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1.
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
2.
Arterioscler Thromb Vasc Biol ; 41(11): 2708-2725, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34551590

RESUMO

Objective: To investigate the role of adipocyte Pcpe2 (procollagen C-endopeptidase enhancer 2) in SR-BI (scavenger receptor class BI)-mediated HDL-C (high-density lipoprotein cholesterol) uptake and contributions to adipose lipid storage. Approach and Results: Pcpe2, a glycoprotein devoid of intrinsic proteolytic activity, is believed to participate in extracellular protein-protein interactions, supporting SR-BI- mediated HDL-C uptake. In published studies, Pcpe2 deficiency increased the development of atherosclerosis by reducing SR-BI-mediated HDL-C catabolism, but the biological impact of this deficiency on adipocyte SR-BI-mediated HDL-C uptake is unknown. Differentiated cells from Ldlr-/-/Pcpe2-/- (Pcpe2-/-) mouse adipose tissue showed elevated SR-BI protein levels, but significantly reduced HDL-C uptake compared to Ldlr-/- (control) adipose tissue. SR-BI-mediated HDL-C uptake was restored by preincubation of cells with exogenous Pcpe2. In diet-fed mice lacking Pcpe2, significant reductions in visceral, subcutaneous, and brown adipose tissue mass were observed, despite elevations in plasma triglyceride and cholesterol concentrations. Significant positive correlations exist between adipose mass and Pcpe2 expression in both mice and humans. Conclusions: Overall, these findings reveal a novel and unexpected function for Pcpe2 in modulating SR-BI expression and function as it relates to adipose tissue expansion and cholesterol balance in both mice and humans.


Assuntos
Adipócitos/metabolismo , Aterosclerose/metabolismo , HDL-Colesterol/metabolismo , Glicoproteínas/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Microdomínios da Membrana/metabolismo , Obesidade/metabolismo , Receptores Depuradores Classe B/metabolismo , Gordura Subcutânea/metabolismo , Adipócitos/patologia , Adipogenia , Adiposidade , Adulto , Animais , Aterosclerose/genética , Aterosclerose/patologia , Células CHO , Caveolina 1/metabolismo , Cricetulus , Dieta Hiperlipídica , Modelos Animais de Doenças , Metabolismo Energético , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Feminino , Glicoproteínas/genética , Humanos , Mediadores da Inflamação/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Microdomínios da Membrana/genética , Microdomínios da Membrana/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Obesidade/genética , Obesidade/patologia , Receptores de LDL/genética , Receptores de LDL/metabolismo , Receptores Depuradores Classe B/genética , Gordura Subcutânea/patologia
3.
Arterioscler Thromb Vasc Biol ; 41(10): e468-e479, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34407633

RESUMO

Objective: ApoM enriches S1P (sphingosine-1-phosphate) within HDL (high-density lipoproteins) and facilitates the activation of the S1P1 (S1P receptor type 1) by S1P, thereby preserving endothelial barrier function. Many protective functions exerted by HDL in extravascular tissues raise the question of how S1P regulates transendothelial HDL transport. Approach and Results: HDL were isolated from plasma of wild-type mice, Apom knockout mice, human apoM transgenic mice or humans and radioiodinated to trace its binding, association, and transport by bovine or human aortic endothelial cells. We also compared the transport of fluorescently-labeled HDL or Evans Blue, which labels albumin, from the tail vein into the peritoneal cavity of apoE-haploinsufficient mice with (apoE-haploinsufficient mice with endothelium-specific knockin of S1P1) or without (control mice, ie, apoE-haploinsufficient mice without endothelium-specific knockin of S1P1) endothelium-specific knockin of S1P1. The binding, association, and transport of HDL from Apom knockout mice and human apoM-depleted HDL by bovine aortic endothelial cells was significantly lower than that of HDL from wild-type mice and human apoM-containing HDL, respectively. The binding, uptake, and transport of 125I-HDL by human aortic endothelial cells was increased by an S1P1 agonist but decreased by an S1P1 inhibitor. Silencing of SR-BI (scavenger receptor BI) abrogated the stimulation of 125I-HDL transport by the S1P1 agonist. Compared with control mice, that is, apoE-haploinsufficient mice without endothelium-specific knockin of S1P1, apoE-haploinsufficient mice with endothelium-specific knockin of S1P1 showed decreased transport of Evans Blue but increased transport of HDL from blood into the peritoneal cavity and SR-BI expression in the aortal endothelium. Conclusions: ApoM and S1P1 promote transendothelial HDL transport. Their opposite effect on transendothelial transport of albumin and HDL indicates that HDL passes endothelial barriers by specific mechanisms rather than passive filtration.


