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1.
Nat Commun ; 12(1): 5103, 2021 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-34429409

RESUMO

Hypercholesterolemia and dyslipidemia are associated with an increased risk for many cancer types and with poor outcomes in patients with established disease. Whereas the mechanisms by which this occurs are multifactorial we determine that chronic exposure of cells to 27-hydroxycholesterol (27HC), an abundant circulating cholesterol metabolite, selects for cells that exhibit increased cellular uptake and/or lipid biosynthesis. These cells exhibit substantially increased tumorigenic and metastatic capacity. Notably, the metabolic stress imposed upon cells by the accumulated lipids requires sustained expression of GPX4, a negative regulator of ferroptotic cell death. We show that resistance to ferroptosis is a feature of metastatic cells and further demonstrate that GPX4 knockdown attenuates the enhanced tumorigenic and metastatic activity of 27HC resistant cells. These findings highlight the general importance of ferroptosis in tumor growth and metastasis and suggest that dyslipidemia/hypercholesterolemia impacts cancer pathogenesis by selecting for cells that are resistant to ferroptotic cell death.


Assuntos
Colesterol/metabolismo , Ferroptose/fisiologia , Homeostase , Metabolismo dos Lipídeos , Neoplasias/metabolismo , Animais , Neoplasias da Mama , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Glutationa Peroxidase/metabolismo , Humanos , Hidroxicolesteróis , Neoplasias Pulmonares , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Metástase Neoplásica , Neoplasias/genética , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Nat Commun ; 12(1): 5073, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417467

RESUMO

The contents of numerous membrane lipids change upon ageing. However, it is unknown whether and how any of these changes are causally linked to lifespan regulation. Acyl chains contribute to the functional specificity of membrane lipids. In this study, working with C. elegans, we identified an acyl chain-specific sphingolipid, C22 glucosylceramide, as a longevity metabolite. Germline deficiency, a conserved lifespan-extending paradigm, induces somatic expression of the fatty acid elongase ELO-3, and behenic acid (22:0) generated by ELO-3 is incorporated into glucosylceramide for lifespan regulation. Mechanistically, C22 glucosylceramide is required for the membrane localization of clathrin, a protein that regulates membrane budding. The reduction in C22 glucosylceramide impairs the clathrin-dependent autophagic lysosome reformation, which subsequently leads to TOR activation and longevity suppression. These findings reveal a mechanistic link between membrane lipids and ageing and suggest a model of lifespan regulation by fatty acid-mediated membrane configuration.


Assuntos
Caenorhabditis elegans/fisiologia , Ácidos Graxos não Esterificados/metabolismo , Glicoesfingolipídeos/metabolismo , Homeostase , Longevidade/fisiologia , Lisossomos/metabolismo , Animais , Proteínas de Caenorhabditis elegans/metabolismo , Ceramidas/metabolismo , Colesterol/metabolismo , Clatrina/metabolismo , Mutação em Linhagem Germinativa/genética , Proteínas de Fluorescência Verde/metabolismo , Larva/metabolismo , Modelos Biológicos , Interferência de RNA , Estresse Fisiológico
3.
FASEB J ; 35(9): e21831, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34383982

RESUMO

The nuclear factor of activated T-cells 5 (NFAT5) is a transcriptional regulator of macrophage activation and T-cell development, which controls stabilizing responses of cells to hypertonic and biomechanical stress. In this study, we detected NFAT5 in the media layer of arteries adjacent to human arteriosclerotic plaques and analyzed its role in vascular smooth muscle cells (VSMCs) known to contribute to arteriosclerosis through the uptake of lipids and transformation into foam cells. Exposure of both human and mouse VSMCs to cholesterol stimulated the nuclear translocation of NFAT5 and increased the expression of the ATP-binding cassette transporter Abca1, required to regulate cholesterol efflux from cells. Loss of Nfat5 promoted cholesterol accumulation in these cells and inhibited the expression of genes involved in the management of oxidative stress or lipid handling, such as Sod1, Plin2, Fabp3, and Ppard. The functional relevance of these observations was subsequently investigated in mice fed a high-fat diet upon induction of a smooth muscle cell-specific genetic ablation of Nfat5 (Nfat5(SMC)-/- ). Under these conditions, Nfat5(SMC)-/- but not Nfat5fl/fl mice developed small, focal lipid-rich lesions in the aorta after 14 and 25 weeks, which were formed by intracellular lipid droplets deposited in the sub-intimal VSMCs layer. While known for being activated by external stimuli, NFAT5 was found to mediate the expression of VSMC genes associated with the handling of lipids in response to a cholesterol-rich environment. Failure of this protective function may promote the formation of lipid-laden arterial VSMCs and pro-atherogenic vascular responses.


