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1.
Hypertension ; 79(1): 126-138, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34784737

RESUMO

Dyslipidemia-induced endothelial dysfunction is an important factor in the progression of cardiovascular disease; however, the underlying mechanisms are unclear. Our recent studies demonstrated that flow-induced vasodilation (FIV) is regulated by inwardly rectifying K+ channels (Kir2.1) in resistance arteries. Furthermore, we showed that hypercholesterolemia inhibits Kir2.1-dependent vasodilation. In this study, we introduced 2 new mouse models: (1) endothelial-specific deletion of Kir2.1 to demonstrate the role of endothelial Kir2.1 in FIV and (2) cholesterol-insensitive Kir2.1 mutant to determine the Kir2.1 regulation in FIV under hypercholesterolemia. FIV was significantly reduced in endothelial-specific Kir2.1 knock-out mouse mesenteric arteries compared with control groups. In cholesterol-insensitive Kir2.1 mutant mice, Kir2.1 currents were not affected by cyclodextrin and FIV was restored in cells and arteries, respectively, with a hypercholesterolemic background. To extend our observations to humans, 16 healthy subjects were recruited with LDL (low-density lipoprotein)-cholesterol ranging from 51 to 153 mg/dL and FIV was assessed in resistance arteries isolated from gluteal adipose. Resistance arteries from participants with >100 mg/dL LDL (high-LDL) exhibited reduced FIV as compared with those participants with <100 mg/dL LDL (low-LDL). A significant negative correlation was observed between LDL cholesterol and FIV in high-LDL. Expressing dominant-negative Kir2.1 in endothelium blunted FIV in arteries from low-LDL but had no further effect on FIV in arteries from high-LDL. The Kir2.1-dependent vasodilation more negatively correlated to LDL cholesterol in high-LDL. Overexpressing wild-type Kir2.1 in endothelium fully recovered FIV in arteries from participants with high-LDL. Our data suggest that cholesterol-induced suppression of Kir2.1 is a major mechanism underlying endothelial dysfunction in hypercholesterolemia.


Assuntos
Endotélio Vascular/metabolismo , Hipercolesterolemia/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Vasodilatação/fisiologia , Adulto , Animais , LDL-Colesterol/metabolismo , Células Endoteliais/metabolismo , Feminino , Humanos , Hipercolesterolemia/genética , Masculino , Camundongos , Camundongos Knockout , Canais de Potássio Corretores do Fluxo de Internalização/genética
2.
Nutrients ; 13(12)2021 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-34959959

RESUMO

Red cell distribution width (RDW) predicts cardiovascular outcomes, but it is unstudied with regard to intermittent fasting. In WONDERFUL trial subjects, the effect of the interaction between baseline RDW and intermittent fasting on changes in insulin and other cardiometabolic endpoints and the effect of fasting on changes in RDW were evaluated. The subjects enrolled were aged 21-70 years and were free of statins, anti-diabetes medications, and chronic diseases, and had ≥1 metabolic syndrome feature, as well as elevated low-density lipoprotein cholesterol. Subjects were randomized to 24-h, water-only fasting (twice per week for 4 weeks, once per week for 22 weeks) or 26 weeks of ad libitum eating. Subjects (N = 71; n = 38 intermittent fasting, n = 33 controls) had more substantial changes in insulin in intermittent fasting vs. controls (-3.45 ± 2.27 vs. 0.48 ± 3.55 mIU/L) when baseline RDW size distribution (RDW-SD) was ≥median (42.6 fL) than

Assuntos
Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/prevenção & controle , Índices de Eritrócitos , Jejum/fisiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Adulto , Idoso , Biomarcadores/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/etiologia , LDL-Colesterol/metabolismo , Feminino , Fatores de Risco de Doenças Cardíacas , Humanos , Insulina/metabolismo , Masculino , Pessoa de Meia-Idade , Adulto Jovem
3.
PLoS One ; 16(10): e0258617, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34653200

RESUMO

BACKGROUND: It has been shown that vitamin D is associated with obesity and the development of atherosclerosis. Less is known about this association among adolescents with obesity. OBJECTIVES: To determine the association of vitamin D level and metabolic risk factors with carotid intima-media thickness (CIMT) among obese adolescents. METHODS: We conducted a cross-sectional study among obese children aged 15 to 17 years in Yogyakarta, Indonesia. The association of vitamin D and other metabolic risk factors (triglyceride, low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C), and insulin resistance using homeostasis model assessment of insulin resistance (HOMA-IR)) with CIMT was explored by multivariable linear regression models. RESULTS: Out of 156 obese adolescents, 55.8% were boys. Compared to girls, boys had higher BMI z-score, waist circumference, and HDL-cholesterol. After adjustment for age, sex and second-hand smoke exposure, high HOMA-IR, total cholesterol, LDL-cholesterol and triglyceride levels were associated with higher odds of elevated CIMT. In analyses stratified by sex, a similar trend was observed in boys, while none of the risk factors were associated with CIMT in girls. We observed no association between vitamin D and CIMT. CONCLUSIONS: Hyperinsulinemia, higher total cholesterol and LDL cholesterol were associated with greater odds of elevated CIMT among obese adolescent boys.


