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1.
Mol Nutr Food Res ; 68(1): e2300508, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37933702

RESUMEN

SCOPE: Extra virgin olive oil has numerous cardiopreventive effects, largely due to its high content of (poly)phenols such as hydroxytyrosol (HT). However, some animal studies suggest that its excessive consumption may alter systemic lipoprotein metabolism. Because human lipoprotein metabolism differs from that of rodents, this study examines the effects of HT in a humanized mouse model that approximates human lipoprotein metabolism. METHODS AND RESULTS: Mice are treated as follows: control diet or diet enriched with HT. Serum lipids and lipoproteins are determined after 4 and 8 weeks. We also analyzed the regulation of various genes and miRNA by HT, using microarrays and bioinformatic analysis. An increase in body weight is found after supplementation with HT, although food intake was similar in both groups. In addition, HT induced the accumulation of triacylglycerols but not cholesterol in different tissues. Systemic dyslipidemia after HT supplementation and impaired glucose metabolism are observed. Finally, HT modulates the expression of genes related to lipid metabolism, such as Pltp or Lpl. CONCLUSION: HT supplementation induces systemic dyslipidemia and impaired glucose metabolism in humanized mice. Although the numerous health-promoting effects of HT far outweigh these potential adverse effects, further carefully conducted studies are needed.


Asunto(s)
Dislipidemias , Alcohol Feniletílico , Humanos , Ratones , Animales , Aceite de Oliva/farmacología , Dislipidemias/etiología , Alcohol Feniletílico/farmacología , Lipoproteínas , Modelos Animales de Enfermedad , Glucosa
2.
Nat Commun ; 14(1): 8316, 2023 Dec 14.
Artículo en Inglés | MEDLINE | ID: mdl-38097578

RESUMEN

Accumulation of lipid-laden macrophages within the arterial neointima is a critical step in atherosclerotic plaque formation. Here, we show that reduced levels of the cellular plasticity factor ZEB1 in macrophages increase atherosclerotic plaque formation and the chance of cardiovascular events. Compared to control counterparts (Zeb1WT/ApoeKO), male mice with Zeb1 ablation in their myeloid cells (Zeb1∆M/ApoeKO) have larger atherosclerotic plaques and higher lipid accumulation in their macrophages due to delayed lipid traffic and deficient cholesterol efflux. Zeb1∆M/ApoeKO mice display more pronounced systemic metabolic alterations than Zeb1WT/ApoeKO mice, with higher serum levels of low-density lipoproteins and inflammatory cytokines and larger ectopic fat deposits. Higher lipid accumulation in Zeb1∆M macrophages is reverted by the exogenous expression of Zeb1 through macrophage-targeted nanoparticles. In vivo administration of these nanoparticles reduces atherosclerotic plaque formation in Zeb1∆M/ApoeKO mice. Finally, low ZEB1 expression in human endarterectomies is associated with plaque rupture and cardiovascular events. These results set ZEB1 in macrophages as a potential target in the treatment of atherosclerosis.


Asunto(s)
Aterosclerosis , Placa Aterosclerótica , Animales , Humanos , Masculino , Ratones , Apolipoproteínas E/genética , Aterosclerosis/genética , Aterosclerosis/metabolismo , Regulación hacia Abajo , Lipoproteínas LDL/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Placa Aterosclerótica/metabolismo , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/genética , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/metabolismo
3.
Cell Rep ; 41(2): 111468, 2022 10 11.
Artículo en Inglés | MEDLINE | ID: mdl-36223741

RESUMEN

Atherosclerosis is a chronic inflammatory disease of the arteries that can lead to thrombosis, infarction, and stroke and is the leading cause of mortality worldwide. Immunization of pro-atherogenic mice with malondialdehyde-modified low-density lipoprotein (MDA-LDL) neo-antigen is athero-protective. However, the immune response to MDA-LDL and the mechanisms responsible for this athero-protection are not completely understood. Here, we find that immunization of mice with MDA-LDL elicits memory B cells, plasma cells, and switched anti-MDA-LDL antibodies as well as clonal expansion and affinity maturation, indicating that MDA-LDL triggers a bona fide germinal center antibody response. Further, Prdm1fl/flAicda-Cre+/kiLdlr-/- pro-atherogenic chimeras, which lack germinal center-derived plasma cells, show accelerated atherosclerosis. Finally, we show that MDA-LDL immunization is not athero-protective in mice lacking germinal-center-derived plasma cells. Our findings give further support to the development of MDA-LDL-based vaccines for the prevention or treatment of atherosclerosis.