Assuntos
Apolipoproteínas M/metabolismo , Aterosclerose/metabolismo , Células Endoteliais/metabolismo , Lipoproteínas HDL/metabolismo , Receptores de Esfingosina-1-Fosfato/metabolismo , Animais , Aterosclerose/genética , Aterosclerose/patologia , Transporte Biológico , Bovinos , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/patologia , Feminino , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Permeabilidade , Placa Aterosclerótica , Receptores Depuradores Classe B/genética , Receptores Depuradores Classe B/metabolismo , Receptores de Esfingosina-1-Fosfato/genética
4.
Phytother Res ; 35(10): 5623-5633, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34327759

RESUMO

The dysregulation of cholesterol metabolism is a high-risk factor for non-alcoholic fatty liver disease (NAFLD), dyslipidemia, and atherosclerosis (AS). Cholesterol transport maintains whole-body cholesterol homeostasis. Low-density apolipoprotein receptor (LDLR) mediates cholesterol uptake in cells and plays an important role in the primary route of circulatory cholesterol clearance in liver cells. Caveolins 1 is an integral membrane protein and shuttle between the cytoplasm and cell membrane. Caveolins 1 not only plays a role in promoting cholesterol absorption in cells but also in the transport of cellular cholesterol efflux by interacting with the ATP-binding cassette transporter A1 (ABCA1) and scavenger receptor class B type I (SR-BI). These proteins, which are associated with reverse cholesterol transport (RCT), are potential therapeutic targets for NAFLD and AS. Many studies have indicated that natural products have lipid-lowering effects. Moreover, natural molecules, derived from natural products, have the potential to be developed into novel drugs. However, the mechanisms underlying the regulation of cholesterol transport by natural molecules have not yet been adequately investigated. In this review, we briefly describe the process of cholesterol transport and summarize the mechanisms by which molecules regulate cholesterol transport. This article provides an overview of recent studies and focuses on the potential therapeutic effects of natural molecules; however, further high-quality studies are needed to firmly establish the clinical efficacies of natural molecules.


Assuntos
Transportadores de Cassetes de Ligação de ATP , Aterosclerose , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Aterosclerose/tratamento farmacológico , Transporte Biológico , Colesterol , Humanos , Receptores Depuradores Classe B/metabolismo
5.
Infect Immun ; 89(10): e0030121, 2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34097506

RESUMO

Recent studies suggest an anti-inflammatory protective role for class B scavenger receptor BI (SR-BI) in endotoxin-induced inflammation and sepsis. Other data, including ours, provide evidence for an alternative role of SR-BI, facilitating bacterial and endotoxin uptake and contributing to inflammation and bacterial infection. Enhanced endotoxin susceptibility of SR-BI-deficient mice due to their anti-inflammatory glucocorticoid deficiency complicates the understanding of SR-BI's role in endotoxemia/sepsis, calling for the use of alternative models. In this study, using human SR-BI (hSR-BI) and hSR-BII transgenic mice, we found that SR-BI and, to a lesser extent, its splicing variant SR-BII protect against LPS-induced lung damage. At 20 h after intratracheal LPS instillation, the extent of pulmonary inflammation and vascular leakage was significantly lower in hSR-BI and hSR-BII transgenic mice than in wild-type mice. Higher bronchoalveolar lavage fluid (BALF) inflammatory cell count and protein content and lung tissue neutrophil infiltration found in wild-type mice were associated with markedly (2 to 3 times) increased proinflammatory cytokine production compared to these parameters in transgenic mice following LPS administration. The markedly lower endotoxin levels detected in BALF of transgenic versus wild-type mice and the significantly increased BODIPY-LPS uptake observed in lungs of hSR-BI and hSR-BII mice 20 h after the i.t. LPS injection suggest that hSR-BI- and hSR-BII-mediated enhanced LPS clearance in the airways could represent the mechanism of their protective role against LPS-induced acute lung injury.


Assuntos
Lesão Pulmonar Aguda/metabolismo , Glicoproteínas de Membrana Associadas ao Lisossomo/metabolismo , Receptores Depuradores/metabolismo , Receptores Depuradores Classe B/metabolismo , Células A549 , Lesão Pulmonar Aguda/induzido quimicamente , Animais , Líquido da Lavagem Broncoalveolar , Linhagem Celular Tumoral , Citocinas/metabolismo , Modelos Animais de Doenças , Endotoxemia/metabolismo , Humanos , Inflamação/imunologia , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neutrófilos/metabolismo , Sepse/metabolismo
6.
Biochim Biophys Acta Mol Cell Res ; 1868(7): 119043, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33862056