Assuntos
Aterosclerose/diagnóstico por imagem , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Obesidade Pediátrica/complicações , Triglicerídeos/metabolismo , Adolescente , Aterosclerose/etiologia , Aterosclerose/metabolismo , Espessura Intima-Media Carotídea , Estudos Transversais , Feminino , Humanos , Indonésia , Resistência à Insulina , Masculino , Obesidade Pediátrica/diagnóstico por imagem , Obesidade Pediátrica/metabolismo , Caracteres Sexuais , Vitamina D
4.
Int J Mol Sci ; 22(19)2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34638860

RESUMO

(1) Background: Sepsis is one of the most common critical care illnesses with increasing survivorship. The quality of life in sepsis survivors is adversely affected by several co-morbidities, including increased incidence of dementia, stroke, cardiac disease and at least temporary deterioration in cognitive dysfunction. One of the potential explanations for their progression is the persistence of lipid profile abnormalities induced during acute sepsis into recovery, resulting in acceleration of atherosclerosis. (2) Methods: This is a targeted review of the abnormalities in the long-term lipid profile abnormalities after sepsis; (3) Results: There is a well-established body of evidence demonstrating acute alteration in lipid profile (HDL-c ↓↓, LDL-C -c ↓↓). In contrast, a limited number of studies demonstrated depression of HDL-c levels with a concomitant increase in LDL-C -c in the wake of sepsis. VLDL-C -c and Lp(a) remained unaltered in few studies as well. Apolipoprotein A1 was altered in survivors suggesting abnormalities in lipoprotein metabolism concomitant to overall lipoprotein abnormalities. However, most of the studies were limited to a four-month follow-up and patient groups were relatively small. Only one study looked at the atherosclerosis progression in sepsis survivors using clinical correlates, demonstrating an acceleration of plaque formation in the aorta, and a large metanalysis suggested an increase in the risk of stroke or acute coronary event between 3% to 9% in sepsis survivors. (4) Conclusions: The limited evidence suggests an emergence and persistence of the proatherogenic lipid profile in sepsis survivors that potentially contributes, along with other factors, to the clinical sequel of atherosclerosis.


Assuntos
Aterosclerose/metabolismo , Colesterol/metabolismo , Lipoproteínas/metabolismo , Sepse/metabolismo , Apolipoproteínas/metabolismo , Aterosclerose/complicações , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Progressão da Doença , Humanos , Sepse/complicações , Triglicerídeos/metabolismo
5.
Int J Mol Sci ; 22(19)2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34638955

RESUMO

Sphingosine 1 phosphate (S1P) lyase (Sgpl1) catalyses the irreversible cleavage of S1P and thereby the last step of sphingolipid degradation. Loss of Sgpl1 in humans and mice leads to accumulation of sphingolipids and multiple organ injuries. Here, we addressed the role of hepatocyte Sgpl1 for regulation of sphingolipid homoeostasis by generating mice with hepatocyte-specific deletion of Sgpl1 (Sgpl1HepKO mice). Sgpl1HepKO mice had normal body weight, liver weight, liver structure and liver enzymes both at the age of 8 weeks and 8 months. S1P, sphingosine and ceramides, but not glucosylceramides or sphingomyelin, were elevated by ~1.5-2-fold in liver, and this phenotype did not progress with age. Several ceramides were elevated in plasma, while plasma S1P was normal. Interestingly, S1P and glucosylceramides, but not ceramides, were elevated in bile of Sgpl1HepKO mice. Furthermore, liver cholesterol was elevated, while LDL cholesterol decreased in 8-month-old mice. In agreement, the LDL receptor was upregulated, suggesting enhanced uptake of LDL cholesterol. Expression of peroxisome proliferator-activated receptor-γ, liver X receptor and fatty acid synthase was unaltered. These data show that mouse hepatocytes largely compensate the loss of Sgpl1 by secretion of accumulating sphingolipids in a specific manner into blood and bile, so that they can be excreted or degraded elsewhere.


Assuntos
Aldeído Liases/genética , Aldeído Liases/metabolismo , Bile/metabolismo , Fígado/metabolismo , Esfingolipídeos/sangue , Animais , Células Cultivadas , Ceramidas/metabolismo , LDL-Colesterol/metabolismo , Técnicas de Inativação de Genes , Hepatócitos/metabolismo , Homeostase/genética , Lisofosfolipídeos/metabolismo , Camundongos , Camundongos Knockout , Fenótipo , Receptores de LDL/metabolismo , Esfingosina/análogos & derivados , Esfingosina/metabolismo
6.
Arch Biochem Biophys ; 711: 109032, 2021 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-34520731