Asunto(s)
Aterosclerosis , Vacunas , Animales , Formación de Anticuerpos , Aterosclerosis/prevención & control , Centro Germinal , Lipoproteínas LDL , Malondialdehído/farmacología , Ratones , Vacunación
4.
Sci Adv ; 8(11): eabm7322, 2022 03 18.
Artículo en Inglés | MEDLINE | ID: mdl-35294231

RESUMEN

Pathological vascular remodeling is the underlying cause of atherosclerosis and abdominal aortic aneurysm (AAA). Here, we analyzed the role of galectin-1 (Gal-1), a ß-galactoside-binding protein, as a therapeutic target for atherosclerosis and AAA. Mice lacking Gal-1 (Lgals1-/-) developed severe atherosclerosis induced by pAAV/D377Y-mPCSK9 adenovirus and displayed higher lipid levels and lower expression of contractile markers of vascular smooth muscle cells (VSMCs) in plaques than wild-type mice. Proteomic analysis of Lgals1-/- aortas showed changes in markers of VSMC phenotypic switch and altered composition of mitochondrial proteins. Mechanistically, Gal-1 silencing resulted in increased foam cell formation and mitochondrial dysfunction in VSMCs, while treatment with recombinant Gal-1 (rGal-1) prevented these effects. Furthermore, rGal-1 treatment attenuated atherosclerosis and elastase-induced AAA, leading to higher contractile VSMCs in aortic tissues. Gal-1 expression decreased in human atheroma and AAA compared to control tissue. Thus, Gal-1-driven circuits emerge as potential therapeutic strategies in atherosclerosis and AAA.


Asunto(s)
Aneurisma de la Aorta Abdominal , Aterosclerosis , Animales , Aneurisma de la Aorta Abdominal/etiología , Aneurisma de la Aorta Abdominal/metabolismo , Aneurisma de la Aorta Abdominal/patología , Aterosclerosis/genética , Aterosclerosis/metabolismo , Modelos Animales de Enfermedad , Galectina 1/genética , Galectina 1/metabolismo , Galectina 1/farmacología , Ratones , Ratones Endogámicos C57BL , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Proteómica , Remodelación Vascular
5.
Biomed Pharmacother ; 141: 111871, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-34225017

RESUMEN

Selective estrogen receptor modulators (SERMs) are nonsteroidal drugs that display an estrogen-agonist or estrogen-antagonist effect depending on the tissue targeted. SERMs have attracted great clinical interest for the treatment of several pathologies, most notably breast cancer and osteoporosis. There is strong evidence that SERMs secondarily affect cholesterol metabolism, although the mechanism has not been fully elucidated. In this study, we analysed the effect of the SERMs tamoxifen, raloxifene, and toremifene on the expression of lipid metabolism genes by microarrays and quantitative PCR in different cell types, and ascertained the main mechanisms involved. The three SERMs increased the expression of sterol regulatory element-binding protein (SREBP) target genes, especially those targeted by SREBP-2. In consonance, SERMs increased SREBP-2 processing. These effects were associated to the interference with intracellular LDL-derived cholesterol trafficking. When the cells were exposed to LDL, but not to cholesterol/methyl-cyclodextrin complexes, the SERM-induced increases in gene expression were synergistic with those induced by lovastatin. Furthermore, the SERMs reduced the stimulation of the transcriptional activity of the liver X receptor (LXR) by exogenous cholesterol. However, their impact on the expression of the LXR canonical target ABCA1 in the presence of LDL was cell-type dependent. These actions of SERMs were independent of estrogen receptors. We conclude that, by inhibiting the intracellular trafficking of LDL-derived cholesterol, SERMs promote the activation of SREBP-2 and prevent the activation of LXR, two master regulators of cellular cholesterol metabolism. This study highlights the impact of SERMs on lipid homeostasis regulation beyond their actions as estrogen receptor modulators.