Assuntos
Aorta/metabolismo , Metabolismo dos Lipídeos/fisiologia , Lipídeos/fisiologia , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Fatores de Transcrição/metabolismo , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Idoso , Animais , Aterosclerose/metabolismo , Células Cultivadas , Colesterol/metabolismo , Feminino , Células Espumosas/metabolismo , Regulação da Expressão Gênica/fisiologia , Humanos , Hipercolesterolemia/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Estresse Oxidativo/fisiologia , Túnica Íntima/metabolismo
4.
Molecules ; 26(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34361718

RESUMO

Several classes of polysaccharides have been described to have hypocholesterolemic potential, namely cholesterol bioaccessibility and bioavailability. This review will highlight the main mechanisms by which polysaccharides are known to affect cholesterol homeostasis at the intestine, namely the effect (i) of polysaccharide viscosity and its influence on cholesterol bioaccessibility; (ii) on bile salt sequestration and its dependence on the structural diversity of polysaccharides; (iii) of bio-transformations of polysaccharides and bile salts by the gut microbiota. Different quantitative structure-hypocholesterolemic activity relationships have been explored depending on the mechanism involved, and these were based on polysaccharide physicochemical properties, such as sugar composition and ramification degree, linkage type, size/molecular weight, and charge. The information gathered will support the rationalization of polysaccharides' effect on cholesterol homeostasis and highlight predictive rules towards the development of customized hypocholesterolemic functional food.


Assuntos
Anticolesterolemiantes/química , Ácidos e Sais Biliares/química , Colesterol/química , Alimento Funcional/análise , Mucosa Intestinal/metabolismo , Polissacarídeos/química , Anticolesterolemiantes/metabolismo , Anticolesterolemiantes/uso terapêutico , Ácidos e Sais Biliares/metabolismo , Disponibilidade Biológica , Biotransformação , Colesterol/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/fisiologia , Homeostase/efeitos dos fármacos , Homeostase/fisiologia , Humanos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/microbiologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Estrutura Molecular , Peso Molecular , Polissacarídeos/metabolismo , Polissacarídeos/uso terapêutico , Eletricidade Estática
5.
J Agric Food Chem ; 69(34): 9813-9821, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34415766

RESUMO

ι-Carrageenan tetrasaccharide (ιCTs), a novel oligosaccharide, was hydrolyzed from ι-carrageenan with targeting marine tool-enzyme Cgi82A. Previously, we have found ιCTs exhibited a hypoglycemic effect, whether it could regulate lipid metabolism remains unknown. In this study, the insulin-resistant mice induced by high-fat-high-sucrose diet were orally administrated with ιCTs (30 mg/kg·bw) for 20 weeks. The results showed that the contents of triglyceride and cholesterol in both serum and liver were reduced by ιCTs, and their excretion in feces were promoted, suggesting lipid accumulation was inhibited. Intriguingly, the overall levels of bile acid in serum, liver, and feces were all raised by ιCTs. Given that bile acids are the essential signal factors for regulating lipid metabolism via the farnesoid-X-receptor (FXR), we conducted serum bile acid profile analysis and found that the levels of high-affinity agonists deoxycholic acid and lithocholic acid were decreased in the ιCTs group, showing that ιCTs failed to activate FXR. Western blot analysis showed that ιCTs downregulated hepatic FXR and small heterodimer partner (SHP) expression and increased downstream CYP7A1 expression via regulating the FXR-SHP signal to accelerate liver cholesterol conversion. Meanwhile, ιCTs decreased the expression of PXR and SREBP1c and elevated the expression of PPARα and CPT1α via regulating the FXR-PXR-SREBP1c/PPARα signal to inhibit fatty acid synthesis and promote fatty acid ß-oxidation. To the best of our knowledge, this study for the first time reported that ιCTs alleviated liver lipid accumulation via the bile acid-FXR-SHP/PXR signal to regulate cholesterol conversion and fatty acid metabolism, which highlighted a new idea for ameliorating insulin resistance.