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is considered the hepatic representation of the metabolic disorders. Inorganic nitrate/nitrite can be converted to nitric oxide, regulate glucose metabolism, lower lipid levels, and reduce inflammation, thus raising the hypothesis that inorganic nitrate/nitrite could be beneficial for improving NAFLD. This study assessed the therapeutic effects of chronic dietary nitrate on NAFLD in a mouse model. 60 ApoE-/- mice were fed a high-fat diet (HFD) for 12 weeks to allow for the development of atherosclerosis with associated NAFLD. The mice were then randomly assigned to different groups (20/group) for a further 12 weeks: (i) HFD + NaCl (1 mmol/kg/day), (ii) HFD + NaNO3 (1 mmol/kg/day), and (iii) HFD + NaNO3 (10 mmol/kg/day). A fourth group of ApoE-/- mice consumed a normal chow diet for the duration of the study. At the end of the treatment, caecum contents, serum, and liver were collected. Consumption of the HFD resulted in significantly greater lipid accumulation in the liver compared to mice on the normal chow diet. Mice whose HFD was supplemented with dietary nitrate for the second half of the study, showed an attenuation in hepatic lipid accumulation. This was also associated with an increase in hepatic AMPK activity compared to mice on the HFD. In addition, a significant difference in bile acid profile was detected between mice on the HFD and those receiving the high dose nitrate supplemented HFD. In conclusion, dietary nitrate attenuates the progression of liver steatosis in ApoE-/- mice fed a HFD.


Assuntos
Nitratos/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Ácidos e Sais Biliares/sangue , Ácidos e Sais Biliares/metabolismo , Ceco/efeitos dos fármacos , Ceco/metabolismo , LDL-Colesterol/sangue , LDL-Colesterol/metabolismo , Dieta Hiperlipídica , Suplementos Nutricionais , Ácidos Graxos Voláteis/sangue , Ácidos Graxos Voláteis/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Triglicerídeos/sangue , Triglicerídeos/metabolismo
7.
Int J Med Sci ; 18(15): 3533-3543, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34522180

RESUMO

Importance: Despite the availability of a vaccine against the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), humans will have to live with this virus and the after-effects of the coronavirus disease 2019 (COVID-19) infection for a long time. Cholesterol plays an important role in the infection and prognosis of SARS-CoV-2, and the study of its mechanism is of great significance not only for the treatment of COVID-19 but also for research on generic antiviral drugs. Observations: Cholesterol promotes the development of atherosclerosis by activating NLR family pyrin domain containing 3 (NLRP3), and the resulting inflammatory environment indirectly contributes to COVID-19 infection and subsequent deterioration. In in vitro studies, membrane cholesterol increased the number of viral entry sites on the host cell membrane and the number of angiotensin-converting enzyme 2 (ACE2) receptors in the membrane fusion site. Previous studies have shown that the fusion protein of the virus interacts with cholesterol, and the spike protein of SARS-CoV-2 also requires cholesterol to enter the host cells. Cholesterol in blood interacts with the spike protein to promote the entry of spike cells, wherein the scavenger receptor class B type 1 (SR-B1) plays an important role. Because of the cardiovascular protective effects of lipid-lowering therapy and the additional anti-inflammatory effects of lipid-lowering drugs, it is currently recommended to continue lipid-lowering therapy for patients with COVID-19, but the safety of extremely low LDL-C is questionable. Conclusions and Relevance: Cholesterol can indirectly increase the susceptibility of patients to SARS-CoV-2 and increase the risk of death from COVID-19, which are mediated by NLRP3 and atherosclerotic plaques, respectively. Cholesterol present in the host cell membrane, virus, and blood may also directly participate in the virus cell entry process, but the specific mechanism still needs further study. Patients with COVID-19 are recommended to continue lipid-lowering therapy.


Assuntos
COVID-19/complicações , Hipercolesterolemia/complicações , Enzima de Conversão de Angiotensina 2/metabolismo , Antivirais/uso terapêutico , Aterosclerose/fisiopatologia , COVID-19/diagnóstico , COVID-19/tratamento farmacológico , COVID-19/terapia , Membrana Celular/metabolismo , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Endocitose , Humanos , Hipercolesterolemia/diagnóstico , Hipercolesterolemia/terapia , Inflamação , Macrófagos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/sangue , Prognóstico , SARS-CoV-2 , Receptores Depuradores Classe B/metabolismo
8.
Arterioscler Thromb Vasc Biol ; 41(10): e453-e467, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34380332