Asunto(s)
Colesterol/metabolismo , Homeostasis/efectos de los fármacos , Receptores X del Hígado/metabolismo , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Proteína 2 de Unión a Elementos Reguladores de Esteroles/metabolismo , LDL-Colesterol/metabolismo , Células Hep G2 , Homeostasis/fisiología , Humanos , Receptores X del Hígado/antagonistas & inhibidores , Células MCF-7
6.
FASEB J ; 34(11): 14960-14976, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32924185

RESUMEN

Atherosclerosis is an inflammatory disease characterized by the accumulation of macrophages in the vessel wall. Macrophages depend on their polarization to exert either pro-inflammatory or anti-inflammatory effects. Macrophages of the anti-inflammatory phenotype express high levels of CD163, a scavenger receptor for the hemoglobin-haptoglobin complex. CD163 can also bind to the pro-inflammatory cytokine TWEAK. Using ApoE-deficient or ApoE/CD163 double-deficient mice we aim to investigate the involvement of CD163 in atherosclerosis development and its capacity to neutralize the TWEAK actions. ApoE/CD163 double-deficient mice displayed a more unstable plaque phenotype characterized by an increased lipid and macrophage content, plaque size, and pro-inflammatory cytokine expression. In vitro experiments demonstrated that the absence of CD163 in M2-type macrophages-induced foam cell formation through upregulation of CD36 expression. Moreover, exogenous TWEAK administration increased atherosclerotic lesion size, lipids, and macrophages content in ApoE-/- /CD163-/- compared with ApoE-/- /CD163+/+ mice. Treatment with recombinant CD163 was able to neutralize the proatherogenic effects of TWEAK in ApoE/CD163 double-deficient mice. Recombinant CD163 abolished the pro-inflammatory actions of TWEAK on vascular smooth muscle cells, decreasing NF-kB activation, cytokines and metalloproteinases expression, and macrophages migration. In conclusion, CD163-expressing macrophages serve as a protective mechanism to prevent the deleterious effects of TWEAK on atherosclerotic plaque development and progression.


Asunto(s)
Antígenos CD/fisiología , Antígenos de Diferenciación Mielomonocítica/fisiología , Aterosclerosis/patología , Citocina TWEAK/metabolismo , Células Espumosas/patología , Macrófagos/patología , Placa Aterosclerótica/patología , Receptores de Superficie Celular/fisiología , Animales , Aterosclerosis/etiología , Aterosclerosis/metabolismo , Citocinas/metabolismo , Femenino , Células Espumosas/metabolismo , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Noqueados para ApoE , Placa Aterosclerótica/etiología , Placa Aterosclerótica/metabolismo
7.
Food Funct ; 10(8): 4897-4910, 2019 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-31339147

RESUMEN

Hydroxytyrosol (HT) is involved in healthful activities and is beneficial to lipid metabolism. Many investigations focused on finding tissue-specific targets of HT through the use of different omics approaches such as transcriptomics and proteomics. However, it is not clear which (if any) of the potential molecular targets of HT reported in different studies are concurrently affected in various tissues. Following the bioinformatic analyses of publicly available data from a selection of in vivo studies involving HT-supplementation, we selected differentially expressed lipid metabolism-related genes and proteins common to more than one study, for validation in rodent liver samples from the entire selection. Four miRNAs (miR-802-5p, miR-423-3p, miR-30a-5p, and miR-146b-5p) responded to HT supplementation. Of note, miR-802-5p was commonly regulated in the liver and intestine. Our premise was that, in an organ crucial for lipid metabolism such as the liver, consistent modulation should be found for a specific target of HT even if different doses and duration of HT supplementation were used in vivo. Even though our results show inconsistency regarding differentially expressed lipid metabolism-related genes and proteins across studies, we found Fgf21 and Rora as potential novel targets of HT. Omics approaches should be fine-tuned to better exploit the available databases.


