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Low-density lipoprotein receptor (LDLR) family orchestrates cholesterol homeostasis.

Go GW, Mani A - Yale J Biol Med (2012)

Bottom Line: The LDLR family of proteins is involved in lipoproteins trafficking.LRP6 is a unique member of this family for its function as a co-receptor for Wnt signal transduction.The role of these receptor proteins in pathogenesis of diverse metabolic risk factors is emerging, rendering them targets of novel therapeutics for metabolic syndrome and atherosclerosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.

ABSTRACT
The LDLR family of proteins is involved in lipoproteins trafficking. While the role of LDLR in cardiovascular disease has been widely studied, only recently the role of other members of the LDLR proteins in lipoprotein homeostasis and atherosclerosis has emerged. LDLR, VLDLR, and LRPs bind and internalize apoE- and apoB-containing lipoprotein, including LDL and VLDL, and regulate their cellular uptake. LRP6 is a unique member of this family for its function as a co-receptor for Wnt signal transduction. The work in our laboratory has shown that LRP6 also plays a key role in lipoprotein and TG clearance, glucose homoeostasis, and atherosclerosis. The role of these receptor proteins in pathogenesis of diverse metabolic risk factors is emerging, rendering them targets of novel therapeutics for metabolic syndrome and atherosclerosis. This manuscript reviews the physiological role of the LDLR family of proteins and describes its involvement in pathogenesis of hyperlipidemia and atherosclerosis.

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Related in: MedlinePlus

Cellular cholesterol homeostasis. Vesicular uptake oflipoproteins is essential for lipoprotein and lipid metabolism. This processis regulated by the LDLR family of proteins. Recognition of apolipoproteinsby the receptor at neutral pH initiates the internalization, followed by ARH(also known as LDLR adaptor protein) binding of the cytoplasmic NPxY motifand clustering of receptor-ligand complexes into clathrin-coated pits.Coated vehicle dispenses to endosomes, in which acidic condition activatesthe release of internalized ligands from the receptor. Released ligandparticles travel further to lysosome, in which ligand is degraded by enzyme.The receptors recycle back to the cell surface. Internalized cholesterolreduces cholesterol biosynthesis and LDLR transcription by inhibitingSREBP-2. PCSK9 binds to LDLR, which is targeting LDLR to lysosome fordegradation. De novo lipogenesis is also reduced by inhibition of SREBP-1c.TG undergoes adipogenesis to form lipid droplet.
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Figure 2: Cellular cholesterol homeostasis. Vesicular uptake oflipoproteins is essential for lipoprotein and lipid metabolism. This processis regulated by the LDLR family of proteins. Recognition of apolipoproteinsby the receptor at neutral pH initiates the internalization, followed by ARH(also known as LDLR adaptor protein) binding of the cytoplasmic NPxY motifand clustering of receptor-ligand complexes into clathrin-coated pits.Coated vehicle dispenses to endosomes, in which acidic condition activatesthe release of internalized ligands from the receptor. Released ligandparticles travel further to lysosome, in which ligand is degraded by enzyme.The receptors recycle back to the cell surface. Internalized cholesterolreduces cholesterol biosynthesis and LDLR transcription by inhibitingSREBP-2. PCSK9 binds to LDLR, which is targeting LDLR to lysosome fordegradation. De novo lipogenesis is also reduced by inhibition of SREBP-1c.TG undergoes adipogenesis to form lipid droplet.

Mentions: LDLR is a cell membrane glycoprotein that functions in the binding and internalizingof circulating cholesterol-containing lipoprotein particles. LDLR is ubiquitouslyexpressed and is a key receptor for maintaining cholesterol homeostasis in mammals.LDLR-mediated endocytosis is essential for lipoprotein and lipid metabolism[14] (Figure 2). The clearance of LDL, a major carrierof cholesterol in human, by LDLR is extensively studied [14-19]. Recognition of apoB-100 of LDL particles occurs with astoichiometry of a single copy of apoB-100 per one LDL particle per receptor monomer[20]. VLDL, IDL,high-density lipoprotein (HDL), and chylomicron remnant are also recognized by LDLRat neutral pH [21,22]. Receptor-ligand complexes undergoendocytosis via clathrin-coated pits. Coated vehicle dispenses to endosomes withLRP6 and autosomal recessive hypercholesterolemia protein (ARH, also known as LDLRadaptor protein), connecting the LDLR family protein and the endocytic machinery;thereby, acidic condition activates dissociation of internalized ligands. Releasedligand particles further travel to the lysosome, in which the ligand is degraded byenzyme, while the receptors recycle back to the cell surface. LDLR contains sevenLDLR type A repeats in binding domain, immediately followed by EGF-like modules,transmembrane anchor, and NPxY-repeats containing cytoplasmic domain. LDL particlestrigger three steps after internalization: 1) reducing gene expression of3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) to suppress cholesterolbiosynthesis; 2) enhancing activity of acyl-CoA cholesteryl acyl transferase (ACAT)to reduce toxic free cholesterol; and 3) suppressing LDLR synthesis to reduce LDLuptake via SREBPs [23-25].