RESUMO

Objective: Overall and atherosclerosis-associated mortality is elevated in humans with very high HDL (high-density lipoprotein) cholesterol concentrations. Mice with a deficiency of the HDL receptor, Scarb1 (scavenger receptor class B type 1), are a robust model of this phenotype and exhibit several additional pathologies. We hypothesized that the previously reported high plasma concentration of free cholesterol (FC)-rich HDL in Scarb1-/- mice produces a state of high HDL-FC bioavailability that increases whole-body FC and dysfunction in multiple tissue sites. Approach and Results: The higher mol% FC in Scarb1-/- versus WT (wild type) HDL (41.1 versus 16.0 mol%) affords greater FC bioavailability for transfer to multiple sites. Plasma clearance of autologous HDL-FC mass was faster in WT versus Scarb1-/- mice. FC influx from Scarb1-/- HDL to LDL (low-density lipoprotein) and J774 macrophages was greater ([almost equal to]4x) than that from WT HDL, whereas FC efflux capacity was similar. The higher mol% FC of ovaries, erythrocytes, heart, and macrophages of Scarb1-/- versus WT mice is associated with previously reported female infertility, impaired cell maturation, cardiac dysfunction, and atherosclerosis. The FC contents of other tissues were similar in the two genotypes, and these tissues were not associated with any overt pathology. In addition to the differences between WT versus Scarb1-/- mice, there were many sex-dependent differences in tissue-lipid composition and plasma FC clearance rates. Conclusions: Higher HDL-FC bioavailability among Scarb1-/- versus WT mice drives increased FC content of multiple cell sites and is a potential biomarker that is mechanistically linked to multiple pathologies.


Assuntos
Aterosclerose/metabolismo , Colesterol/metabolismo , Macrófagos/metabolismo , Receptores Depuradores Classe B/deficiência , Animais , Aterosclerose/genética , Aterosclerose/patologia , Disponibilidade Biológica , Linhagem Celular , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Feminino , Humanos , Cinética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Placa Aterosclerótica , Receptores Depuradores Classe B/genética , Fatores Sexuais , Distribuição Tecidual
9.
Cells ; 10(8)2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34440777

RESUMO

Vitamin D and cholesterol metabolism overlap significantly in the pathways that contribute to their biosynthesis. However, our understanding of their independent and co-regulation is limited. Cardiovascular disease is the leading cause of death globally and atherosclerosis, the pathology associated with elevated cholesterol, is the leading cause of cardiovascular disease. It is therefore important to understand vitamin D metabolism as a contributory factor. From the literature, we compile evidence of how these systems interact, relating the understanding of the molecular mechanisms involved to the results from observational studies. We also present the first systems biology pathway map of the joint cholesterol and vitamin D metabolisms made available using the Systems Biology Graphical Notation (SBGN) Markup Language (SBGNML). It is shown that the relationship between vitamin D supplementation, total cholesterol, and LDL-C status, and between latitude, vitamin D, and cholesterol status are consistent with our knowledge of molecular mechanisms. We also highlight the results that cannot be explained with our current knowledge of molecular mechanisms: (i) vitamin D supplementation mitigates the side-effects of statin therapy; (ii) statin therapy does not impact upon vitamin D status; and critically (iii) vitamin D supplementation does not improve cardiovascular outcomes, despite improving cardiovascular risk factors. For (iii), we present a hypothesis, based on observations in the literature, that describes how vitamin D regulates the balance between cellular and plasma cholesterol. Answering these questions will create significant opportunities for advancement in our understanding of cardiovascular health.


Assuntos
Doenças Cardiovasculares/metabolismo , Colesterol/metabolismo , Dislipidemias/metabolismo , Deficiência de Vitamina D/metabolismo , Vitamina D/metabolismo , Animais , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Colesterol/sangue , LDL-Colesterol/metabolismo , Dislipidemias/tratamento farmacológico , Dislipidemias/epidemiologia , Fatores de Risco de Doenças Cardíacas , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Modelos Biológicos , Prognóstico , Medição de Risco , Biologia de Sistemas , Vitamina D/uso terapêutico , Deficiência de Vitamina D/tratamento farmacológico , Deficiência de Vitamina D/epidemiologia
10.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1866(10): 159004, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34245925

RESUMO

The atherosclerosis "iron hypothesis" generates a fair amount of debate since it has been proposed. Here, we revisited the "iron hypothesis" by examining whether dietary iron overload would intensify iron deposition in plaques and thus lead to further exacerbation of atherosclerosis in apolipoprotein E knockout (ApoE KO) mice. ApoE KO mice were fed either a normal chow diet (ND) or a high fat diet (HFD) supplemented with or without 2% carbonyl iron (Fe) for 16 weeks. However, contrary to our assumption, dietary iron overloading did not intensify, but rather diminished the atherosclerotic lesion area by 65.3%, which was accompanied by significantly decreased serum total cholesterol, triglyceride and low-density lipoprotein cholesterol contents, together with hepatic lipid accumulation decline, despite the evident existence of aortic iron accumulation and the typical signs of iron overload in ApoE KO mice. Using isobaric tag for absolute quantification (iTRAQ) proteomics approach, hepatic CD36 and fatty acid binding proteins-mediated fatty acid (FA) uptake and trafficking impairment were identified as the key potential pathomechanisms by which iron overload diminishes atherosclerotic lesions. Furthermore, downstream hepatic FA de novo biosynthesis was enhanced and FA oxidation was inhibited to compensate for the FA deficiency triggered by iron overload-impaired fatty acid uptake and trafficking. Our findings suggested that dietary iron overload is not atherogenic in ApoE KO mice, and more research efforts are warranted to revisit the "iron hypothesis" of atherosclerosis.