RESUMO

In this study, we developed a method to analyze liposomal binding to a cell membrane receptor using fluorescence-labeled liposomes and demonstrated that scavenger class B type 1 (SR-B1) plays a crucial role in binding of liposomes containing phosphatidylcholine (PC) to HEK293T cell membrane and phosphatidic acid (PA) can modulate it. Site-directed mutagenesis of SR-B1 revealed that S112F and T175A mutations in its ectodomain abrogated binding and endocytosis of PC liposomes in HEK293T cells. K151A and K156A mutations attenuated their binding and endocytosis too. Although the effects of mutations on binding and endocytosis were similar between PC liposomes and PC/PA and PA liposomes, SR-B1 dependency appeared to be PC > PC/PA > PA liposomes. Our data indicate that (i) nanoparticles including high-density lipoprotein (HDL), silica, and liposomes bind to a common or close site of SR-B1, and (ii) PC/PA and PA liposomes bind not only to SR-B1 but also other receptor(s) in HEK293T cells. In addition, PC/PA liposomes induced lipid droplet (LD) formation in HEK293T cells more than PC liposomes. Treatment of HEK293T cells with SR-B1 siRNA suppressed PC/PA liposome-induced LD formation. Taken together, our results demonstrate that SR-B1 plays an essential role in binding PC-containing liposomes and the subsequent induction of cellular responses, while PA can modulate them.


Assuntos
Lipossomos/metabolismo , Receptores Depuradores Classe B/genética , Receptores Depuradores Classe B/metabolismo , Fenômenos Biofísicos , Células HEK293 , Humanos , Ácidos Fosfatídicos/química , Ácidos Fosfatídicos/metabolismo , Fosfatidilcolinas/química , Fosfatidilcolinas/metabolismo , Ligação Proteica , Receptores Depuradores/metabolismo , Receptores Depuradores Classe B/fisiologia
7.
Int J Mol Sci ; 22(7)2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33805921

RESUMO

Colorectal cancer (CRC) is a highly prevalent malignancy with multifactorial etiology, which includes metabolic alterations as contributors to disease development. Studies have shown that lipid status disorders are involved in colorectal carcinogenesis. In line with this, previous studies have also suggested that the serum high-density lipoprotein cholesterol (HDL-C) level decreases in patients with CRC, but more recently, the focus of investigations has shifted toward the exploration of qualitative properties of HDL in this malignancy. Herein, a comprehensive overview of available evidences regarding the putative role of HDL in CRC will be presented. We will analyze existing findings regarding alterations of HDL-C levels but also HDL particle structure and distribution in CRC. In addition, changes in HDL functionality in this malignancy will be discussed. Moreover, we will focus on the genetic regulation of HDL metabolism, as well as the involvement of HDL in disturbances of cholesterol trafficking in CRC. Finally, possible therapeutic implications related to HDL will be presented. Given the available evidence, future studies are needed to resolve all raised issues concerning the suggested protective role of HDL in CRC, its presumed function as a biomarker, and eventual therapeutic approaches based on HDL.


Assuntos
Neoplasias Colorretais/metabolismo , Lipoproteínas HDL/metabolismo , Animais , Apolipoproteína A-I/metabolismo , Apolipoproteínas M/metabolismo , Arildialquilfosfatase/metabolismo , Biomarcadores/metabolismo , Carcinogênese , Colesterol/metabolismo , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , HDL-Colesterol/metabolismo , Homeostase , Humanos , Camundongos , Polimorfismo de Nucleotídeo Único , Medicina de Precisão , Receptores Depuradores Classe B/metabolismo
8.
J Clin Invest ; 131(7)2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33661763

RESUMO

Autophagy modulates lipid turnover, cell survival, inflammation, and atherogenesis. Scavenger receptor class B type I (SR-BI) plays a crucial role in lysosome function. Here, we demonstrate that SR-BI regulates autophagy in atherosclerosis. SR-BI deletion attenuated lipid-induced expression of autophagy mediators in macrophages and atherosclerotic aortas. Consequently, SR-BI deletion resulted in 1.8- and 2.5-fold increases in foam cell formation and apoptosis, respectively, and increased oxidized LDL-induced inflammatory cytokine expression. Pharmacological activation of autophagy failed to reduce lipid content or apoptosis in Sr-b1-/- macrophages. SR-BI deletion reduced both basal and inducible levels of transcription factor EB (TFEB), a master regulator of autophagy, causing decreased expression of autophagy genes encoding VPS34 and Beclin-1. Notably, SR-BI regulated Tfeb expression by enhancing PPARα activation. Moreover, intracellular macrophage SR-BI localized to autophagosomes, where it formed cholesterol domains resulting in enhanced association of Barkor and recruitment of the VPS34-Beclin-1 complex. Thus, SR-BI deficiency led to lower VPS34 activity in macrophages and in atherosclerotic aortic tissues. Overexpression of Tfeb or Vps34 rescued the defective autophagy in Sr-b1-/- macrophages. Taken together, our results show that macrophage SR-BI regulates autophagy via Tfeb expression and recruitment of the VPS34-Beclin-1 complex, thus identifying previously unrecognized roles for SR-BI and potentially novel targets for the treatment of atherosclerosis.