Low-density lipoprotein receptor (LDLR) family orchestrates cholesterol homeostasis.

Go GW, Mani A - Yale J Biol Med (2012)

Cellular cholesterol homeostasis. Vesicular uptake oflipoproteins is essential for lipoprotein and lipid metabolism. This processis regulated by the LDLR family of proteins. Recognition of apolipoproteinsby the receptor at neutral pH initiates the internalization, followed by ARH(also known as LDLR adaptor protein) binding of the cytoplasmic NPxY motifand clustering of receptor-ligand complexes into clathrin-coated pits.Coated vehicle dispenses to endosomes, in which acidic condition activatesthe release of internalized ligands from the receptor. Released ligandparticles travel further to lysosome, in which ligand is degraded by enzyme.The receptors recycle back to the cell surface. Internalized cholesterolreduces cholesterol biosynthesis and LDLR transcription by inhibitingSREBP-2. PCSK9 binds to LDLR, which is targeting LDLR to lysosome fordegradation. De novo lipogenesis is also reduced by inhibition of SREBP-1c.TG undergoes adipogenesis to form lipid droplet.
© Copyright Policy - open access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3313535&req=5

Figure 2: Cellular cholesterol homeostasis. Vesicular uptake oflipoproteins is essential for lipoprotein and lipid metabolism. This processis regulated by the LDLR family of proteins. Recognition of apolipoproteinsby the receptor at neutral pH initiates the internalization, followed by ARH(also known as LDLR adaptor protein) binding of the cytoplasmic NPxY motifand clustering of receptor-ligand complexes into clathrin-coated pits.Coated vehicle dispenses to endosomes, in which acidic condition activatesthe release of internalized ligands from the receptor. Released ligandparticles travel further to lysosome, in which ligand is degraded by enzyme.The receptors recycle back to the cell surface. Internalized cholesterolreduces cholesterol biosynthesis and LDLR transcription by inhibitingSREBP-2. PCSK9 binds to LDLR, which is targeting LDLR to lysosome fordegradation. De novo lipogenesis is also reduced by inhibition of SREBP-1c.TG undergoes adipogenesis to form lipid droplet.
Mentions: LDLR is a cell membrane glycoprotein that functions in the binding and internalizingof circulating cholesterol-containing lipoprotein particles. LDLR is ubiquitouslyexpressed and is a key receptor for maintaining cholesterol homeostasis in mammals.LDLR-mediated endocytosis is essential for lipoprotein and lipid metabolism[14] (Figure 2). The clearance of LDL, a major carrierof cholesterol in human, by LDLR is extensively studied [14-19]. Recognition of apoB-100 of LDL particles occurs with astoichiometry of a single copy of apoB-100 per one LDL particle per receptor monomer[20]. VLDL, IDL,high-density lipoprotein (HDL), and chylomicron remnant are also recognized by LDLRat neutral pH [21,22]. Receptor-ligand complexes undergoendocytosis via clathrin-coated pits. Coated vehicle dispenses to endosomes withLRP6 and autosomal recessive hypercholesterolemia protein (ARH, also known as LDLRadaptor protein), connecting the LDLR family protein and the endocytic machinery;thereby, acidic condition activates dissociation of internalized ligands. Releasedligand particles further travel to the lysosome, in which the ligand is degraded byenzyme, while the receptors recycle back to the cell surface. LDLR contains sevenLDLR type A repeats in binding domain, immediately followed by EGF-like modules,transmembrane anchor, and NPxY-repeats containing cytoplasmic domain. LDL particlestrigger three steps after internalization: 1) reducing gene expression of3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) to suppress cholesterolbiosynthesis; 2) enhancing activity of acyl-CoA cholesteryl acyl transferase (ACAT)to reduce toxic free cholesterol; and 3) suppressing LDLR synthesis to reduce LDLuptake via SREBPs [23-25].

Bottom Line: The LDLR family of proteins is involved in lipoproteins trafficking.LRP6 is a unique member of this family for its function as a co-receptor for Wnt signal transduction.The role of these receptor proteins in pathogenesis of diverse metabolic risk factors is emerging, rendering them targets of novel therapeutics for metabolic syndrome and atherosclerosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.

ABSTRACT
The LDLR family of proteins is involved in lipoproteins trafficking. While the role of LDLR in cardiovascular disease has been widely studied, only recently the role of other members of the LDLR proteins in lipoprotein homeostasis and atherosclerosis has emerged. LDLR, VLDLR, and LRPs bind and internalize apoE- and apoB-containing lipoprotein, including LDL and VLDL, and regulate their cellular uptake. LRP6 is a unique member of this family for its function as a co-receptor for Wnt signal transduction. The work in our laboratory has shown that LRP6 also plays a key role in lipoprotein and TG clearance, glucose homoeostasis, and atherosclerosis. The role of these receptor proteins in pathogenesis of diverse metabolic risk factors is emerging, rendering them targets of novel therapeutics for metabolic syndrome and atherosclerosis. This manuscript reviews the physiological role of the LDLR family of proteins and describes its involvement in pathogenesis of hyperlipidemia and atherosclerosis.

Show MeSH
Related in: MedlinePlus