Assuntos
Ácidos e Sais Biliares , Insulina , Animais , Ácidos e Sais Biliares/metabolismo , Carragenina , Colesterol/metabolismo , Colesterol 7-alfa-Hidroxilase/metabolismo , Ácidos Graxos/metabolismo , Insulina/metabolismo , Metabolismo dos Lipídeos , Fígado/metabolismo , Camundongos , Oligossacarídeos/metabolismo
6.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360839

RESUMO

Hypercholesterolemia plays a causal role in the development of atherosclerosis and is one of the main risk factors for cardiovascular disease (CVD), the leading cause of death worldwide especially in developed countries. Current data show that the role of microbiota extends beyond digestion by being implicated in several metabolic and inflammatory processes linked to several diseases including CVD. Studies have reported associations between bacterial metabolites and hypercholesterolemia. However, such associations remain poorly investigated and characterized. In this review, the mechanisms of microbial derived metabolites such as primary and secondary bile acids (BAs), trimethylamine N-oxide (TMAO), and short-chain fatty acids (SCFAs) will be explored in the context of cholesterol metabolism. These metabolites play critical roles in maintaining cardiovascular health and if dysregulated can potentially contribute to CVD. They can be modulated via nutritional and pharmacological interventions such as statins, prebiotics, and probiotics. However, the mechanisms behind these interactions also remain unclear, and mechanistic insights into their impact will be provided. Therefore, the objectives of this paper are to present current knowledge on potential mechanisms whereby microbial metabolites regulate cholesterol homeostasis and to discuss the feasibility of modulating intestinal microbes and metabolites as a novel therapeutic for hypercholesterolemia.


Assuntos
Aterosclerose/metabolismo , Colesterol/metabolismo , Microbioma Gastrointestinal/fisiologia , Animais , Aterosclerose/microbiologia , Humanos , Hipercolesterolemia
7.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445501

RESUMO

Lipid dysregulation in diabetes mellitus escalates endothelial dysfunction, the initial event in the development and progression of diabetic atherosclerosis. In addition, lipid-laden macrophage accumulation in the arterial wall plays a significant role in the pathology of diabetes-associated atherosclerosis. Therefore, inhibition of endothelial dysfunction and enhancement of macrophage cholesterol efflux is the important antiatherogenic mechanism. Rosmarinic acid (RA) possesses beneficial properties, including its anti-inflammatory, antioxidant, antidiabetic and cardioprotective effects. We previously reported that RA effectively inhibits diabetic endothelial dysfunction by inhibiting inflammasome activation in endothelial cells. However, its effect on cholesterol efflux remains unknown. Therefore, in this study, we aimed to assess the effect of RA on cholesterol efflux and its underlying mechanisms in macrophages. RA effectively reduced oxLDL-induced cholesterol contents under high glucose (HG) conditions in macrophages. RA enhanced ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1) expression, promoting macrophage cholesterol efflux. Mechanistically, RA differentially regulated ABCA1 expression through JAK2/STAT3, JNK and PKC-p38 and ABCG1 expression through JAK2/STAT3, JNK and PKC-ERK1/2/p38 in macrophages. Moreover, RA primarily stabilized ABCA1 rather than ABCG1 protein levels by impairing protein degradation. These findings suggest RA as a candidate therapeutic to prevent atherosclerotic cardiovascular disease complications related to diabetes by regulating cholesterol efflux in macrophages.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Colesterol/metabolismo , Cinamatos/farmacologia , Depsídeos/farmacologia , Glucose/efeitos adversos , Lipoproteínas LDL/efeitos adversos , Macrófagos/citologia , Transportador 1 de Cassete de Ligação de ATP/química , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Modelos Biológicos , Proteólise/efeitos dos fármacos , Transdução de Sinais , Células THP-1
8.
Int J Mol Sci ; 22(16)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34445564

RESUMO

Niemann-Pick type C (NPC) disease is a wide-spectrum clinical condition classified as a neurovisceral disorder affecting mainly the liver and the brain. It is caused by mutations in one of two genes, NPC1 and NPC2, coding for proteins located in the lysosomes. NPC proteins are deputed to transport cholesterol within lysosomes or between late endosome/lysosome systems and other cellular compartments, such as the endoplasmic reticulum and plasma membrane. The first trait of NPC is the accumulation of unesterified cholesterol and other lipids, like sphingosine and glycosphingolipids, in the late endosomal and lysosomal compartments, which causes the blockade of autophagic flux and the impairment of mitochondrial functions. In the brain, the main consequences of NPC are cerebellar neurodegeneration, neuroinflammation, and myelin defects. This review will focus on myelin defects and the pivotal importance of cholesterol for myelination and will offer an overview of the molecular targets and the pharmacological strategies so far proposed, or an object of clinical trials for NPC. Finally, it will summarize recent data on a new and promising pharmacological perspective involving A2A adenosine receptor stimulation in genetic and pharmacological NPC dysmyelination models.