Assuntos
Aorta/metabolismo , Doenças da Aorta/metabolismo , Aterosclerose/metabolismo , Autofagia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Classe III de Fosfatidilinositol 3-Quinases/metabolismo , Células Espumosas/metabolismo , PPAR alfa/metabolismo , Receptores Depuradores Classe B/metabolismo , Transcrição Genética , Animais , Doenças da Aorta/genética , Aterosclerose/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Proteína Beclina-1/genética , Classe III de Fosfatidilinositol 3-Quinases/genética , Camundongos , Camundongos Knockout , Complexos Multiproteicos/genética , Complexos Multiproteicos/metabolismo , PPAR alfa/genética , Receptores Depuradores Classe B/deficiência
9.
J Mol Histol ; 52(3): 539-544, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33608777

RESUMO

Both clear cell renal carcinoma (ccRCC) and clear cell carcinoma of the ovary (CCOC) have a clear cytoplasmic morphological feature, hence it is difficult to identify metastatic ccRCC and CCOC by morphology alone. At present, there are no effective immunohistochemical markers to distinguish between these two tumors. Studies have shown that the clear cytoplasm of ccRCC is mainly caused by cholesterol-rich lipids in the cytoplasm, while that of CCOC is due to the accumulation of cytoplasmic glycogen. OBJECTIVE: to hypothesize that the scavenger receptor class B-type 1 (SR-B1) protein responsible for HDL cholesterol uptake may be differentially expressed in ccRCC and CCOC, and high CD10 expression in the renal tubular epithelium may assist in distinguishing between ccRCC and CCOC. METHODS: effective immunohistochemical markers were applied in 90 cases of renal clear cell carcinoma and 31 cases of ovarian cancer to distinguish between the two types of tumors. RESULT: SR-B1 and CD10 expression is significantly higher in ccRCC than CCOC. Both SR-B1 and CD10 exhibited focal weak-medium intensity staining in CCOC, and their staining extent and intensity were significantly lower than ccRCC. The sensitivity and specificity of SR-B1 for identifying ccRCC were 74.4% and 83.9%, respectively. The sensitivity and specificity of CD10 for identifying CCOC were 93.3% and 80.6%, respectively. The combined SR-B1( +) CD10( +) immunoprofile supports the diagnosis of ccRCC with a specificity of 93.5%. The combined SR-B1(-) CD10(-) immunoprofile supports the diagnosis of CCOC with a specificity of 93.3%. CONCLUSIONS: our findings demonstrate that the combination of SR-B1 and CD10 immunoprofiling is a valuable tool for differential diagnosis of ccRCC and CCOC.


Assuntos
Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/imunologia , Neoplasias Renais/diagnóstico , Neoplasias Renais/imunologia , Neprilisina/metabolismo , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/imunologia , Receptores Depuradores Classe B/metabolismo , Adulto , Idoso , Carcinoma de Células Renais/patologia , Diagnóstico Diferencial , Feminino , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Sensibilidade e Especificidade
10.
Histochem Cell Biol ; 155(5): 529-545, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33404706

RESUMO

Cholesterol has long been suspected of influencing hair biology, with dysregulated homeostasis implicated in several disorders of hair growth and cycling. Cholesterol transport proteins play a vital role in the control of cellular cholesterol levels and compartmentalisation. This research aimed to determine the cellular localisation, transport capability and regulatory control of cholesterol transport proteins across the hair cycle. Immunofluorescence microscopy in human hair follicle sections revealed differential expression of ATP-binding cassette (ABC) transporters across the hair cycle. Cholesterol transporter expression (ABCA1, ABCG1, ABCA5 and SCARB1) reduced as hair follicles transitioned from growth to regression. Staining for free cholesterol (filipin) revealed prominent cholesterol striations within the basement membrane of the hair bulb. Liver X receptor agonism demonstrated active regulation of ABCA1 and ABCG1, but not ABCA5 or SCARB1 in human hair follicles and primary keratinocytes. These results demonstrate the capacity of human hair follicles for cholesterol transport and trafficking. Future studies examining the role of cholesterol transport across the hair cycle may shed light on the role of lipid homeostasis in human hair disorders.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Colesterol/metabolismo , Folículo Piloso/metabolismo , Receptores Depuradores Classe B/metabolismo , Transportador 1 de Cassete de Ligação de ATP/análise , Transportador 1 de Cassete de Ligação de ATP/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/análise , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/análise , Transportadores de Cassetes de Ligação de ATP/genética , Transporte Biológico , Células Cultivadas , Folículo Piloso/química , Folículo Piloso/crescimento & desenvolvimento , Humanos , Microscopia de Fluorescência , Receptores Depuradores Classe B/análise , Receptores Depuradores Classe B/genética
11.
Curr Atheroscler Rep ; 23(1): 5, 2021 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-33398433

