ARH missense polymorphisms and plasma cholesterol levels

2004 ◽  
Vol 42 (9) ◽  
Author(s):  
Jaroslav A. Hubacek ◽  
Tommy Hyatt
Keyword(s):  
Plasma Cholesterol ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Adaptor Protein ◽  
Low Density ◽  
Cholesterol Levels

AbstractMutations in a putative low-density lipoprotein (LDL) receptor adaptor protein called

Bone morphogenetic protein 1 cleaves the linker region between ligand-binding repeats 4 and 5 of the LDL receptor and makes the LDL receptor non-functional

2019 ◽  
Vol 29 (8) ◽  
pp. 1229-1238
Author(s):  
Thea Bismo Strøm ◽  
Katrine Bjune ◽  
Trond P Leren
Keyword(s):  
Ligand Binding ◽  
Bone Morphogenetic Protein ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Low Density ◽  
Linker Region ◽  
Cholesterol Levels ◽  
Morphogenetic Protein ◽  
Bone Morphogenetic Protein 1

Abstract The cell-surface low-density lipoprotein receptor (LDLR) internalizes low-density lipoprotein (LDL) by receptor-mediated endocytosis and plays a key role in the regulation of plasma cholesterol levels. The ligand-binding domain of the LDLR contains seven ligand-binding repeats of approximately 40 residues each. Between ligand-binding repeats 4 and 5, there is a 10-residue linker region that is subject to enzymatic cleavage. The cleaved LDLR is unable to bind LDL. In this study, we have screened a series of enzyme inhibitors in order to identify the enzyme that cleaves the linker region. These studies have identified bone morphogenetic protein 1 (BMP1) as being the cleavage enzyme. This conclusion is based upon the use of the specific BMP1 inhibitor UK 383367, silencing of the BMP1 gene by the use of siRNA or CRISPR/Cas9 technology and overexpression of wild-type BMP1 or the loss-of-function mutant E214A-BMP1. We have also shown that the propeptide of BMP1 has to be cleaved at RSRR120↓ by furin-like proprotein convertases for BMP1 to have an activity towards the LDLR. Targeting BMP1 could represent a novel strategy to increase the number of functioning LDLRs in order to lower plasma LDL cholesterol levels. However, a concern by using BMP1 inhibitors as cholesterol-lowering drugs could be the risk of side effects based on the important role of BMP1 in collagen assembly.

scholarly journals The low-density lipoprotein receptor-related protein 1 (LRP1) mediates the endocytosis of the cellular prion protein

2007 ◽  
Vol 402 (1) ◽  
pp. 17-23 ◽  
Author(s):  
David R. Taylor ◽  
Nigel M. Hooper
Keyword(s):  
Prion Protein ◽  
Low Density Lipoprotein ◽  
Neuronal Cells ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Adaptor Protein ◽  
Cellular Prion Protein ◽  
Low Density ◽  
Related Protein ◽  
Density Lipoprotein Receptor

PrPC (cellular prion protein) is located at the surface of neuronal cells in detergent-insoluble lipid rafts, yet is internalized by clathrin-dependent endocytosis. As PrPC is glycosyl-phosphatidylinositol-anchored, it requires a transmembrane adaptor protein to connect it to the clathrin endocytosis machinery. Using receptor-associated protein and small interfering RNA against particular LDL (low-density lipoprotein) family members, in combination with immunofluorescence microscopy and surface biotinylation assays, we show that the transmembrane LRP1 (LDL receptor-related protein 1) is required for the Cu2+-mediated endocytosis of PrPC in neuronal cells. We show also that another LRP1 ligand that can cause neurodegenerative disease, the Alzheimer's amyloid precursor protein, does not modulate the endocytosis of PrPC.

scholarly journals Loss of TIMP4 (Tissue Inhibitor of Metalloproteinase 4) Promotes Atherosclerotic Plaque Deposition in the Abdominal Aorta Despite Suppressed Plasma Cholesterol Levels

2021 ◽  
Author(s):  
Mei Hu ◽  
Sayantan Jana ◽  
Tolga Kilic ◽  
Faqi Wang ◽  
Mengcheng Shen ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Thoracic Aorta ◽  
Abdominal Aorta ◽  
Plasma Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Plaque Deposition ◽  
Cholesterol Levels