Assuntos
Aterosclerose/dietoterapia , Dieta Hiperlipídica/efeitos adversos , Compostos de Ferro/administração & dosagem , Sobrecarga de Ferro/induzido quimicamente , Administração Oral , Animais , Aterosclerose/sangue , Aterosclerose/etiologia , Aterosclerose/metabolismo , LDL-Colesterol/sangue , LDL-Colesterol/metabolismo , Suplementos Nutricionais , Modelos Animais de Doenças , Feminino , Humanos , Sobrecarga de Ferro/sangue , Sobrecarga de Ferro/metabolismo , Metabolismo dos Lipídeos , Lipogênese/fisiologia , Masculino , Camundongos , Camundongos Knockout para ApoE , Triglicerídeos/sangue , Triglicerídeos/metabolismo
11.
Nutrients ; 13(6)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207558

RESUMO

Hypercholesterolemia can cause many diseases, but it can effectively regulated by Lactobacillus. This study aimed to evaluate the cholesterol-lowering mechanism of Enterococcus faecium strain 132 and Lactobacillusparacasei strain 201. These results showed that both the strains decreased serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), liver TC and TG and increased fecal TC, TG and total bile acid (TBA) levels. Additionally, both strains also reduced glutamic-pyruvic transaminase (ALT), glutamic oxaloacetic transaminase (AST) and levels of tissue inflammation levels to improve the lipid profile, and they reduced fat accumulation partially by alleviating inflammatory responses. Furthermore, both strains regulated the expression of the CYP8B1, CYP7A1, SREBP-1, SCD1 and LDL-R gene to promote cholesterol metabolism and reduce TG accumulation. Interventions with both strains also altered the gut microbiota, and decreasing the abundance of Veillonellaceae, Erysipelotrichaceae and Prevotella. Furthermore, fecal acetic acid and propionic acid were increased by this intervention. Overall, the results suggested that E. faecium strain 132 and L. paracasei strain 201 can alleviate hypercholesterolemia in rats and might be applied as a new type of hypercholesterolemia agent in functional foods.


Assuntos
Anticolesterolemiantes/farmacologia , Colesterol/metabolismo , Enterococcus faecium , Hipercolesterolemia/microbiologia , Lactobacillus paracasei , Probióticos/farmacologia , Ácido Acético/análise , Animais , Colesterol 7-alfa-Hidroxilase/metabolismo , LDL-Colesterol/metabolismo , Modelos Animais de Doenças , Fezes/química , Fezes/microbiologia , Alimento Funcional/microbiologia , Microbioma Gastrointestinal/fisiologia , Humanos , Hipercolesterolemia/metabolismo , Fígado/metabolismo , Fígado/microbiologia , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Masculino , Propionatos/análise , Ratos , Estearoil-CoA Dessaturase/metabolismo , Esteroide 12-alfa-Hidroxilase/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Triglicerídeos/metabolismo
12.
Int J Mol Sci ; 22(12)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207810

RESUMO

Excess lipid droplets are frequently observed in arterial endothelial cells at sites of advanced atherosclerotic plaques. Here, the role of tumor necrosis factor alpha (TNFα) in modulating the low-density lipoprotein (LDL) content in confluent primary human aortic endothelial cells (pHAECs) was investigated. TNFα promoted an up to 2 folds increase in cellular cholesterol, which was resistant to ACAT inhibition. The cholesterol increase was associated with increased 125I-LDL surface binding. Using the non-hydrolysable label, Dil, TNFα could induce a massive increase in Dil-LDL by over 200 folds. The elevated intracellular Dil-LDL was blocked with excess unlabeled LDL and PCSK9, but not oxidized LDL (oxLDL), or apolipoprotein (apoE) depletion. Moreover, the TNFα-induced increase of LDL-derived lipids was elevated through lysosome inhibition. Using specific LDLR antibody, the Dil-LDL accumulation was reduced by over 99%. The effects of TNFα included an LDLR cell surface increase of 138%, and very large increases in ICAM-1 total and surface proteins, respectively. In contrast, that of scavenger receptor B1 (SR-B1) was reduced. Additionally, LDLR antibody bound rapidly in TNFα-treated cells by about 30 folds, inducing a migrating shift in the LDLR protein. The effect of TNFα on Dil-LDL accumulation was inhibited by the antioxidant tetramethythiourea (TMTU) dose-dependently, but not by inhibitors against NF-κB, stress kinases, ASK1, JNK, p38, or apoptosis caspases. Grown on Transwell inserts, TNFα did not enhance apical to basolateral LDL cholesterol or Dil release. It is concluded that TNFα promotes LDLR functions through combined increase at the cell surface and SR-B1 downregulation.