Assuntos
Agonistas do Receptor A2 de Adenosina/farmacologia , Colesterol/metabolismo , Bainha de Mielina/patologia , Doença de Niemann-Pick Tipo C/patologia , Receptor A2A de Adenosina/metabolismo , Animais , Humanos , Bainha de Mielina/efeitos dos fármacos , Doença de Niemann-Pick Tipo C/tratamento farmacológico , Doença de Niemann-Pick Tipo C/metabolismo
9.
Int J Mol Sci ; 22(16)2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34445139

RESUMO

Recent evidence pinpoints extracellular vesicles (EVs) as key players in intercellular communication. Given the importance of cholesterol and sphingomyelin in EV biology, and the relevance of mitochondria-associated endoplasmic reticulum membranes (MAMs) in cholesterol/sphingomyelin homeostasis, we evaluated if MAMs and sphingomyelinases (SMases) could participate in ethanol-induced EV release. EVs were isolated from the extracellular medium of BV2 microglia treated or not with ethanol (50 and 100 mM). Radioactive metabolic tracers combined with thin layer chromatography were used as quantitative methods to assay phospholipid transfer, SMase activity and cholesterol uptake/esterification. Inhibitors of SMase (desipramine and GW4869) and MAM (cyclosporin A) activities were also utilized. Our data show that ethanol increases the secretion and inflammatory molecule concentration of EVs. Ethanol also upregulates MAM activity and alters lipid metabolism by increasing cholesterol uptake, cholesterol esterification and SMase activity in microglia. Notably, the inhibition of either SMase or MAM activity prevented the ethanol-induced increase in EV secretion. Collectively, these results strongly support a lipid-driven mechanism, specifically via SMases and MAM, to explain the effect of ethanol on EV secretion in glial cells.


Assuntos
Retículo Endoplasmático/efeitos dos fármacos , Etanol/farmacologia , Vesículas Extracelulares/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Membranas Mitocondriais/efeitos dos fármacos , Esfingomielina Fosfodiesterase/metabolismo , Compostos de Anilina/farmacologia , Animais , Compostos de Benzilideno/farmacologia , Células Cultivadas , Colesterol/metabolismo , Ciclosporina/farmacologia , Retículo Endoplasmático/metabolismo , Vesículas Extracelulares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Mitocôndrias/metabolismo , Membranas Mitocondriais/metabolismo , Fosfolipídeos/metabolismo
10.
Int J Mol Sci ; 22(16)2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34445279

RESUMO

Hepatocellular carcinoma (HCC) is the most common primary malignant tumor in the world. Sorafenib is the first-line drug for patients with advanced HCC. However, long-term treatment with sorafenib often results in reduced sensitivity of tumor cells to the drug, leading to acquired resistance. Identifying biomarkers which can predict the response to sorafenib treatment may represent a clinical challenge in the personalized treatment era. Niemann-Pick type C2 (NPC2), a secretory glycoprotein, plays an important role in regulating intracellular free cholesterol homeostasis. In HCC patients, downregulation of hepatic NPC2 is correlated with poor clinical pathological features through regulating mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) activation. This study aimed to investigate the roles of secretory NPC2-mediated free cholesterol levels as biomarkers when undergoing sorafenib treatment and evaluate its impact on acquired sorafenib resistance in HCC cells. Herein, we showed that NPC2 downregulation and free cholesterol accumulation weakened sorafenib's efficacy through enhancing MAPK/AKT signaling in HCC cells. Meanwhile, NPC2 overexpression slightly enhanced the sorafenib-induced cytotoxic effect. Compared to normal diet feeding, mice fed a high-cholesterol diet had much higher tumor growth rates, whereas treatment with the free cholesterol-lowering agent, hydroxypropyl-ß-cyclodextrin, enhanced sorafenib's tumor-inhibiting ability. In addition, sorafenib treatment induced higher NPC2 secretion, which was mediated by inhibition of the Ras/Raf/MAPK kinase (MEK)/ERK signaling pathway in HCC cells. In both acquired sorafenib-resistant cell and xenograft models, NPC2 and free cholesterol secretion were increased in culture supernatant and serum samples. In conclusion, NPC2-mediated free cholesterol secretion may represent a candidate biomarker for the likelihood of HCC cells developing resistance to sorafenib.