RESUMO

PURPOSE OF THE REVIEW: To evaluate recent studies related to the paradox of high HDL-C with mortality and atherosclerotic cardiovascular disease (ASCVD) risk. RECENT FINDINGS: Two observational studies (Cardiovascular Health in Ambulatory Care Research Team [CANHEART] and Copenhagen City Heart Study and the Copenhagen General Population Study [Copenhagen Heart Studies]) of adults without pre-existing ASCVD have shown a significant U-shaped association of HDL-C with all-cause and cause-specific mortality. Both studies showed that low HDL-C levels consistently increased hazard risk (HR) for all-cause and cause-specific mortality. In the CANHEART study, high HDL-C levels, HDL-C > 90 mg/dL, were associated with increased HR for non-CVD/non-cancer mortality. In the Copenhagen Heart Studies, women with HDL-C ≥ 135 mg/dL showed increased HR for all-cause and CVD mortality, while men with HDL-C > 97 mg/dL showed increased HR for all-cause and CVD mortality. Genetic association studies failed to show that genetic etiologies of high HDL-C significantly reduced risk for myocardial infarction (MI), while hepatocyte nuclear factor-4 (HNF4A) was significantly associated with high HDL-C and increased MI risk. Candidate gene studies have identified scavenger receptor B class I (SCARB1) and lymphocyte activation gene-3 (LAG3) as genes significantly associated with high HDL-C and increased MI risk. Low HDL-C remains as a significant factor for increased disease risk while high HDL-C levels are not associated with cardioprotection. Clinical CVD risk calculators need revision.


Assuntos
Antígenos CD/metabolismo , Aterosclerose/metabolismo , HDL-Colesterol/metabolismo , Receptores Depuradores Classe B/metabolismo , Antígenos CD/genética , Aterosclerose/genética , Aterosclerose/mortalidade , HDL-Colesterol/sangue , HDL-Colesterol/genética , Regulação da Expressão Gênica/fisiologia , Humanos , Receptores Depuradores Classe B/genética
12.
Nat Metab ; 3(1): 59-74, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33462514

RESUMO

Activating transcription factor (ATF)3 is known to have an anti-inflammatory function, yet the role of hepatic ATF3 in lipoprotein metabolism or atherosclerosis remains unknown. Here we show that overexpression of human ATF3 in hepatocytes reduces the development of atherosclerosis in Western-diet-fed Ldlr-/- or Apoe-/- mice, whereas hepatocyte-specific ablation of Atf3 has the opposite effect. We further show that hepatic ATF3 expression is inhibited by hydrocortisone. Mechanistically, hepatocyte ATF3 enhances high-density lipoprotein (HDL) uptake, inhibits intestinal fat and cholesterol absorption and promotes macrophage reverse cholesterol transport by inducing scavenger receptor group B type 1 (SR-BI) and repressing cholesterol 12α-hydroxylase (CYP8B1) in the liver through its interaction with p53 and hepatocyte nuclear factor 4α, respectively. Our data demonstrate that hepatocyte ATF3 is a key regulator of HDL and bile acid metabolism and atherosclerosis.


Assuntos
Fator 3 Ativador da Transcrição/fisiologia , Aterosclerose/prevenção & controle , Ácidos e Sais Biliares/metabolismo , Hepatócitos/metabolismo , Lipoproteínas HDL/metabolismo , Animais , Apolipoproteínas E/genética , Colesterol na Dieta/metabolismo , Gorduras na Dieta/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Fator 4 Nuclear de Hepatócito/metabolismo , Humanos , Hidrocortisona/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de LDL/genética , Receptores Depuradores Classe B/metabolismo , Esteroide 12-alfa-Hidroxilase/metabolismo , Proteína Supressora de Tumor p53/metabolismo
13.
J Nat Prod ; 84(2): 373-381, 2021 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-33492139

RESUMO

Natural piperine from black pepper is known to function as hypocholesterolemic agent, but how it lowers the blood cholesterol remains unclear. In this study, we found that intragastric administrations of piperine (25 mg/kg/day) for 8 weeks significantly reduced the plasma triglyceride (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) in high-fat diet (HFD)-fed mice. H&E staining indicated that piperine significantly decreased hepatic lipid accumulation compared with the control group. The Oil Red O staining further showed that piperine attenuated lipid deposition in liver HepG2 cells in a concentration-dependent manner. Mechanistically, piperine treatment caused a significant upregulation of hepatic scavenger receptor B1 (SR-B1) in the liver and transporter protein of ATP binding cassette SGM8 (ABCG8) in the small intestine. Taken together, our findings demonstrate the role of natural piperine in improving lipid metabolic profile that is involved in the reverse cholesterol transport (RCT)-mediated mechanism through upregulation of SR-B1 in the liver and ABCG8 in the small intestine.