Asunto(s)
Alcohol Feniletílico/análogos & derivados , Proteínas/genética , Biología Computacional , Humanos , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , MicroARNs/metabolismo , Alcohol Feniletílico/farmacología , Proteínas/metabolismo , Proteómica
8.
Sci Rep ; 6: 32105, 2016 09 07.
Artículo en Inglés | MEDLINE | ID: mdl-27601313

RESUMEN

Selective estrogen receptor modulators (SERMs) are widely prescribed drugs that alter cellular and whole-body cholesterol homeostasis. Here we evaluate the effect of SERMs on the macrophage-specific reverse cholesterol transport (M-RCT) pathway, which is mediated by HDL. Treatment of human and mouse macrophages with tamoxifen, raloxifene or toremifene induced the accumulation of cytoplasmic vesicles of acetyl-LDL-derived free cholesterol. The SERMs impaired cholesterol efflux to apolipoprotein A-I and HDL, and lowered ABCA1 and ABCG1 expression. These effects were not altered by the antiestrogen ICI 182,780 nor were they reproduced by 17ß-estradiol. The treatment of mice with tamoxifen or raloxifene accelerated HDL-cholesteryl ester catabolism, thereby reducing HDL-cholesterol concentrations in serum. When [(3)H]cholesterol-loaded macrophages were injected into mice intraperitoneally, tamoxifen, but not raloxifene, decreased the [(3)H]cholesterol levels in serum, liver and feces. Both SERMs downregulated liver ABCG5 and ABCG8 protein expression, but tamoxifen reduced the capacity of HDL and plasma to promote macrophage cholesterol efflux to a greater extent than raloxifene. We conclude that SERMs interfere with intracellular cholesterol trafficking and efflux from macrophages. Tamoxifen, but not raloxifene, impair M-RCT in vivo. This effect is primarily attributable to the tamoxifen-mediated reduction of the capacity of HDL to promote cholesterol mobilization from macrophages.


Asunto(s)
Colesterol/metabolismo , Lipoproteínas HDL/metabolismo , Macrófagos/efectos de los fármacos , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Transportador 1 de Casete de Unión a ATP/biosíntesis , Transportador 1 de Casete de Unión a ATP/genética , Transportador de Casetes de Unión a ATP, Subfamilia G/biosíntesis , Transportador de Casetes de Unión a ATP, Subfamilia G/genética , Acetil-CoA C-Acetiltransferasa/antagonistas & inhibidores , Animales , Apolipoproteína A-I/metabolismo , Transporte Biológico/efectos de los fármacos , Colesterol/análisis , Colesterol/sangre , Ésteres del Colesterol/metabolismo , Dieta Occidental , Esterificación/efectos de los fármacos , Estradiol/análogos & derivados , Estradiol/farmacología , Heces/química , Fulvestrant , Humanos , Lipoproteínas LDL/metabolismo , Hígado/química , Hígado/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Clorhidrato de Raloxifeno/farmacología , Células THP-1 , Tamoxifeno/farmacología , Toremifeno/farmacología
9.
Mol Nutr Food Res ; 57(10): 1814-24, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23754667