Assuntos
Carcinoma Hepatocelular/metabolismo , Colesterol/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas de Neoplasias/metabolismo , Sorafenibe/farmacologia , Proteínas de Transporte Vesicular/metabolismo , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Feminino , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID
11.
Molecules ; 26(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34361779

RESUMO

Delivering nucleic acids into the endothelium has great potential in treating vascular diseases. However, endothelial cells, which line the vasculature, are considered as sensitive in nature and hard to transfect. Low transfection efficacies in endothelial cells limit their potential therapeutic applications. Towards improving the transfection efficiency, we made an effort to understand the internalization of lipoplexes into the cells, which is the first and most critical step in nucleic acid transfections. In this study, we demonstrated that the transient modulation of caveolae/lipid rafts mediated endocytosis with the cholesterol-sequestrating agents, nystatin, filipin III, and siRNA against Cav-1, which significantly increased the transfection properties of cationic lipid-(2-hydroxy-N-methyl-N,N-bis(2-tetradecanamidoethyl)ethanaminium chloride), namely, amide liposomes in combination with 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) (AD Liposomes) in liver sinusoidal endothelial cells (SK-Hep1). In particular, nystatin was found to be highly effective with 2-3-fold enhanced transfection efficacy when compared with amide liposomes in combination with Cholesterol (AC), by switching lipoplex internalization predominantly through clathrin-mediated endocytosis and macropinocytosis.


Assuntos
Cavéolas/efeitos dos fármacos , Colesterol/química , Células Endoteliais/efeitos dos fármacos , Lipossomos/química , Microdomínios da Membrana/efeitos dos fármacos , Transfecção/métodos , Animais , Cavéolas/química , Cavéolas/metabolismo , Caveolina 1/antagonistas & inibidores , Caveolina 1/genética , Caveolina 1/metabolismo , Linhagem Celular Transformada , Colesterol/metabolismo , Clatrina/metabolismo , DNA/química , DNA/metabolismo , Endocitose/efeitos dos fármacos , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Filipina/química , Filipina/farmacologia , Expressão Gênica , Lipossomos/metabolismo , Microdomínios da Membrana/química , Microdomínios da Membrana/metabolismo , Nistatina/química , Nistatina/farmacologia , Fosfatidiletanolaminas/química , Fosfatidiletanolaminas/farmacologia , Pinocitose/efeitos dos fármacos , Plasmídeos/química , Plasmídeos/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos
12.
Nat Commun ; 12(1): 4662, 2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34341345

RESUMO

Impaired cellular cholesterol efflux is a key factor in the progression of renal, cardiovascular, and autoimmune diseases. Here we describe a class of 5-arylnicotinamide compounds, identified through phenotypic drug discovery, that upregulate ABCA1-dependent cholesterol efflux by targeting Oxysterol Binding Protein Like 7 (OSBPL7). OSBPL7 was identified as the molecular target of these compounds through a chemical biology approach, employing a photoactivatable 5-arylnicotinamide derivative in a cellular cross-linking/immunoprecipitation assay. Further evaluation of two compounds (Cpd A and Cpd G) showed that they induced ABCA1 and cholesterol efflux from podocytes in vitro and normalized proteinuria and prevented renal function decline in mouse models of proteinuric kidney disease: Adriamycin-induced nephropathy and Alport Syndrome. In conclusion, we show that small molecule drugs targeting OSBPL7 reveal an alternative mechanism to upregulate ABCA1, and may represent a promising new therapeutic strategy for the treatment of renal diseases and other disorders of cellular cholesterol homeostasis.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Colesterol/metabolismo , Nefropatias Diabéticas/metabolismo , Compostos Orgânicos/farmacologia , Podócitos/metabolismo , Proteinúria/metabolismo , Receptores de Esteroides/antagonistas & inibidores , Transportador 1 de Cassete de Ligação de ATP/genética , Animais , Transporte Biológico/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Células HEK293 , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Camundongos da Linhagem 129 , Camundongos Knockout , Estrutura Molecular , Niacinamida/química , Niacinamida/farmacologia , Compostos Orgânicos/síntese química , Compostos Orgânicos/química , Podócitos/citologia , Interferência de RNA , Receptores de Esteroides/genética , Receptores de Esteroides/metabolismo , Células THP-1
13.
Nat Commun ; 12(1): 4898, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34385431