Assuntos
Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Alcaloides/farmacologia , Anticolesterolemiantes/farmacologia , Benzodioxóis/farmacologia , Lipoproteínas/metabolismo , Metaboloma , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Receptores Depuradores Classe B/metabolismo , Animais , Transporte Biológico , Dieta Hiperlipídica , Células Hep G2 , Humanos , Intestino Delgado/metabolismo , Lipídeos/sangue , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Regulação para Cima
15.
J Biol Chem ; 296: 100100, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33208460

RESUMO

Normal human cells can either synthesize cholesterol or take it up from lipoproteins to meet their metabolic requirements. In some malignant cells, de novo cholesterol synthesis genes are transcriptionally silent or mutated, meaning that cholesterol uptake from lipoproteins is required for survival. Recent data suggest that lymphoma cells dependent upon lipoprotein-mediated cholesterol uptake are also subject to ferroptosis, an oxygen- and iron-dependent cell death mechanism triggered by accumulation of oxidized lipids in cell membranes unless the lipid hydroperoxidase, glutathione peroxidase 4 (GPX4), reduces these toxic lipid species. To study mechanisms linking cholesterol uptake with ferroptosis and determine the potential role of the high-density lipoprotein (HDL) receptor as a target for cholesterol depleting therapy, we treated lymphoma cell lines known to be sensitive to the reduction of cholesterol uptake with HDL-like nanoparticles (HDL NPs). HDL NPs are a cholesterol-poor ligand that binds to the receptor for cholesterol-rich HDLs, scavenger receptor type B1 (SCARB1). Our data reveal that HDL NP treatment activates a compensatory metabolic response in treated cells toward increased de novo cholesterol synthesis, which is accompanied by nearly complete reduction in expression of GPX4. As a result, oxidized membrane lipids accumulate, leading to cell death through a mechanism consistent with ferroptosis. We obtained similar results in vivo after systemic administration of HDL NPs in mouse lymphoma xenografts and in primary samples obtained from patients with lymphoma. In summary, targeting SCARB1 with HDL NPs in cholesterol uptake-addicted lymphoma cells abolishes GPX4, resulting in cancer cell death by a mechanism consistent with ferroptosis.


Assuntos
Colesterol/metabolismo , Ferroptose , Linfoma/metabolismo , Animais , Colesterol/genética , Humanos , Células Jurkat , Linfoma/genética , Linfoma/patologia , Camundongos , Camundongos SCID , Proteínas de Neoplasias/metabolismo , Oxirredução , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Receptores Depuradores Classe B/genética , Receptores Depuradores Classe B/metabolismo , Células U937
16.
Food Chem ; 341(Pt 2): 128000, 2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33059273

RESUMO

Phenolic acids (caffeic acid, p-coumaric acid,) and carotenes (ß-carotene, lycopene) were mixed in different ratios to investigate antioxidant interactions on H2O2-induced H9c2 cells with ezetimibe (inhibitor of carotenes membrane transporters). Cellular uptake of carotenes, expression of membrane transporters, reactive oxygen species (ROS), nuclear factor erythroid 2-related factor 2 (Nrf2), NAD(P)H dehydrogenase quinone1 (NQO1), heme oxygenase-1 (HO-1), glutamate-cysteine ligase catalytic subunit (GCLC) were analyzed. Results revealed that phenolic acids increased cellular uptake of carotenes and expression of their membrane transporters. Combination groups contained more phenolic acids showed synergistic effects. For example, ß-carotene: caffeic acid = 1:2 significantly suppressed the intracellular ROS (+EZT, 66.34 ±â€¯51.53%) and enhanced the accumulation of nucleus-Nrf2 (+EZT, 30.23 ±â€¯5.30) compared to the groups contained more ß-carotene (+EZT, ROS: 75.48 ±â€¯2.55%, nucleus-Nrf2: 19.48 ±â€¯4.22). This study provided an implication of functional foods formulation and demonstrated that antioxidant synergism may due to the up-regulation of carotenes membrane transporters by phenolic acids.