Assuntos
Artérias/metabolismo , LDL-Colesterol/metabolismo , Regulação para Baixo/efeitos dos fármacos , Células Endoteliais/metabolismo , Receptores de LDL/biossíntese , Receptores Depuradores Classe B/biossíntese , Fator de Necrose Tumoral alfa/farmacologia , Artérias/patologia , Células Endoteliais/patologia , Humanos , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , Fator de Necrose Tumoral alfa/metabolismo
13.
Sci Rep ; 11(1): 11905, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099806

RESUMO

Retinal vein occlusion (RVO) is associated with atherosclerotic cardiovascular risk factors; however, its association with the specific markers of subclinical atherosclerosis has not yet been established. To investigate this association, we compared 70 patients with RVO to 70 age- and sex-matched patients without RVO. Low-density lipoprotein cholesterol (LDL-C) levels and brachial-ankle pulse wave velocity (baPWV) were significantly higher in the RVO group than in the control group. Carotid plaques (54.3% vs. 28.6%, p = 0.004) were more frequent in the RVO group. Multivariate logistic regression analysis showed that the presence of carotid plaques (odds ratio [OR]: 3.15, 95% confidence interval [CI] 1.38-7.16, p = 0.006), as well as smoking, LDL-C level, and baPWV were associated with RVO. Additionally, a multinomial logistic regression model showed that the presence of carotid plaques (OR: 3.94, 95% CI 1.65-9.41, p = 0.002) and LDL-C level were associated with branch RVO, whereas smoking and baPWV were associated with central RVO. In conclusion, RVO was associated with subclinical atherosclerosis markers, including carotid plaques and baPWV. These results support the hypothesis that atherosclerosis contributes to the etiology of RVO and suggest the evaluation of subclinical atherosclerosis in patients with RVO.


Assuntos
Índice Tornozelo-Braço , Aterosclerose/diagnóstico , Biomarcadores/análise , LDL-Colesterol/metabolismo , Análise de Onda de Pulso , Oclusão da Veia Retiniana/diagnóstico , Adulto , Idoso , Aterosclerose/complicações , Aterosclerose/fisiopatologia , Artérias Carótidas/patologia , Estudos de Casos e Controles , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Prospectivos , Oclusão da Veia Retiniana/etiologia , Oclusão da Veia Retiniana/fisiopatologia , Fatores de Risco , Rigidez Vascular
15.
Food Funct ; 12(14): 6416-6431, 2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34076000

RESUMO

Depression is an important global health issue that is associated with serious physical and mental health consequences. The field of nutritional psychiatry has generated observational and efficacy data supporting a role for healthy dietary patterns in depression. Here, we aim to evaluate the effects of high-fat diet (HFD) consumption on depressive-like behaviors. BALB/c mice were grouped randomly: control, chronic restraint stress (CRS), HFD and CRS + HFD groups. The depressive-like behavior was evaluated using behavioral tests. The serotonin content in murine brain tissue and blood lipid concentrations were detected by ELISA. The fatty acid content in the liver, adipose tissue of epididymis, brain tissue, and serum of mice was determined by gas chromatography (GC). Expression of the fatty acid synthesis pathway-related enzymes at the mRNA level was analyzed by qRT-PCR. The results indicated that a high-fat diet could promote depressive-like behavior. In comparison with regular feeding, concentrations of blood lipids were significantly changed in the HFD group. Correlation analysis implied that high-density lipoprotein cholesterol (HDL-c) and low-density lipoprotein cholesterol (LDL-c) were closely related to depressive-like behavior. Based on fatty acid analysis, the palmitoleic acid, linoleic acid, oleic acid, and arachidonic acid content was remarkably changed in mice with depressive-like behavior. In addition, acetyl-CoA carboxylase (ACC), stearoyl-CoA desaturase-1 (SCD1), fatty acid desaturase 1 (FADS1), and fatty acid desaturase 2 (FADS2) expression, which are involved in de novo fatty acid synthesis, desaturation of fatty acids, and arachidonic acid synthesis, were strengthened in HFD mice with depressive-like behavior. Therefore, we postulated that the disorder of lipid metabolism induced by HFD consumption accelerated the development of depressive-like behavior.


Assuntos
Comportamento Animal , Depressão/etiologia , Dieta Hiperlipídica/efeitos adversos , Metabolismo dos Lipídeos , Tecido Adiposo/metabolismo , Animais , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Depressão/metabolismo , Depressão/psicologia , Ácidos Graxos/metabolismo , Lipídeos/sangue , Lipogênese , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Serotonina/metabolismo
16.
EMBO J ; 40(14): e106871, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34124795

RESUMO

Low-density lipoprotein (LDL)-cholesterol delivery from late endosomes to the plasma membrane regulates focal adhesion dynamics and cell migration, but the mechanisms controlling it are poorly characterized. Here, we employed auxin-inducible rapid degradation of oxysterol-binding protein-related protein 2 (ORP2/OSBPL2) to show that endogenous ORP2 mediates the transfer of LDL-derived cholesterol from late endosomes to focal adhesion kinase (FAK)-/integrin-positive recycling endosomes in human cells. In vitro, cholesterol enhances membrane association of FAK to PI(4,5)P2 -containing lipid bilayers. In cells, ORP2 stimulates FAK activation and PI(4,5)P2 generation in endomembranes, enhancing cell adhesion. Moreover, ORP2 increases PI(4,5)P2 in NPC1-containing late endosomes in a FAK-dependent manner, controlling their tubulovesicular trafficking. Together, these results provide evidence that ORP2 controls FAK activation and LDL-cholesterol plasma membrane delivery by promoting bidirectional cholesterol/PI(4,5)P2 exchange between late and recycling endosomes.