Objective: Atherosclerosis is accumulation of lipids and extracellular matrix in the arterial wall. TIMPs (tissue inhibitor of metalloproteinases) can impact plaque deposition by regulating ECM (extracellular matrix) turnover. TIMP4 also influences lipid metabolism and smooth muscle cell (SMC) proliferation. We investigated the role of TIMP4 in atherosclerosis. Approach and Results: Mice lacking low-density lipoprotein receptor ( Ldlr −/− ) and Timp4 ( Timp4 −/− / Ldlr −/− ) were fed high-fat diet (HFD) or regular laboratory diet. After 3 or 6 months, HFD-fed male and female Timp4 −/− / Ldlr −/− mice exhibited higher plaque density in the abdominal aorta (but not in aortic valves, arch, thoracic aorta) compared with Ldlr −/− mice. Although plasma lipid and cholesterol levels were lower in Timp4 −/− / Ldlr −/− -HFD, cholesterol content in the abdominal aorta was higher along with elevated inflammatory cytokines, MMP (matrix metalloproteinase) activities, CD68 + /calponin + macrophage-like SMCs in Timp4 −/− / Ldlr −/− -HFD compared with Ldlr −/− -HFD mice. In vitro, oxidized LDL (low-density lipoprotein) markedly increased CD68 expression, reduced SMC markers, increased lipid uptake, and reduced cholesterol efflux protein ABCA1 (ATP-binding cassette transporter A1) in Timp4 −/− / Ldlr −/− compared with Ldlr −/− primary SMCs from abdominal, but not thoracic aorta. TIMP4 expression in the abdominal aorta (in vivo) and its corresponding SMCs (in vitro) was ≈2-fold higher than in the thoracic aorta and SMCs; TIMP4 levels decreased following HFD. Timp4 -deficiency in bone marrow–derived macrophages did not alter their foam cell formation capacity. Conclusions: TIMP4 protects against plaque deposition in the abdominal aorta independent of plasma cholesterol levels. TIMP4 prevents proteolytic degradation of ABCA1 in SMCs, hindering cholesterol accumulation and transdifferentiation to macrophage-like foam cells, representing a novel negative regulator of atherosclerosis.

Plasma Lipid and Lipoprotein Abnormalities in Patients with Malabsorption

1973 ◽  
Vol 45 (5) ◽  
pp. 583-592 ◽  
Author(s):  
Gilbert R. Thompson ◽  
J. Paul Miller
Keyword(s):  
Plasma Lipids ◽  
Plasma Cholesterol ◽  
Low Density Lipoprotein ◽  
Plasma Lipid ◽  
Density Lipoprotein ◽  
Serum Triglyceride ◽  
Plasma Lipoproteins ◽  
Low Density ◽  
Cholesterol Levels ◽  
Lipids And Lipoproteins

1. Plasma lipids and lipoproteins have been studied in control subjects and patients with various types of steatorrhoea. 2. Low plasma cholesterol levels were found in malabsorbers and were associated with decreased amounts of low-density lipoprotein (LDL) in males and high-density lipoprotein (HDL) in females. 3. Serum triglyceride levels were normal in males, but exceeded control values in some of the females, due to an increase in very-low-density lipoprotein. 4. LDL composition was abnormal in both male and female malabsorbers, with a decreased proportion of cholesterol ester and an increased proportion of triglyceride. There was also an increased proportion of triglyceride in HDL. 5. These findings show that malabsorption markedly influences not only the concentration but also the composition of plasma lipoproteins.

Mutations that affect membrane receptor for LDL are useful for studying normal receptor function

1982 ◽  
Vol 243 (1) ◽  
pp. E5-E14
Author(s):  
R. G. Anderson
Keyword(s):  
Cell Biology ◽  
Cholesterol Metabolism ◽  
Plasma Cholesterol ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Cholesterol Transport ◽  
Low Density ◽  
Receptor Function ◽  
Coated Pits

Low-density lipoprotein (LDL), the major plasma cholesterol transport protein, is taken up by cells through a receptor-mediated process. After internalization through specialized segments of the cell surface called coated pits, the LDL is degraded in the lysosome and the released cholesterol is used by cells to meet various metabolic needs. The discovery of the LDL receptor and the studies of its function have provided new insights into both the biochemical aspects of cholesterol metabolism and the cell biology of receptor-mediated endocytosis. Of paramount importance in all of these studies has been the availability of human cells that express one or more allelic mutations that affect the function of the LDL receptor. These mutations have been valuable for assessing normal receptor function. Just as important, these mutations have been used as a reference point in the development of various cytochemical and biochemical techniques for studying receptor activity.

