WITHDRAWN: Low Density Lipoprotein Receptor Related Protein 6-mediated Cardiovascular Diseases and associated signaling pathways
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According to the secretion-capture model of remnant lipoprotein clearance, apo E secreted by hepatocytes into the space of Disse serves to enrich the remnants with a ligand for receptor-mediated lipoprotein endocytosis. Current evidence supports a two-receptor model of lipoprotein removal, in which apo E-containing remnants bind either the low density lipoprotein receptor (LDLR) or the LDLR-related protein (LRP). Recently, we demonstrated that reconstitution of apo E(-/-) mice with apo E(+/+) marrow results in normalization of plasma lipoprotein levels, indicating that hepatic expression of apo E is not required for remnant clearance and calling into question the relevance of the secretion-capture mechanism. To dissect the relative contributions of LDLR and LRP to the cellular catabolism of remnant lipoproteins by the hepatocyte, bone marrow transplantation (BMT) was used to reconstitute macrophage expression of apo E in mice that were null for expression of both apo E and the LDLR. Reconstitution of macrophage apo E in apo E(-/-)/LDLR(-/-) mice had no effect on serum lipid and lipoprotein concentrations, although it produced plasma apo E levels up to 16-fold higher than in C57BL/6 controls. Immunocytochemistry of hepatic sections revealed abundant staining for apo E in the space of Disse, but no evidence of receptor-mediated endocytosis of remnant lipoproteins. Transient expression of human LDLR in the livers of apo E(+/+)--> apo E(-/-)/LDLR(-/-) mice by adenoviral gene transfer resulted in normalization of serum lipid levels and in the clearance of apo E-containing lipoproteins from the space of Disse. We conclude that whereas the LDLR efficiently clears remnant lipoproteins irrespective of the site of origin of apo E, endocytosis by the chylomicron remnant receptor (LRP) is absolutely dependent on hepatic expression of apo E. These data demonstrate in vivo the physiologic relevance of the apo E secretion-capture mechanism in the liver.
Perisinusoidal space
Apolipoprotein E
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Lack of animal models with human-like lipoprotein metabolism and pathology has hampered translational research in atherosclerosis. Recently, a model of familial hypercholesterolemia was developed in Yucatan miniature pigs, in which the LDL receptor (LDLR) was deleted through gene targeting of exon 4. The objective of the present study was to determine the plasma lipoprotein response to a high fat diet and the kinetics of apolipoprotein (apo) B metabolism in LDLR-deficient miniature pigs. LDLR+/+ (n=5), LDLR+/- pigs (n=6) and LDLR-/- pigs (n=5) were fed a diet containing 34% kcal from fat and 0.2% cholesterol (C). At 6 weeks, the kinetics of plasma apoB100 (fasting) were measured using stable isotopic techniques and multi-compartmental modeling. In chow-fed pigs, LDL-C was 0.8mM, 1.3mM and 14mM in LDLR+/+, LDLR+/- and LDLR-/- pigs, respectively. On diet for 6 weeks, LDL-C increased 1.3-fold (to 1.09mM), 1.7-fold (to 2.3mM) and 1.2-fold (to 15.8mM) in LDLR+/+, LDLR+/- and LDLR-/- pigs, respectively. The effect of genotype or diet on plasma TG and HDL-C was modest. Compared to LDLR+/+ pigs, VLDL apoB100 pool sizes increased 1.4-fold in LDLR+/- and 1.7-fold in LDLR-/- pigs, due primarily to a decrease in fractional catabolic rates (FCR) of 18% and 63%, respectively. Compared to LDL+/+ pigs, LDL apoB100 pool sizes increased 2.2-fold and 14-fold in LDLR+/- and LDLR-/-, respectively, which was due to both 1.5-fold and 2-fold increases in production rates and 24% and 85% decreases in FCR, respectively. At 23 weeks, raised lesion area in the abdominal aorta was 3.3% in LDLR+/- pigs and 48.5% in LDLR-/- pigs. In the left anterior descending coronary artery, lesion area was 14.7x10 3 μm 2 in LDLR+/- pigs and 656x10 3 μm 2 in LDLR-/- pigs. This model should prove useful for translational research in lipoprotein metabolism and atherosclerosis.
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Scavenger receptor class B type 1 (SR-B1) and low-density lipoprotein receptor (LDLR) are known to be involved in entry of hepatitis C virus (HCV), but their precise roles and their interplay are not fully understood. In this study, deficiency of both SR-B1 and LDLR in Huh7 cells was shown to impair the entry of HCV more strongly than deficiency of either SR-B1 or LDLR alone. In addition, exogenous expression of not only SR-B1 and LDLR but also very low-density lipoprotein receptor (VLDLR) rescued HCV entry in the SR-B1 and LDLR double-knockout cells, suggesting that VLDLR has similar roles in HCV entry. VLDLR is a lipoprotein receptor, but the level of its hepatic expression was lower than those of SR-B1 and LDLR. Moreover, expression of mutant lipoprotein receptors incapable of binding to or uptake of lipid resulted in no or slight enhancement of HCV entry in the double-knockout cells, suggesting that binding and/or uptake activities of lipid by lipoprotein receptors are essential for HCV entry. In addition, rescue of infectivity in the double-knockout cells by the expression of the lipoprotein receptors was not observed following infection with pseudotype particles bearing HCV envelope proteins produced in non-hepatic cells, suggesting that lipoproteins associated with HCV particles participate in the entry through their interaction with lipoprotein receptors. Buoyant density gradient analysis revealed that HCV utilizes these lipoprotein receptors in a manner dependent on the lipoproteins associated with HCV particles. Collectively, these results suggest that lipoprotein receptors redundantly participate in the entry of HCV.