Assuntos
Transporte Biológico/fisiologia , LDL-Colesterol/metabolismo , Endossomos/metabolismo , Quinase 1 de Adesão Focal/metabolismo , Fosfatos de Fosfatidilinositol/metabolismo , Receptores de Esteroides/metabolismo , Adesão Celular/fisiologia , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Movimento Celular/fisiologia , Humanos
17.
Biomed Res Int ; 2021: 6662704, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34159197

RESUMO

Objective: Secretion of glucagon-like peptide 1 (GLP-1) and its effect on target organs were impaired in individuals with obesity. However, its mechanism needs to be further studied. We aim to explore the roles of the receptor of GLP-1 (GLP-1R) involved in high-fat-diet- (HFD-) induced kidney damage improved by emodin. Methods: Male C57bl/6 mice were fed with HFD diet and therapied by emodin. NRK-52E cells were cultured and treated with palmitic acid or low-density lipoprotein cholesterol (LDL-C). Emodin was used to remedy the NRK-52E cell damage. GW9662 was administrated to block the function of peroxisome proliferator-activated receptor γ (PPAR-γ). GLP-1 in the plasma was measured by ELISA. PPAR-γ and GLP-1R in the kidney and NRK-52E cells were detected by western blotting. The interaction between PPAR-γ protein and GLP-1R promoter regions was observed by chromatin immunoprecipitation (ChIP). Results: Postprandial GLP-1 levels in plasma, as well as PPAR-γ and GLP-1R, decreased in kidney tissue of HFD mice, while they were reserved by emodin treatment. Although PPAR-γ and GLP-1R were not downregulated by LDL-C, they were suppressed by palmitic acid. Interestingly, GLP-1R mRNA was detected by PCR in the mixture pulled down with PPAR-γ antibody. Additionally, downregulation of PPAR-γ and GLP-1R by palmitic acid was remanded by emodin. Moreover, GW9662, an inhibitor of PPAR-γ, abolished the protective effect of emodin. Conclusion: The kidney damage of HFD mice seems to be alleviated by emodin via the upregulation of GLP-1R in kidney tissue.


Assuntos
Dieta Hiperlipídica , Emodina/farmacologia , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Nefropatias/metabolismo , Anilidas/farmacologia , Animais , Peso Corporal , LDL-Colesterol/metabolismo , Ensaio de Imunoadsorção Enzimática , Metabolismo dos Lipídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , PPAR gama/antagonistas & inibidores , Ácido Palmítico/farmacologia , Regiões Promotoras Genéticas , Regulação para Cima
18.
Int J Mol Sci ; 22(11)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070931

RESUMO

It is now about 20 years since the first case of a gain-of-function mutation involving the as-yet-unknown actor in cholesterol homeostasis, proprotein convertase subtilisin/kexin type 9 (PCSK9), was described. It was soon clear that this protein would have been of huge scientific and clinical value as a therapeutic strategy for dyslipidemia and atherosclerosis-associated cardiovascular disease (CVD) management. Indeed, PCSK9 is a serine protease belonging to the proprotein convertase family, mainly produced by the liver, and essential for metabolism of LDL particles by inhibiting LDL receptor (LDLR) recirculation to the cell surface with the consequent upregulation of LDLR-dependent LDL-C levels. Beyond its effects on LDL metabolism, several studies revealed the existence of additional roles of PCSK9 in different stages of atherosclerosis, also for its ability to target other members of the LDLR family. PCSK9 from plasma and vascular cells can contribute to the development of atherosclerotic plaque and thrombosis by promoting platelet activation, leukocyte recruitment and clot formation, also through mechanisms not related to systemic lipid changes. These results further supported the value for the potential cardiovascular benefits of therapies based on PCSK9 inhibition. Actually, the passive immunization with anti-PCSK9 antibodies, evolocumab and alirocumab, is shown to be effective in dramatically reducing the LDL-C levels and attenuating CVD. While monoclonal antibodies sequester circulating PCSK9, inclisiran, a small interfering RNA, is a new drug that inhibits PCSK9 synthesis with the important advantage, compared with PCSK9 mAbs, to preserve its pharmacodynamic effects when administrated every 6 months. Here, we will focus on the major understandings related to PCSK9, from its discovery to its role in lipoprotein metabolism, involvement in atherothrombosis and a brief excursus on approved current therapies used to inhibit its action.


