Sterol Regulatory Element-binding Protein-2 Negatively Regulates Low Density Lipoprotein Receptor-related Protein Transcription

Llorente‐Cortés, Vicenta; Costales, Paula; Bernués, Jordi; Camino-López, Sandra; Badimon, Lina

doi:10.1016/j.jmb.2006.04.008

Cited by 59 publications

(62 citation statements)

References 52 publications

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“…Increased expression of srebp2 and hmgcr , however, implicate their responsiveness to intracellular LDL similar to the mammalian system ( 88 ). Increased circulating LDL-c as a result of impaired Ldlr function likely results in low intracellular levels of LDL, which in turn activate srebp2 aimed at producing more LDLRs to increase uptake and more hmgcr to increase cholesterol synthesis [reviewed in ( 63,89 )]. Consistent with this, we observed increased expression of srebp2 and hmgcr in ldlr morphants.…”

Section: Increased Liver Lipid Accumulation and Hepatomegaly In Ldlr supporting

confidence: 81%

Disruption of ldlr causes increased LDL-c and vascular lipid accumulation in a zebrafish model of hypercholesterolemia

O’Hare

Wang

Montasser

et al. 2014

Journal of Lipid Research

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Hypercholesterolemia is a primary cause of atherosclerosis and subsequent cardiovascular events. Genetic factors play a major role in regulation of plasma cholesterol levels, with heritability estimated to range from 40 to 70% [reviewed in ( 1 )]. Over 100 genomic regions have been associated with changes in plasma lipid levels ( 2-5 ). Despite the large number of putative candidate genes identifi ed, the functions of many remain largely unknown, owing in part to the lack of physiologically relevant in vivo models with which to validate and characterize the functionality of associated variants ( 3, 4, 6-13 ). Development of novel models in which genes can be individually targeted will likely reveal functional roles for genetic determinants of blood lipid levels and may facilitate discovery of novel targets for drug development.The zebrafi sh is an excellent candidate for establishing genetic models of hyperlipidemia due to conservation of cell types and molecular pathways involved in lipid metabolism and cholesterol synthesis ( 8,(14)(15)(16)(17)(18)(19)(20). These include hepatocytes, adipocytes, and pancreatic acinar cells ( 17 ) as well as expression of genes involved in lipid transport and metabolism, such as LDL receptor ( ldlr ), sterol regulatory element binding protein ( srebp ) 1/2 , and HMG-CoA reductase ( Hmgcr ) ( 18-29 ). Consequently, mechanisms of lipid metabolism, storage, absorption, and transport are highly conserved in zebrafi sh, allowing for physiologically relevant investigation of these processes ( 20,28,(30)(31)(32)(33)(34). Moreover, targeted suppression of gene expression can be easily achieved in zebrafi sh embryos, making assessment of the resulting larval phenotypes feasible for a large number

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Section: Increased Liver Lipid Accumulation and Hepatomegaly In Ldlr supporting

confidence: 81%

Disruption of ldlr causes increased LDL-c and vascular lipid accumulation in a zebrafish model of hypercholesterolemia

O’Hare

Wang

Montasser

et al. 2014

Journal of Lipid Research

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“…We have recently demonstrated that LRP1 also mediates agLDL uptake by macrophages (14), in agreement with previous results showing that LRP1 participates in the uptake of matrix-retained LDL and of LDL degraded by sphyngomyelinase, mainly agLDL (15,16). LRP1-mediated agLDL uptake can be considered a highcapacity mechanism that allows the uptake of large amounts of ligand, because LRP1, unlike LDLR, has multiple binding sites (17,18) and it is not downregulated by intracellular cholesterol (19,20). We have previously demonstrated that large lipid vacuoles filled with CE derived from LRP1-mediated agLDL-selective uptake colocalize with adipose differentiation-related protein (ADRP) in human VSMCs (13).…”

supporting

confidence: 91%

“…Human gapdh (4326317E) was used as endogenous control for human VSMCs and 18srRNA (4319413E) for HMDMs. Taqman real-time PCR was performed as previously described (19,20,29).…”

Section: Real-time Pcrmentioning

confidence: 99%

Adipocyte differentiation-related protein is induced by LRP1-mediated aggregated LDL internalization in human vascular smooth muscle cells and macrophages

