| 1. |
- Flood, Christofer, 1974, et al.
(författare)
-
Molecular mechanism for changes in proteoglycan binding on compositional changes of the core and the surface of low-density lipoprotein-containing human apolipoprotein B100
- 2004
-
Ingår i: Arterioscler Thromb Vasc Biol. - 1524-4636. ; 24:3, s. 564-70
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The aim of this study was to investigate the molecular mechanism for changes in proteoglycan binding and LDL receptor affinity on two compositional changes in LDL that have been associated with atherosclerosis: cholesterol enrichment of the core and modification by secretory group IIA phospholipase A2 (sPLA2) of the surface. METHODS AND RESULTS: Transgenic mice expressing recombinant apolipoprotein (apo) B and sPLA2 were generated. Recombinant LDL were isolated and tested for their proteoglycan and LDL receptor-binding activity. The results show site A (residues 3148-3158) in apoB100 becomes functional in sPLA2-modified LDL and that site A acts cooperatively with site B (residues 3359-3369), the primary proteoglycan-binding site in native LDL, in the binding of sPLA2-modified LDL to proteoglycans. Our results also show that cholesterol enrichment of LDL is associated with increased affinity for proteoglycans and for the LDL receptor. This mechanism is likely mediated by a conformational change of site B and is independent of site A in apoB100. CONCLUSIONS: Site A in apoB100 becomes functional in sPLA2-modified LDL and acts cooperatively with site B resulting in increased proteoglycan-binding activity. The increased binding for proteoglycans of cholesterol-enriched LDL is solely dependent on site B.
|
|
| 2. |
- Gustafsson, Maria, 1976, et al.
(författare)
-
Mechanism of lipoprotein retention by the extracellular matrix
- 2004
-
Ingår i: Curr Opin Lipidol. - 0957-9672. ; 15:5, s. 505-14
-
Tidskriftsartikel (refereegranskat)abstract
- PURPOSE OF REVIEW: Considerable evidence suggests that the subendothelial retention of atherogenic lipoproteins is a key early step in atherogenesis. In humans and experimental animals, elevated levels of plasma lipoproteins are associated with increased atherosclerosis, and lipoproteins with higher affinity for arterial proteoglycans are more atherogenic. Here we discuss the molecular mechanisms underlying lipoprotein retention in the arterial wall and how this interaction can be modulated. RECENT FINDINGS: Functional proteoglycan binding sites in lipoproteins containing apolipoprotein B have been identified and shown to have atherogenic potential in vivo. In addition to apolipoprotein B, novel bridging molecules, those that can interact with both proteoglycans and lipoproteins, have been identified that mediate the retention of atherogenic particles in the vessel wall. The interaction between lipoproteins and proteoglycans can be enhanced by the modification of lipoproteins in the circulation and in the arterial wall, by alterations in the subendothelium, and by changes in proteoglycan synthesis that result in a more atherogenic profile. The retention of atherogenic lipoproteins is a potential target for therapies to reverse atherosclerosis, and in-vitro studies have identified compounds that decrease the affinity of proteoglycans for lipoproteins. SUMMARY: Considerable progress has been made in understanding the association between lipoproteins and cardiovascular disease. This review highlights the importance of the interaction between lipoproteins and the arterial matrix.
|
|
| 3. |
- Gustafsson, Maria, 1976, et al.
(författare)
-
Retention of atherogenic lipoproteins in atherogenesis
- 2004
-
Ingår i: Cell Mol Life Sci. - : Springer Science and Business Media LLC. - 1420-682X. ; 61:1, s. 4-9
-
Tidskriftsartikel (refereegranskat)abstract
- Atherosclerosis is a multifactorial disease whose pathogenesis is still unclear. Mounting evidence, however, supports the concept that subendothelial retention of apoB100-containing lipoproteins is the initiating event in atherogenesis. Subsequently, a series of biological responses to this retained material leads to specific molecular and cellular processes that promote lesion formation.