RESUMO

Hedgehog (Hh) signaling is essential during development and in organ physiology. In the canonical pathway, Hh binding to Patched (PTCH) relieves the inhibition of Smoothened (SMO). Yet, PTCH may also perform SMO-independent functions. While the PTCH homolog PTC-3 is essential in C. elegans, worms lack SMO, providing an excellent model to probe non-canonical PTCH function. Here, we show that PTC-3 is a cholesterol transporter. ptc-3(RNAi) leads to accumulation of intracellular cholesterol and defects in ER structure and lipid droplet formation. These phenotypes were accompanied by a reduction in acyl chain (FA) length and desaturation. ptc-3(RNAi)-induced lethality, fat content and ER morphology defects were rescued by reducing dietary cholesterol. We provide evidence that cholesterol accumulation modulates the function of nuclear hormone receptors such as of the PPARα homolog NHR-49 and NHR-181, and affects FA composition. Our data uncover a role for PTCH in organelle structure maintenance and fat metabolism.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/genética , Colesterol/metabolismo , Homeostase/genética , Metabolismo dos Lipídeos/genética , Receptor Patched-1/genética , Animais , Western Blotting , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/ultraestrutura , Proteínas de Caenorhabditis elegans/metabolismo , Regulação da Expressão Gênica , Microscopia Eletrônica de Transmissão , Receptor Patched-1/metabolismo , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa
14.
Int J Mol Sci ; 22(11)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34205975

RESUMO

High-density lipoproteins (HDLs) are a class of blood particles, principally involved in mediating reverse cholesterol transport from peripheral tissue to liver. Omics approaches have identified crucial mediators in the HDL proteomic and lipidomic profile, which are involved in distinct pleiotropic functions. Besides their role as cholesterol transporter, HDLs display anti-inflammatory, anti-apoptotic, anti-thrombotic, and anti-infection properties. Experimental and clinical studies have unveiled significant changes in both HDL serum amount and composition that lead to dysregulated host immune response and endothelial dysfunction in the course of sepsis. Most SARS-Coronavirus-2-infected patients admitted to the intensive care unit showed common features of sepsis disease, such as the overwhelmed systemic inflammatory response and the alterations in serum lipid profile. Despite relevant advances, episodes of mild to moderate acute kidney injury (AKI), occurring during systemic inflammatory diseases, are associated with long-term complications, and high risk of mortality. The multi-faceted relationship of kidney dysfunction with dyslipidemia and inflammation encourages to deepen the clarification of the mechanisms connecting these elements. This review analyzes the multifaced roles of HDL in inflammatory diseases, the renal involvement in lipid metabolism, and the novel potential HDL-based therapies.


Assuntos
COVID-19/patologia , Lipoproteínas HDL/metabolismo , Sepse/patologia , Injúria Renal Aguda/etiologia , COVID-19/complicações , COVID-19/metabolismo , COVID-19/virologia , Colesterol/metabolismo , Proteínas do Sistema Complemento/metabolismo , Humanos , Metabolismo dos Lipídeos , Lipoproteínas HDL/química , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/fisiologia , Sepse/complicações , Sepse/metabolismo , Internalização do Vírus
15.
Arterioscler Thromb Vasc Biol ; 41(9): 2370-2383, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34261330

RESUMO

Thrombosis is a major complication of cardiovascular disease, leading to myocardial infarction, acute ischemic stroke, or venous thromboembolism. Thrombosis occurs when a thrombus forms inside blood vessels disrupting blood flow. Developments in thrombectomy to remove thrombi from vessels have provided new opportunities to study thrombus composition which may help to understand mechanisms of disease and underpin improvements in treatments. We aimed to review thrombus compositions, roles of components in thrombus formation and stability, and methods to investigate thrombi. Also, we summarize studies on thrombus structure obtained from cardiovascular patients and animal models. Thrombi are composed of fibrin, red blood cells, platelets, leukocytes, and neutrophil extracellular traps. These components have been analyzed by several techniques, including scanning electron microscopy, laser scanning confocal microscopy, histochemistry, and immunohistochemistry; however, each technique has advantages and limitations. Thrombi are heterogenous in composition, but overall, thrombi obtained from myocardial infarction are composed of mainly fibrin and other components, including platelets, red blood cells, leukocytes, and cholesterol crystals. Thrombi from patients with acute ischemic stroke are characterized by red blood cell- and platelet-rich regions. Thrombi from patients with venous thromboembolism contain mainly red blood cells and fibrin with some platelets and leukocytes. Thrombus composition from patients with myocardial infarction is influenced by ischemic time. Animal thrombosis models are crucial to gain further mechanistic information about thrombosis and thrombus structure, with thrombi being similar in composition compared with those from patients. Further studies on thrombus composition and function are key to improve treatment and clinical outcome of thrombosis.