RESUMEN

SCOPE: High plasma homocysteine concentrations have been associated with increased risk of cardiovascular disease both in humans and experimental animal models, whereas plasma HDL-cholesterol concentration is inversely correlated with such disorders. This work aimed to study the impact of methionine-induced hyperhomocysteinemia (HHcy) on two major antiatherogenic functions of HDL, namely their capacity to prevent LDL oxidation and induce in vivo macrophage-specific reverse cholesterol transport. METHODS AND RESULTS: Methionine-induced HHcy in mice resulted in an approximately 20% decreased concentration of HDL-cholesterol and HDL main protein component, apolipoprotein A-I. The HDL potential to resist oxidation as well as to prevent LDL oxidative modification was impaired in hyperhomocysteinemic mice. Activities of paraoxonase-1 and platelet activation factor acetylhydrolase, two of the main HDL-associated enzymes with antioxidant activity, were reduced. The ability of HDL to efflux cholesterol from macrophages was decreased in hyperhomocysteinemic mice; however, the in vivo macrophage-specific reverse cholesterol transport measured as the output of labeled cholesterol into feces did not significantly differ between groups. CONCLUSION: Our data indicate that the HDL from methionine-induced hyperhomocysteinemic mice was more prone to oxidation and displayed lower capacity to protect LDL against oxidative modification than that of control mice, highlighting a mechanism by which a diet-induced HHcy may facilitate progression of atherosclerosis.


Asunto(s)
Antioxidantes/metabolismo , HDL-Colesterol/antagonistas & inhibidores , Hiperhomocisteinemia/inducido químicamente , Macrófagos/metabolismo , Metionina/efectos adversos , Animales , Apolipoproteína A-I/sangre , Arildialquilfosfatasa/sangre , Aterosclerosis/patología , Transporte Biológico , Línea Celular , HDL-Colesterol/sangre , Modelos Animales de Enfermedad , Femenino , Homocisteína/sangre , Hiperhomocisteinemia/complicaciones , Hiperhomocisteinemia/patología , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Metionina/administración & dosificación , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos
10.
Curr Vasc Pharmacol ; 9(2): 220-37, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21143175

RESUMEN

Epidemiologic studies have demonstrated that increased high-density lipoprotein cholesterol (HDL-C) is a protective factor against cardiovascular disease. However, the beneficial therapeutic effects of raising HDL-C are proving difficult to confirm in humans. Macrophage-specific reverse cholesterol transport (RCT) is thought to be one of the most important HDL-mediated cardioprotective mechanisms. A new approach was developed to measure in vivo RCT from labeled cholesterol macrophages to liver and feces in mice. Since its original publication, this method has been extensively used to assess the effects of genetic manipulation of pivotal genes involved in HDL metabolism on this major HDL antiatherogenic function in mice. These studies indicate that in vivo macrophage-specific RTC is a strong predictor of atherosclerosis susceptibility compared with steady-state plasma HDL-C levels or other global RCT measurements. This review aims to identify the best molecular targets for improving this HDL antiatherogenic function. Strong evidence supports a positive effect of interventions on macrophage adenosine triphosphate-binding cassette transporter (ABC) A1 and neutral cholesteryl ester hydrolase, apolipoprotein (apo) A-I, apoE, liver scavenger receptor class B type I and ABCG5/G8 on in vivo macrophage-specific RCT and atherosclerosis susceptibility. However, other genetic modifications have yielded conflicting results. Several preclinical studies tested the effects on macrophage-specific RCT in vivo of promising new HDL-based therapeutic agents, which include cholesteryl ester transfer protein inhibitors, apoA-I-directed therapies, liver X receptor and peroxisome proliferator-activated receptor agonists, intestinal cholesterol absorption inhibitors, fish oil and phenolic acid intake, inflammatory modulation and non-nucleoside reverse transcriptase inhibitors. This review also discusses recent findings on the potential effects of these therapeutic approaches on macrophage RCT in mice and cardiovascular risk in humans.


Asunto(s)
Aterosclerosis/metabolismo , Colesterol/metabolismo , Reguladores del Metabolismo de Lípidos/farmacología , Macrófagos/metabolismo , Animales , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/prevención & control , HDL-Colesterol/metabolismo , Circulación Enterohepática/efectos de los fármacos , Humanos , Reguladores del Metabolismo de Lípidos/uso terapéutico , Macrófagos/efectos de los fármacos , Terapia Molecular Dirigida
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