|
|
| 4. |
- Gustafsson, Maria, 1976
(författare)
-
Retention of atherogenic lipoproteins in atherogenesis
- 2004
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Atherosclerosis is the most common cause of death in the industrialized world. The diseaseis characterized by lipid accumulation and inflammation in the arterial wall, which may leadto obstruction of the blood flow. Lipoprotein retention is a key step in the pathogenesis of thedisease and it has been debated that this is the initiating step of atherosclerosis. Accumulationof lipids in the arterial wall can provoke all known features seen in atherogenesis.In this thesis we have investigated how hyperlipidemia induces the pathobiological changesthat lead to atherosclerosis. The aim was to investigate the mechanisms for lipid retention inthe initiation and progress of atherosclerosis and to elucidate the proteoglycan affinity ofmodified low density lipoprotein (LDL). First we identified site B in apolipoprotein (apo)B100 as the important feature for retention in early atherosclerosis. By creating transgenicmice expressing proteoglycan binding defective LDL we demonstrated that lipoproteinretention is an early step of atherosclerosis. This effect was abrogated by apoE, which showedthat apoE has the potential to retain lipoproteins in vivo. Furthermore, apoB48, which lackssite B, was demonstrated to contain a proteoglycan binding site in the amino-terminal. Thepresence of a proteoglycan binding site in the amino-terminal region of apoB may explainwhy apoB48- and apoB100-containing lipoproteins are equally atherogenic. In addition, theresults implicate that this site is masked in apoB100 and therefore non-functional. Theinteraction between LDL and proteoglycans can be modulated by changes in the composition(both surface and core lipids) of the particles. We identified site A in apoB100 to be responsiblefor the increased interaction with proteoglycans seen in secretory group IIA phospholipaseA2 (sPLA2) modified LDL. However, site A was dependent on site B to increase the affinityfor proteoglycans. In addition, cholesterol enriched LDL has been shown to be moreatherogenic than triglyceride-rich LDL. We demonstrated that the increased atherogenicitycould be due to an enhanced affinity for proteoglycans, which probably is dependent onconformational changes of apoB100. In the last study we investigated the lipid retention inadvanced lesions. We demonstrated an increased retention in atherosclerotic plaques, whichcould partly be explained by an alteration in the proteoglycan phenotype. In addition, wewere able to demonstrate that the retention was increased by facilitated interaction mediatedby bridging molecules including lipoprotein lipase (LpL) in the arterial wall. Finally, thepro-atherogenic effect of LpL seen in the vessel wall was shown to be dependent on its noncatalyticalfunction.Taken together, the results presented in this thesis reinforce the importance of retention ofapoB-containing lipoproteins in early and advanced atherosclerosis.
|
|
| 5. |
- Lindén, Daniel, 1971, et al.
(författare)
-
Influence of peroxisome proliferator-activated receptor alpha agonists on the intracellular turnover and secretion of apolipoprotein (Apo) B-100 and ApoB-48.
- 2002
-
Ingår i: The Journal of biological chemistry. - 0021-9258. ; 277:25, s. 23044-53
-
Tidskriftsartikel (refereegranskat)abstract
- The peroxisome proliferator-activated receptor (PPAR) alpha agonist WY 14,643 increased the secretion of apolipoprotein (apo) B-100, but not that of apoB-48, and decreased triglyceride biosynthesis and secretion from primary rat hepatocytes. These effects resulted in decreased secretion of apoB-100-very low density lipoprotein (VLDL) and an increased secretion of apoB-100 on low density lipoproteins/intermediate density lipoproteins. ApoB-48-VLDL was also replaced by more dense particles. The proteasomal inhibitor lactacystin did not influence the recovery of apoB-100 or apoB-48 in primary rat hepatocytes, indicating that co-translational (proteasomal) degradation is of less importance in these cells. Treatment with WY 14,643 made the recovery of apoB-100 sensitive to lactacystin, most likely reflecting the decreased biosynthesis of triglycerides. The PPAR alpha agonist induced a significant increase in the accumulation of pulse-labeled apoB-100 even after a short pulse (2-5 min). There was also an increase in apoB-100 nascent polypeptides, indicating that the co-translational degradation of apoB-100 was inhibited. However, a minor influence on an early posttranslation degradation cannot be excluded. This decreased co-translational degradation of apoB-100 explained the increased secretion of the protein. The levels of apoB-48 remained unchanged during these pulse-chase experiments, and albumin production was not affected, indicating a specific effect of PPAR alpha agonists on the co-translational degradation of apoB-100. These findings explain the difference in the rate of secretion of the two apoB proteins seen after PPAR alpha activation. PPAR alpha agonists increased the expression and biosynthesis of liver fatty acid-binding protein (LFABP). Increased expression of LFABP by transfection of McA-RH7777 cells increased the secretion of apoB-100, decreased triglyceride biosynthesis and secretion, and increased PPAR alpha mRNA levels. These findings suggest that PPAR alpha and LFABP could interact to amplify the effect of endogenous PPAR alpha agonists on the assembly of VLDL.
|
|