Assuntos
Coagulação Sanguínea , Plaquetas/metabolismo , Eritrócitos/metabolismo , Fibrina/metabolismo , Trombose/metabolismo , Animais , Plaquetas/patologia , Colesterol/metabolismo , Modelos Animais de Doenças , Eritrócitos/patologia , Humanos , Leucócitos/metabolismo , Trombectomia , Trombose/patologia , Trombose/terapia
16.
J Physiol Biochem ; 77(3): 405-417, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34212313

RESUMO

Cholesterol efflux from macrophages is the first step of reverse cholesterol transport (RCT), whose increase inhibits cholesterol accumulation and foam cell formation to suppress atherogenesis. Hesperetin has been reported to exert several protective effects on cardiovascular diseases, while little is known about the role of hesperetin and its underlying mechanism in macrophage foam cell formation. In this study, we sought to investigate the potential effects of hesperetin on foam cell formation and cholesterol efflux by using human macrophages, focusing on liver X receptor alpha (LXRα) and AMPK. We found that hesperetin treatment reduced foam cell formation, intracellular cholesterol levels and the cholesterol esterification rate, and increased cholesterol efflux in THP-1 macrophages. Hesperetin increased the levels of LXRα protein and its targets, including ABCA1, ABCG1, SR-BI, and phosphorylated-AMPK. Meanwhile, the hesperetin-induced increase in LXRα expression was further increased by the AMPK agonist and inhibited by an AMPK inhibitor. Meanwhile, hesperetin increased the levels of LXRα mRNA and its target genes, all of which were decreased in cells transfected with the AMPKα1/α2 small interfering RNA (siRNA). Furthermore, the hesperetin-induced inhibition of foam cell formation and promotion of cholesterol efflux were decreased by transfection of AMPKα1/α2 siRNA. In conclusions, We are the first to report that hesperetin activate AMPK in THP-1-derived macrophages. This activation upregulats LXRα and its targets, including ABCA1, ABCG1 and SR-BI, which significantly inhibits foam cell formation and promotes cholesterol efflux. Our results highlight the therapeutic potential of hesperetin to possibly reduce foam cell formation. This new mechanism might contribute the anti-atherogenic effects of hesperetin.


Assuntos
Colesterol/metabolismo , Células Espumosas/efeitos dos fármacos , Hesperidina/farmacologia , Aterosclerose/metabolismo , Células Espumosas/patologia , Humanos , Receptores X do Fígado/metabolismo , Proteínas Quinases/metabolismo , Células THP-1
17.
Fish Physiol Biochem ; 47(4): 1299-1311, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34241762

RESUMO

Genistein is an abundant phytoestrogen in soybean. This study aimed to determine the effects of genistein on cholesterol distribution and metabolism in female yellow catfish. Three hundred fish (49.2 ± 1.4 g) were randomly divided into five treatments and received intraperitoneal injections as follows: (1) blank, no injection; (2) control, vehicle only; (3) E2, 17ß-estradiol at 10 µg·g-1 body weight; (4) low genistein doses, genistein at 10 µg·g-1 body weight; (5) high genistein doses, genistein at 100 µg·g-1 body weight. Both high and low genistein doses significantly reduced (p < 0.05) serum TC and LDL-C 24 h after injection. Moreover, the high genistein doses significantly reduced (p < 0.05) serum HDL-C. Both high and low doses of genistein significantly increased (p < 0.05) hepatic TC. Only high genistein doses significantly increased (p < 0.05) ovary TC. In the liver, both high and low genistein doses significantly increased (p < 0.05) protein and mRNA expression of ldlr. Meanwhile, high genistein doses significantly decreased (p < 0.05) mRNA expression of hmgcr. In ovary tissue, high genistein doses significantly decreased (p < 0.05) mRNA expression of cyp11a1. These results suggested that genistein affected the cholesterol distribution in female yellow catfish. Both high and low doses of genistein reduced cholesterol content in blood and increased its content in the liver by increasing the uptake of blood cholesterol. Meanwhile, high genistein doses may inhibit hepatic cholesterol synthesis. Additionally, high genistein doses could increase cholesterol transfer from serum into the ovary and disturb cholesterol conversion to pregnenolone.


Assuntos
Peixes-Gato/metabolismo , Colesterol/metabolismo , Genisteína/farmacologia , Proteínas Quinases Ativadas por AMP/genética , Animais , Peixes-Gato/sangue , Peixes-Gato/genética , Colesterol/sangue , Enzima de Clivagem da Cadeia Lateral do Colesterol/genética , Feminino , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Hidroximetilglutaril-CoA Redutases/genética , Hidroximetilglutaril-CoA Redutases/metabolismo , Injeções Intraperitoneais , Fígado/efeitos dos fármacos , Fígado/metabolismo , Ovário/efeitos dos fármacos , Ovário/metabolismo , Fosfoproteínas/genética , Receptores de LDL/genética , Receptores de LDL/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/genética
18.
Int J Mol Sci ; 22(14)2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34299217

RESUMO

The mycobacterial cell wall is composed of large amounts of lipids with varying moieties. Some mycobacteria species hijack host cells and promote lipid droplet accumulation to build the cellular environment essential for their intracellular survival. Thus, lipids are thought to be important for mycobacteria survival as well as for the invasion, parasitization, and proliferation within host cells. However, their physiological roles have not been fully elucidated. Recent studies have revealed that mycobacteria modulate the peroxisome proliferator-activated receptor (PPAR) signaling and utilize host-derived triacylglycerol (TAG) and cholesterol as both nutrient sources and evasion from the host immune system. In this review, we discuss recent findings that describe the activation of PPARs by mycobacterial infections and their role in determining the fate of bacilli by inducing lipid metabolism, anti-inflammatory function, and autophagy.