Scavenger Receptor
Low-density lipoprotein
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Clearance of circulating low-density lipoprotein cholesterol (LDLc) by hepatic LDL receptors (LDLR) is central for vascular health. Secreted by hepatocytes, PCSK9 induces the degradation of LDLR, resulting in higher plasma LDLc levels. Still, it remains unknown why LDLR and PCSK9 co-exist within the secretory pathway of hepatocytes without leading to complete degradation of LDLR. Herein, we identified the ER-resident GRP94, and more precisely its client-binding C-terminal domain, as a PCSK9-LDLR inhibitory binding protein. Depletion of GRP94 did not affect calcium homeostasis, induce ER stress, nor did it alter PCSK9 processing or its secretion but greatly increased its capacity to induce LDLR degradation. Accordingly, we found that hepatocyte-specific Grp94-deficient mice have higher plasma LDLc levels correlated with ∼ 80% reduction in hepatic LDLR protein levels. Thus, we provide evidence that, in physiological conditions, binding of PCSK9 to GRP94 protects LDLR from degradation likely by preventing early binding of PCSK9 to LDLR within the ER.
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The hepatic low-density lipoprotein receptor( LDLR) pathway is essential for clearing circulating LDL and is an important therapeutic target for treating cardiovascular disease.Abundance of the LDLR is subject to both transcriptional and non-transcriptional control.Here,we highlight a new post-transcriptional mechanism for controlling LDLR function via ubiquitination of the receptor by the inducible degrader of the LDLR( Idol).Idol is a recently identified transcriptional target of the liver X receptors( LXR),acting as an E3-ubiquitin ligase.Idol promotes ubiquitination of the LDLR,thereby marking it for lysosomal degradation.Idol also targets two related lipoprotein receptors,the very low-density lipoprotein receptor and apolipoprotein E receptor 2.Despite several similarities,the Idol and PCSK9 pathways for controlling LDLR abundance seem independent of each other.Recent work has also suggested links between Idol and human LDL levels,thereby highlighting the possible role of Idol in human lipoprotein metabolism.
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Low-density lipoprotein
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Familial hypercholesterolemia is the consequence of various mutations in the low-density lipoprotein receptor (LDLR). In the current study, we show that a specialized molecular chaperone, the receptor-associated protein (RAP), promotes proper folding and subsequent exocytic trafficking of the wild-type LDLR and several of its class 2 mutants. Co-immunoprecipitation with anti-RAP antibody demonstrates that RAP interacts with the LDLR. Kinetic analyses of LDLR posttranslational folding and maturation in the absence or presence of RAP coexpression show that RAP prevents aggregation and promotes the maturation of the LDLR. Additionally, depletion of Ca(2+) in intact cells impairs LDLR folding, and coexpression of RAP partially corrects this misfolding. Finally, we show that the increased mature cell surface LDLR in the presence of RAP coexpression is functional in its ability to endocytose and degrade (125)I-LDL. Taken together, our results show that the folding, trafficking, and maturation of the LDLR and its class 2 mutants are promoted by RAP.
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Chaperone (clinical)
Folding (DSP implementation)
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CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL
The low-density lipoprotein receptor (LDLR) plays a pivotal role in clearing atherogenic circulating low-density lipoprotein (LDL) cholesterol. Here we show that the COMMD/CCDC22/CCDC93 (CCC) and the Wiskott-Aldrich syndrome protein and SCAR homologue (WASH) complexes are both crucial for endosomal sorting of LDLR and for its function. We find that patients with X-linked intellectual disability caused by mutations in CCDC22 are hypercholesterolaemic, and that COMMD1-deficient dogs and liver-specific Commd1 knockout mice have elevated plasma LDL cholesterol levels. Furthermore, Commd1 depletion results in mislocalization of LDLR, accompanied by decreased LDL uptake. Increased total plasma cholesterol levels are also seen in hepatic COMMD9-deficient mice. Inactivation of the CCC-associated WASH complex causes LDLR mislocalization, increased lysosomal degradation of LDLR and impaired LDL uptake. Furthermore, a mutation in the WASH component KIAA0196 (strumpellin) is associated with hypercholesterolaemia in humans. Altogether, this study provides valuable insights into the mechanisms regulating cholesterol homeostasis and LDLR trafficking.
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Abstract Familial hypercholesterolemia (FH) is a severe inherited lipid metabolism dysfunction, characterized by high low‐density lipoprotein (LDL) cholesterol levels, mostly due to mutations in the LDL receptor ( LDLR ) gene. Whole exome sequencing was performed on a consanguineous Chinese FH family and identified a novel homozygous pathogenic mutation LDLR c.C2164T (p. Q722*), forming a novel truncated soluble LDLR Q722* . LDLR Q722* was secreted via the small extracellular vesicles (sEV) and located on the surface of sEV. LDLR Q722* exhibit ∼6% of the wild‐type LDLR activity. sEV containing LDLR Q722* protein reconstructed the lipid metabolism via heparan sulfate proteoglycans (HSPG) and clathrin‐mediated endocytosis. Currently, statins and PCSK9 inhibitors therapy are the mainstay treatment for FH. However, statins and PCSK9 inhibitors substantially vary depending on the residual LDLR activity, while LDLR Q722* reduced circulating LDL‐C levels independently of LDLR residual activity. The study provided new insight into the treatments of FH.
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