Assuntos
Aterosclerose/genética , LDL-Colesterol/metabolismo , Dislipidemias/genética , Placa Aterosclerótica/genética , Pró-Proteína Convertase 9/genética , Trombose/genética , Anticorpos Monoclonais Humanizados/uso terapêutico , Aterosclerose/tratamento farmacológico , Aterosclerose/enzimologia , Aterosclerose/patologia , Plaquetas/efeitos dos fármacos , Plaquetas/enzimologia , Plaquetas/patologia , LDL-Colesterol/antagonistas & inibidores , Dislipidemias/tratamento farmacológico , Dislipidemias/enzimologia , Dislipidemias/patologia , Fibrinolíticos/uso terapêutico , Regulação da Expressão Gênica , Humanos , Hipolipemiantes/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Placa Aterosclerótica/tratamento farmacológico , Placa Aterosclerótica/enzimologia , Placa Aterosclerótica/patologia , Ativação Plaquetária/efeitos dos fármacos , Pró-Proteína Convertase 9/biossíntese , RNA Interferente Pequeno/uso terapêutico , Receptores de LDL/genética , Receptores de LDL/metabolismo , Transdução de Sinais , Trombose/enzimologia , Trombose/patologia , Trombose/prevenção & controle
19.
PLoS One ; 16(6): e0251560, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34086694

RESUMO

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is a common autosomal dominant disorder that can result in premature atherosclerotic cardiovascular disease (ASCVD). Limited data are available worldwide about the prevalence and management of FH. Here, we aimed to estimate the prevalence and management of patients with FH in five Arabian Gulf countries (Saudi Arabia, Oman, United Arab Emirates, Kuwait, and Bahrain). METHODS: The multicentre, multinational Gulf FH registry included adults (≥18 years old) recruited from outpatient clinics in 14 tertiary-care centres across five Arabian Gulf countries over the last five years. The Gulf FH registry had four phases: 1- screening, 2- classification based on the Dutch Lipid Clinic Network, 3- genetic testing, and 4- follow-up. RESULTS: Among 34,366 screened patient records, 3713 patients had suspected FH (mean age: 49±15 years; 52% women) and 306 patients had definite or probable FH. Thus, the estimated FH prevalence was 0.9% (1:112). Treatments included high-intensity statin therapy (34%), ezetimibe (10%), and proprotein convertase subtilisin/kexin type 9 inhibitors (0.4%). Targets for low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol were achieved by 12% and 30%, respectively, of patients at high ASCVD risk, and by 3% and 6%, respectively, of patients at very high ASCVD risk (p <0.001; for both comparisons). CONCLUSIONS: This snap-shot study was the first to show the high estimated prevalence of FH in the Arabian Gulf region (about 3-fold the estimated prevalence worldwide), and is a "call-to-action" for further confirmation in future population studies. The small proportions of patients that achieved target LDL-C values implied that health care policies need to implement nation-wide screening, raise FH awareness, and improve management strategies for FH.


Assuntos
Hiperlipoproteinemia Tipo II/epidemiologia , Barein/epidemiologia , LDL-Colesterol/metabolismo , Ezetimiba/uso terapêutico , Feminino , Humanos , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo II/metabolismo , Kuweit/epidemiologia , Masculino , Pessoa de Meia-Idade , Omã/epidemiologia , Prevalência , Sistema de Registros , Fatores de Risco , Arábia Saudita/epidemiologia , Serina Endopeptidases/metabolismo , Emirados Árabes Unidos/epidemiologia
20.
Med Sci Monit ; 27: e928784, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33958572

RESUMO

BACKGROUND A small proportion of familial hypercholesterolemia (FH) patients can adequately control this condition, although achieving the recommended targets for low-density lipoprotein cholesterol (LDL-c) levels remains a challenge. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are new and potent lipid-lowering drugs. However, there is scarce literature on real-world data about their use in patients with FH. MATERIAL AND METHODS We examined the reduction in LDL-c levels from the baseline, after PCSK9i initiation in heterozygous familial hypercholesterolemia patients referred for lipoprotein apheresis in our regional lipid clinic. The study was conducted from March 2018 to September 2019, the period immediately after PCSK9i reimbursement was available in France. PCSK9i was added on top of the patients' maximal tolerated lipid-lowering regimens. RESULTS The study had 123 patients with heterozygous FH. The mean age of the patients was 59±11 years. The mean baseline LDL-c for all the participants was 277±78 mg/dl. It was 283±81 mg/dl in the PCSK9i monotherapy group (n=83), 247±68 mg/dl in the PCSK9i plus ezetimibe group (n=12), and 264±78 mg/dl in the PCSK9i plus statin and ezetimibe group (n=28). The mean decrease observed in the LDL-c level from baseline was 136±70 mg/dl (n=123), 125±60 mg/dl (n=83), 103±77 mg/dl (n=12), and 175±70 mg/dl (n=28), respectively. CONCLUSIONS An overall reduction of 49.1% from the baseline LDL-c was observed in the heterozygous FH population after PCSK9i initiation in a real-world experience. The group treated with PCSK9i ezetimibe plus statin showed further reduction of their LDL-c levels with a better responder rate, achieving the target 50% reduction in LDL-c from the baseline.


Assuntos
Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Subtilisinas/uso terapêutico , Remoção de Componentes Sanguíneos/métodos , LDL-Colesterol/metabolismo , Estudos de Coortes , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos , Lipoproteínas/metabolismo , Masculino , Pessoa de Meia-Idade
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