Assuntos
Antioxidantes/farmacologia , Ácidos Cafeicos/farmacologia , Carotenoides/farmacologia , Propionatos/farmacologia , Animais , Carotenoides/farmacocinética , Linhagem Celular , Sinergismo Farmacológico , Ezetimiba/farmacologia , Heme Oxigenase (Desciclizante)/metabolismo , Peróxido de Hidrogênio/toxicidade , Licopeno/farmacologia , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Receptores Depuradores Classe B/metabolismo
17.
Arterioscler Thromb Vasc Biol ; 41(1): 200-216, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33054399

RESUMO

OBJECTIVE: LDL (low-density lipoprotein) transcytosis across the endothelium is performed by the SR-BI (scavenger receptor class B type 1) receptor and contributes to atherosclerosis. HMGB1 (high mobility group box 1) is a structural protein in the nucleus that is released by cells during inflammation; extracellular HMGB1 has been implicated in advanced disease. Whether intracellular HMGB1 regulates LDL transcytosis through its nuclear functions is unknown. Approach and Results: HMGB1 was depleted by siRNA in human coronary artery endothelial cells, and transcytosis of LDL was measured by total internal reflection fluorescence microscopy. Knockdown of HMGB1 attenuated LDL transcytosis without affecting albumin transcytosis. Loss of HMGB1 resulted in reduction in SR-BI levels and depletion of SREBP2 (sterol regulatory element-binding protein 2)-a transcription factor upstream of SR-BI. The effect of HMGB1 depletion on LDL transcytosis required SR-BI and SREBP2. Overexpression of HMGB1 caused an increase in LDL transcytosis that was unaffected by inhibition of extracellular HMGB1 or depletion of RAGE (receptor for advanced glycation endproducts)-a cell surface receptor for HMGB1. The effect of HMGB1 overexpression on LDL transcytosis was prevented by knockdown of SREBP2. Loss of HMGB1 caused a reduction in the half-life of SREBP2; incubation with LDL caused a significant increase in nuclear localization of HMGB1 that was dependent on SR-BI. Animals lacking endothelial HMGB1 exhibited less acute accumulation of LDL in the aorta 30 minutes after injection and when fed a high-fat diet developed fewer fatty streaks and less atherosclerosis. CONCLUSIONS: Endothelial HMGB1 regulates LDL transcytosis by prolonging the half-life of SREBP2, enhancing SR-BI expression. Translocation of HMGB1 to the nucleus in response to LDL requires SR-BI.


Assuntos
Aterosclerose/metabolismo , Células Endoteliais/metabolismo , Proteína HMGB1/metabolismo , Receptores de LDL/metabolismo , Receptores Depuradores Classe B/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Transcitose , Transporte Ativo do Núcleo Celular , Animais , Aterosclerose/genética , Aterosclerose/patologia , Aterosclerose/prevenção & controle , Células Cultivadas , Modelos Animais de Doenças , Feminino , Proteína HMGB1/deficiência , Proteína HMGB1/genética , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estabilidade Proteica , Receptores de LDL/genética , Receptores Depuradores Classe B/genética , Transdução de Sinais , Proteína de Ligação a Elemento Regulador de Esterol 2/genética
18.
J Nutr Biochem ; 89: 108564, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33321184

RESUMO

Scavenger receptor BI (SR-BI) has been suggested to modulate adipocyte function. To uncover the potential relevance of SR-BI for the development of obesity and associated metabolic complications, we compared the metabolic phenotype of wild-type and SR-BI deficient mice fed an obesogenic diet enriched in fat. Both male and female SR-BI knockout mice gained significantly more weight as compared to their wild-type counterparts in response to 12 weeks high fat diet feeding (1.5-fold; P < .01 for genotype). Plasma free cholesterol levels were ~2-fold higher (P < .001) in SR-BI knockout mice of both genders, whilst plasma cholesteryl ester and triglyceride concentrations were only significantly elevated in males. Strikingly, the exacerbated obesity in SR-BI knockout mice was paralleled by a better glucose handling. In contrast, only SR-BI knockout mice developed atherosclerotic lesions in the aortic root, with a higher predisposition in females. Biochemical and histological studies in male mice revealed that SR-BI deficiency was associated with a reduced hepatic steatosis degree as evident from the 29% lower (P < .05) liver triglyceride levels. Relative mRNA expression levels of the glucose uptake transporter GLUT4 were increased (+47%; P < .05), whilst expression levels of the metabolic PPARgamma target genes CD36, HSL, ADIPOQ and ATGL were reduced 39%-58% (P < .01) in the context of unchanged PPARgamma expression levels in SR-BI knockout gonadal white adipose tissue. In conclusion, we have shown that SR-BI deficiency is associated with a decrease in adipocyte PPARgamma activity and a concomitant uncoupling of obesity development from hepatic steatosis and glucose intolerance development in high fat diet-fed mice.