Llorente‐Cortés

Royo

Juan-Babot

et al. 2007

Journal of Lipid Research

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Aggregated LDL (agLDL) is internalized by LDL receptor-related protein (LRP1) in vascular smooth muscle cells (VSMCs) and human monocyte-derived macrophages (HMDMs). AgLDL is, therefore, a potent inducer of massive intracellular cholesteryl ester accumulation in lipid droplets. The adipocyte differentiation-related protein (ADRP) has been found on the surface of lipid droplets. The objectives of this work were to analyze whether agLDL uptake modulates ADRP expression levels and whether the effect of agLDL internalization on ADRP expression depends on LRP1 in human VSMCs and HMDMs. AgLDL strongly upregulates ADRP mRNA (real-time PCR) and protein expression (Western blot) in human VSMCs (mRNA: by 3.06-fold; protein: 8.58-fold) and HMDMs (mRNA: by 3.5-fold; protein: by 3.71-fold). Treatment of VSMCs and HMDMs with small anti-LRP1-interfering RNA (siRNA-LRP1) leads to specific inhibition of LRP1 expression. siRNA-LRP1 treatment significantly reduced agLDL-induced ADRP overexpression in HMDMs (by 69%) and in VSMCs (by 53%). Immunohystochemical studies evidence a colocolocalization between ADRP/macrophages and ADRP/VSMCs in advanced lipid-enriched atherosclerotic plaques. These results demonstrate that agLDL-LRP1 engagement induces ADRP overexpression in both HMDMs and human VSMCs and that ADRP is highly expressed in advanced lipid-enriched human atherosclerotic plaques. Therefore, LRP1-mediated agLDL uptake might play a pivotal role in vascular foam cell formation.-Llorente-Cortés, V., T. Royo, O. Juan-Babot, and L. Badimon. Adipocyte differentiation-related protein is induced by LRP1-mediated aggregated LDL internalization in human vascular smooth muscle cells and macrophages.

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“…Proteins were analyzed by Western blot, as previously described. [8][9][10] Blots were incubated with monoclonal antibodies against LRP1 (Epitomics, 2703-1, dilution 1:7000) or CHFR (Cell Signaling, 4297, dilution 1:1000). LDLR was analyzed using anti-LDLR (Epitomics, 1956-1, dilution 1:500).…”

Section: Western Blot Analysismentioning

confidence: 99%

“…[5][6][7] Uptake of agLDL through LRP1 allows high-intracellular CE accumulation not only because of its high capacity to bind and internalize agLDL, but also because LRP1 is transcriptionally upregulated by intracellular cholesterol. Our group reported that LRP1 is upregulated at transcriptional level by hypercholesterolemia through sterol regulatory element-binding proteins (SREBP) downregulation in human VSMC, [8][9][10] and by hypoxia through hypoxia-inducible factor 1α upregulation in human VSMC 11 and cardiomyocytes. 12,13 Other groups have reported that insulin promotes the presence of LRP1 in the plasma membrane without influencing mRNA expression levels.…”

mentioning

confidence: 99%

Aggregated Low-Density Lipoprotein Induces LRP1 Stabilization Through E3 Ubiquitin Ligase CHFR Downregulation in Human Vascular Smooth Muscle Cells

Cal

García-Arguinzonis

Revuelta‐López

et al. 2013

ATVB

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Objective-Low density lipoprotein retention and aggregation in the arterial intima are key processes in atherogenesis. Aggregated LDL (agLDL) is taken up through low-density lipoprotein receptor-related protein 1 (LRP1) by human vascular smooth muscle cells (VSMC). AgLDL increases LRP1 expression, at least in part, by downregulation of sterol regulatory element-binding proteins. It is unknown whether agLDL has some effect on the ubiquitin-proteasome system, and therefore on the LRP1 receptor turnover. The objective of this study was to analyze the effect of agLDL on the degradation of LRP1 by the ubiquitin-proteasome system in human VSMC. Methods and Results-Human VSMC were isolated from the media of human coronary arteries. Ubiquitinylated LRP1 protein levels were significantly reduced in human VSMC exposed to agLDL (100 μg/mL) for 20 hours (agLDL: 3.70±0.44 a.u. versus control: 9.68±0.55 a.u). Studies performed with cycloheximide showed that agLDL prolongs the LRP1 protein half life. Pulse-chase analysis showed that LRP1 turnover rate is reduced in agLDL-exposed VSMC. Two-dimensional electrophoresis shows an alteration in the proteomic profile of a RING type E3 ubiquitin ligase, CHFR. Real-time PCR and Western blot analysis showed that agLDL (100 μg/mL) decreased the transcriptional and protein expression of CHFR. CHFR silencing increased VSMC, but not macrophage, LRP1 expression. However, CHFR silencing did not exert any effect on the classical low-density lipoprotein receptor protein levels. Furthermore, immunoprecipitation experiments demonstrated that the physical interaction between CHFR and LRP1 decreased in the presence of agLDL. Conclusion-Our results demonstrate that agLDL prolongs the half life of LRP1 by preventing the receptor ubiquitinylation, at least in part, through CHFR targeting. This mechanism seems to be specific for LRP1 and VSMC.

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Sterol Regulatory Element-binding Protein-2 Negatively Regulates Low Density Lipoprotein Receptor-related Protein Transcription

Cited by 59 publications

References 52 publications

Disruption of ldlr causes increased LDL-c and vascular lipid accumulation in a zebrafish model of hypercholesterolemia

Disruption of ldlr causes increased LDL-c and vascular lipid accumulation in a zebrafish model of hypercholesterolemia

Adipocyte differentiation-related protein is induced by LRP1-mediated aggregated LDL internalization in human vascular smooth muscle cells and macrophages

Aggregated Low-Density Lipoprotein Induces LRP1 Stabilization Through E3 Ubiquitin Ligase CHFR Downregulation in Human Vascular Smooth Muscle Cells

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