Hepatic low-density lipoprotein receptor–related protein deficiency in mice increases atherosclerosis independent of plasma cholesterol

Blood ◽  
2004 ◽  
Vol 103 (10) ◽  
pp. 3777-3782 ◽  
Author(s):  
Sonia M. S. Espirito Santo ◽  
Nuno M. M. Pires ◽  
Lianne S. M. Boesten ◽  
Gery Gerritsen ◽  
Niels Bovenschen ◽  
...  
Keyword(s):  
Plasma Cholesterol ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Atherosclerotic Lesion ◽  
Density Lipoprotein ◽  
Coagulation Factor ◽  
Tissue Type ◽  
Low Density ◽  
Related Protein ◽  
Remnant Lipoproteins

Abstract The low-density lipoprotein (LDL) receptor–related protein (LRP) has a well-established role in the hepatic removal of atherogenic apolipoprotein E (APOE)–rich remnant lipoproteins from plasma. In addition, LRP recognizes multiple distinct pro- and antiatherogenic ligands in vitro. Here, we investigated the role of hepatic LRP in atherogenesis independent of its role in removal of APOE-rich remnant lipoproteins. Mice that allow inducible inactivation of hepatic LRP were combined with LDL receptor and APOE double-deficient mice (MX1Cre+LRPflox/floxLDLR–/–APOE–/–). On an LDLR–/–APOE–/– background, hepatic LRP deficiency resulted in decreased plasma cholesterol and triglycerides (cholesterol: 17.1 ± 5.2 vs 23.4 ± 6.3 mM, P = .025; triglycerides: 1.1 ± 0.5 vs 2.2 ± 0.8 mM, P = .002, for MX1Cre+LRPflox/flox-LDLR–/–APOE–/– and control LRPflox/flox-LDLR–/–APOE–/– mice, respectively). Lower plasma cholesterol in MX1Cre+LRPflox/flox-LDLR–/–APOE–/– mice coincided with increased plasma lipoprotein lipase (71.2 ± 7.5 vs 19.1 ± 2.4 ng/ml, P = .002), coagulation factor VIII (4.4 ± 1.1 vs 1.9 ± 0.5 U/mL, P = .001), von Willebrand factor (2.8 ± 0.6 vs 1.4 ± 0.3 U/mL, P = .001), and tissue-type plasminogen activator (1.7 ± 0.7 vs 0.9 ± 0.5 ng/ml, P = .008) compared with controls. Strikingly, MX1Cre+LRPflox/floxLDLR–/–APOE–/– mice showed a 2-fold higher atherosclerotic lesion area compared with controls (408.5 ± 115.1 vs 219.1 ± 86.0 103μm2, P = .003). Our data indicate that hepatic LRP plays a clear protective role in atherogenesis independent of plasma cholesterol, possibly due to maintaining low levels of its proatherogenic ligands.

scholarly journals Membrane type 1 matrix metalloproteinase promotes LDL receptor shedding and accelerates the development of atherosclerosis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Adekunle Alabi ◽  
Xiao-Dan Xia ◽  
Hong-Mei Gu ◽  
Faqi Wang ◽  
Shi-Jun Deng ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Plasma Cholesterol ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
High Plasma ◽  
Extracellular Milieu ◽  
Cholesterol Levels ◽  
Membrane Type

AbstractPlasma low-density lipoprotein (LDL) is primarily cleared by LDL receptor (LDLR). LDLR can be proteolytically cleaved to release its soluble ectodomain (sLDLR) into extracellular milieu. However, the proteinase responsible for LDLR cleavage is unknown. Here we report that membrane type 1-matrix metalloproteinase (MT1-MMP) co-immunoprecipitates and co-localizes with LDLR and promotes LDLR cleavage. Plasma sLDLR and cholesterol levels are reduced while hepatic LDLR is increased in mice lacking hepatic MT1-MMP. Opposite effects are observed when MT1-MMP is overexpressed. MT1-MMP overexpression significantly increases atherosclerotic lesions, while MT1-MMP knockdown significantly reduces cholesteryl ester accumulation in the aortas of apolipoprotein E (apoE) knockout mice. Furthermore, sLDLR is associated with apoB and apoE-containing lipoproteins in mouse and human plasma. Plasma levels of sLDLR are significantly increased in subjects with high plasma LDL cholesterol levels. Thus, we demonstrate that MT1-MMP promotes ectodomain shedding of hepatic LDLR, thereby regulating plasma cholesterol levels and the development of atherosclerosis.

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