Assuntos
Antígenos CD36/deficiência , Fígado Gorduroso/metabolismo , Intolerância à Glucose/metabolismo , Obesidade/metabolismo , Adipócitos/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Aterosclerose/metabolismo , Antígenos CD36/metabolismo , Colesterol/sangue , Ésteres do Colesterol/sangue , Dieta Hiperlipídica/efeitos adversos , Feminino , Humanos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , PPAR gama/genética , PPAR gama/metabolismo , Receptores Depuradores Classe B/metabolismo , Triglicerídeos/sangue
19.
Toxicol Appl Pharmacol ; 412: 115388, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33383043

RESUMO

Phytosterol diosgenin (DG) exhibits cholesterol-lowering properties. Few studies focused on the underlying mechanism of DG attenuation of hypercholesterolemia by promoting cholesterol metabolism. To investigate the roles of SRB1/CES-1/CYP7A1/FXR pathways in accelerating cholesterol elimination and alleviating hypercholesterolemia, a rat model of hypercholesterolemia was induced by providing a high-fat diet (HFD). Experimental rat models were randomly divided into a normal control (Con) group, HFD group, low-dose DG (LDG) group (150 mg/kg/d), high-dose DG (HDG) group (300 mg/kg) and Simvastatin (Sim) group (4 mg/kg/d). Body weights, serum and hepatic lipid parameters of rats were tested. The expression levels of scavenger receptor class B type I (SRB1), carboxylesterase-1 (CES-1), cholesterol7α- hydroxylase (CYP7A1), and farnesoid X receptor (FXR) were determined. The results showed that DG reduced weight and lowered lipid levels in HFD-fed rats. Pathological morphology analyses revealed that DG notably improved hepatic steatosis and intestinal structure. Further studies showed the increased hepatic SRB1, CES-1, CYP7A1 and inhibited FXR-mediated signaling in DG-fed rats, which contributing to the decrease of hepatic cholesterol. DG also increased intestinal SRB1 and CES-1, inhibiting cholesterol absorption and promoting RCT. The expression levels of these receptors in the HDG group were higher than LDG and Sim groups. These data suggested that DG accelerated reverse cholesterol transport (RCT) and enhanced cholesterol elimination via SRB1/CES-1/CYP7A1/FXR pathway, and DG might be a new candidate for the alleviation of hypercholesterolemia.


Assuntos
Anticolesterolemiantes/farmacologia , Hidrolases de Éster Carboxílico/metabolismo , Colesterol 7-alfa-Hidroxilase/metabolismo , Colesterol/sangue , Diosgenina/farmacologia , Hipercolesterolemia/prevenção & controle , Fígado/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Depuradores Classe B/metabolismo , Animais , Biomarcadores/sangue , Dieta Hiperlipídica , Modelos Animais de Doenças , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hipercolesterolemia/sangue , Hipercolesterolemia/enzimologia , Hipercolesterolemia/patologia , Fígado/enzimologia , Fígado/patologia , Masculino , Ratos Sprague-Dawley , Transdução de Sinais , Sinvastatina/farmacologia
20.
Int J Mol Sci ; 22(1)2020 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-33374266

RESUMO

High-density lipoproteins (HDLs) display endothelial protective effects. We tested the role of SR-BI, an HDL receptor expressed by endothelial cells, in the neuroprotective effects of HDLs using an experimental model of acute ischemic stroke. After transient intraluminal middle cerebral artery occlusion (tMCAO), control and endothelial SR-BI deficient mice were intravenously injected by HDLs or saline. Infarct volume and blood-brain barrier (BBB) breakdown were assessed 24 h post tMCAO. The potential of HDLs and the role of SR-BI to maintain the BBB integrity was assessed by using a human cellular model of BBB (hCMEC/D3 cell line) subjected to oxygen-glucose deprivation (OGD). HDL therapy limited the infarct volume and the BBB leakage in control mice relative to saline injection. Interestingly, these neuroprotective effects were thwarted by the deletion of SR-BI in endothelial cells and preserved in mice deficient for SR-BI in myeloid cells. In vitro studies revealed that HDLs can preserve the integrity of the BBB in OGD conditions, and that this effect was reduced by the SR-BI inhibitor, BLT-1. The protection of BBB integrity plays a pivotal role in HDL therapy of acute ischemic stroke. Our results show that this effect is partially mediated by the HDL receptor, SR-BI expressed by endothelial cells.


Assuntos
Barreira Hematoencefálica/metabolismo , Células Endoteliais/metabolismo , Lipoproteínas HDL/farmacologia , Fármacos Neuroprotetores/farmacologia , Receptores Depuradores Classe B/metabolismo , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Linhagem Celular , Ciclopentanos/farmacologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Knockout , Receptores Depuradores Classe B/antagonistas & inibidores , Receptores Depuradores Classe B/genética , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/metabolismo , Tiossemicarbazonas/farmacologia
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