Assuntos
Infecções por Mycobacterium/microbiologia , Mycobacterium/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Animais , Autofagia/fisiologia , Colesterol/metabolismo , Humanos , Metabolismo dos Lipídeos , Mycobacterium/crescimento & desenvolvimento , Mycobacterium/imunologia , Infecções por Mycobacterium/imunologia , Infecções por Mycobacterium/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/genética , Transdução de Sinais
19.
Nat Commun ; 12(1): 4434, 2021 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-34290249

RESUMO

Dyslipidemia is a main driver of cardiovascular diseases. The ability of macrophages to scavenge excess lipids implicate them as mediators in this process and understanding the mechanisms underlying macrophage lipid metabolism is key to the development of new treatments. Here, we investigated how adipose tissue macrophages regulate post-prandial cholesterol transport. Single-cell RNA sequencing and protected bone marrow chimeras demonstrated that ingestion of lipids led to specific transcriptional activation of a population of resident macrophages expressing Lyve1, Tim4, and ABCA1. Blocking the phosphatidylserine receptor Tim4 inhibited lysosomal activation and the release of post-prandial high density lipoprotein cholesterol following a high fat meal. Both effects were recapitulated by chloroquine, an inhibitor of lysosomal function. Moreover, clodronate-mediated cell-depletion implicated Tim4+ resident adipose tissue macrophages in this process. Thus, these data indicate that Tim4 is a key regulator of post-prandial cholesterol transport and adipose tissue macrophage function and may represent a novel pathway to treat dyslipidemia.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Tecido Adiposo/metabolismo , Colesterol/metabolismo , Macrófagos/metabolismo , Proteínas de Membrana/metabolismo , Período Pós-Prandial/fisiologia , Tecido Adiposo/citologia , Animais , HDL-Colesterol/metabolismo , Dieta Hiperlipídica , Metabolismo dos Lipídeos , Lisossomos/metabolismo , Macrófagos/citologia , Camundongos , Obesidade/metabolismo , Obesidade/patologia , Ativação Transcricional , Proteínas de Transporte Vesicular/metabolismo
20.
J Agric Food Chem ; 69(30): 8440-8447, 2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34286573

RESUMO

Hypercholesterolemia is a major risk factor for chronic metabolic diseases. Nevertheless, a whole-grain diet could ameliorate this issue in a number of ways, including by regulating bile acid metabolism. However, the potential mechanism is unclear. The aim of the current study is to explore the effects of whole-grain diets (brown rice diet and whole wheat diet) on bile acid homeostasis. After intervention for 8 weeks in mouse model, whole-grain diets showed reduced feed conversion ratio, and the lipid levels (total cholesterol (TC) and triglycerides (TG)) were also meliorated in the serum and liver of mice. Moreover, whole-grain diets reduced the expression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) (cholesterol synthesis) in the liver of mice. Interestingly, whole-grain diets not only promoted the mRNA expressions of low-density lipoprotein receptor (LDLR), ATP binding cassette transporter G1 (ABCG1), and scavenger receptor class B type I (SR-BI) (reverse cholesterol transport) but also facilitated the expressions of cytochrome P450, family 7, subfamily a, polypeptide 1 (CYP7a1) and cytochrome P450, family 27, subfamily a, polypeptide 1 (CYP27a1) (bile acid synthesis). Further study found that whole-grain diets promoted intestinal bile acid reabsorption and reduced bile acid excretion. Our study provided a novel metabolic regulation of bile acids in response to reduced cholesterol levels induced by whole-grain diets.


Assuntos
Ácidos e Sais Biliares , Colesterol , Animais , Ácidos e Sais Biliares/metabolismo , Colesterol/metabolismo , Colesterol 7-alfa-Hidroxilase/genética , Colesterol 7-alfa-Hidroxilase/metabolismo , Dieta , Metabolismo dos Lipídeos , Fígado/metabolismo , Camundongos , Grãos Integrais
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