.J Biol Chem. 1993; 268: 974-981
- Purified alpha 2-macroglobulin receptor/LDL receptor-related protein binds urokinase plasminogen activator inhibitor type-1 complex. Evidence that the alpha 2-macroglobulin receptor mediates cellular degradation of urokinase receptor-bound complexes.J Biol Chem. 1992; 267: 14543-14546
- Purification of human plasma alpha 2 macroglobulin and alpha 1 proteinase inhibitor using zinc chelate chromatography.Anal Biochem. 1979; 99: 415-420
- Impaired recycling of apolipoprotein E4 is associated with intracellular cholesterol accumulation.J Biol Chem. 2004; 279: 55483-55492
- A radioiodinated, intracellularly trapped ligand for determining the sites of plasma protein degradation in vivo.Biochem J. 1983; 212: 791-800
- Apolipoprotein AV accelerates plasma hydrolysis of triglyceride-rich lipoproteins by interaction with proteoglycan-bound lipoprotein lipase.J Biol Chem. 2005; 280: 21553-21560
- Rat hepatocytes prepared without collagenase: prolonged retention of differentiated characteristics in culture.Cell Biol Toxicol. 1988; 4: 405-425
- Recycling of apolipoprotein E and lipoprotein lipase through endosomal compartments in vivo.J Biol Chem. 2001; 276: 42333-42338
- Differential RNA interference: replacement of endogenous with recombinant low density lipoprotein receptor-related protein (LRP).Eur J Cell Biol. 2004; 83: 113-120
- Improved glucose and lipid metabolism in genetically obese mice lacking aP2.Endocrinology. 2000; 141: 3388-3396
- Current protocols in cell biology.John Wiley & Sons, Hoboken, New York1999 (3.2.1–3.2.16)
- Knockdown of hepatic ABCA1 by RNA interference decreases plasma HDL cholesterol levels and influences postprandial lipemia in mice.Arterioscler Thromb Vasc Biol. 2005; 25: 1433-1438
- Telomerase expression extends the proliferative life-span and maintains the osteogenic potential of human bone marrow stromal cells.Nat Biotechnol. 2002; 20: 592-596
- The 39-kDa receptor-associated protein interacts with two members of the low density lipoprotein receptor family, alpha 2-macroglobulin receptor and glycoprotein 330.J Biol Chem. 1992; 267: 21162-21166
- Surface location and high affinity for calcium of a 500-kd liver membrane protein closely related to the LDL-receptor suggest a physiological role as lipoprotein receptor.EMBO J. 1988; 7: 4119-4127
- Genetic background (C57BL/6J versus FVB/N) strongly influences the severity of diabetes and insulin resistance in ob/ob mice.Endocrinology. 2004; 145: 3258-3264
- Sorting of major cargo glycoproteins into clathrin-coated vesicles.Traffic. 2005; 6: 1014-1026
- Coordinate regulation of the alpha(2)-macroglobulin signaling receptor and the low density lipoprotein receptor-related protein/alpha(2)-macroglobulin receptor by insulin.J Biol Chem. 1999; 274: 25785-25791
- Ins (endocytosis) and outs (exocytosis) of GLUT4 trafficking.Curr Opin Cell Biol. 1999; 19: 466-473
- Interactions of the low density lipoprotein receptor gene family with cytosolic adaptor and scaffold proteins suggest diverse biological functions in cellular communication and signal transduction.J Biol Chem. 2000; 275: 25616-25624
- Structural and evolutionary division of phosphotyrosine binding (PTB) domains.J Mol Biol. 2005; 345: 1-20
- Dissection of the insulin signaling pathway via quantitative phosphoproteomics.Proc Natl Acad Sci USA. 2008; 105: 2451-2456
- Beyond endocytosis: LRP function in cell migration, proliferation and vascular permeability.J Thromb Haemost. 2005; 3: 1884-1893
- Modulation of lipoprotein receptor functions by intracellular adaptor proteins.Cell Signal. 2006; 18: 1560-1571
- The YXXL motif, but not the two NPXY motifs, serves as the dominant endocytosis signal for low density lipoprotein receptor-related protein.J Biol Chem. 2000; 275: 17187-17194
- Serine and threonine phosphorylation of the low density lipoprotein receptor-related protein by protein kinase Calpha regulates endocytosis and association with adaptor molecules.J Biol Chem. 2004; 279: 40536-40544
- Type 2 diabetes, dyslipidemia, and vascular risk: rationale and evidence for correcting the lipid imbalance.Am Heart J. 2005; 150: 859-870
- Insulin facilitates the hepatic clearance of plasma amyloid beta-peptide (1 40) by intracellular translocation of low-density lipoprotein receptor-related protein 1 (LRP-1) to the plasma membrane in hepatocytes.Mol Pharmacol. 2007; 72: 850-855
Article Info
Publication History
Published online: October 03, 2008
Accepted:
July 30,
2008
Received in revised form:
July 28,
2008
Received:
June 20,
2008
Identification
Copyright
© 2008 Elsevier Ireland Ltd. Published by Elsevier Inc. All rights reserved.