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1.
Cell Metab ; 33(10): 1911-1925, 2021 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-34562355

RESUMO

High levels of cholesterol are generally considered to be associated with atherosclerosis. In the past two decades, however, a number of studies have shown that excess cholesterol accumulation in various tissues and organs plays a critical role in the pathogenesis of multiple diseases. Here, we summarize the effects of excess cholesterol on disease pathogenesis, including liver diseases, diabetes, chronic kidney disease, Alzheimer's disease, osteoporosis, osteoarthritis, pituitary-thyroid axis dysfunction, immune disorders, and COVID-19, while proposing that excess cholesterol-induced toxicity is ubiquitous. We believe this concept will help broaden the appreciation of the toxic effect of excess cholesterol, and thus potentially expand the therapeutic use of cholesterol-lowering medications.


Assuntos
Aterosclerose/metabolismo , COVID-19/metabolismo , Colesterol/metabolismo , Hipercolesterolemia/metabolismo , Animais , Anticolesterolemiantes/uso terapêutico , Aterosclerose/diagnóstico , Aterosclerose/tratamento farmacológico , Aterosclerose/epidemiologia , Biomarcadores/metabolismo , COVID-19/diagnóstico , COVID-19/tratamento farmacológico , COVID-19/epidemiologia , Humanos , Hipercolesterolemia/diagnóstico , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/epidemiologia , Prognóstico , Fatores de Risco
2.
Curr Issues Mol Biol ; 43(2): 818-830, 2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34449561

RESUMO

BACKGROUND: A high-cholesterol diet (HCD) induces vascular atherosclerosis through vascular inflammatory and immunological processes via TLRs. The aim of this study is to investigate the mRNA expression of TLRs and other noxious biomarkers expressing inflammation, fibrosis, apoptosis, and cardiac dysfunction in the rabbit myocardium during (a) high-cholesterol diet (HCD), (b) normal diet resumption and (c) fluvastatin or rosuvastatin treatment. METHODS: Forty-eight male rabbits were randomly divided into eight groups (n = 6/group). In the first experiment, three groups were fed with HCD for 1, 2 and 3 months. In the second experiment, three groups were fed with HCD for 3 months, followed by normal chow for 1 month and administration of fluvastatin or rosuvastatin for 1 month. Control groups were fed with normal chow for 90 and 120 days. The whole myocardium was removed; total RNA was isolated from acquired samples, and polymerase chain reaction, reverse transcription PCR and quantitative real-time PCR were performed. RESULTS: mRNA of TLRs 2, 3, 4 and 8; interleukin-6; TNF-a; metalloproteinase-2; tissue inhibitor of metalloproteinase-1; tumor protein 53; cysteinyl aspartate specific proteinase-3; and brain natriuretic peptide (BNP) increased in HCD. Statins but not resumption of a normal diet decreased levels of these biomarkers and increased levels of antifibrotic factors. CONCLUSIONS: HCD increases the levels of TLRs; inflammatory, fibrotic and apoptotic factors; and BNP in the rabbit myocardium. Atherogenic diets adversely affect the myocardium at a molecular level and are reversed by statins.


Assuntos
Colesterol na Dieta/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hipercolesterolemia/tratamento farmacológico , Miocárdio/metabolismo , Receptores Toll-Like/metabolismo , Animais , Modelos Animais de Doenças , Fluvastatina/farmacologia , Hipercolesterolemia/etiologia , Hipercolesterolemia/metabolismo , Hipercolesterolemia/patologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Interleucina-6/metabolismo , Masculino , Miocárdio/patologia , Coelhos , Rosuvastatina Cálcica/farmacologia , Fator de Necrose Tumoral alfa/metabolismo
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(12)2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34205604

RESUMO

Rutin (R) and quercetin (Q) are two widespread dietary flavonoids. Previous studies regarding the plasma cholesterol-lowering activity of R and Q generated inconsistent results. The present study was therefore carried out to investigate the effects of R and Q on cholesterol metabolism in both HepG2 cells and hypercholesterolemia hamsters. Results from HepG2 cell experiments demonstrate that both R and Q decreased cholesterol at doses of 5 and 10 µM. R and Q up-regulated both the mRNA and protein expression of sterol regulatory element binding protein 2 (SREBP2), low-density lipoprotein receptor (LDLR), and liver X receptor alpha (LXRα). The immunofluorescence study revealed that R and Q increased the LDLR expression, while only Q improved LDL-C uptake in HepG2 cells. Results from hypercholesterolemia hamsters fed diets containing R (5.5 g/kg diet) and Q (2.5 g/kg diet) for 8 weeks demonstrate that both R and Q had no effect on plasma total cholesterol. In the liver, only Q reduced cholesterol significantly. The discrepancy between the in vitro and in vivo studies was probably due to a poor bioavailability of flavonoids in the intestine. It was therefore concluded that R and Q were effective in reducing cholesterol in HepG2 cells in vitro, whereas in vivo, the oral administration of the two flavonoids had little effect on plasma cholesterol in hamsters.


Assuntos
Colesterol/sangue , Colesterol/metabolismo , Quercetina/farmacologia , Rutina/farmacologia , Administração Oral , Animais , Linhagem Celular Tumoral , Cricetinae , Flavonoides/farmacologia , Células Hep G2 , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Receptores X do Fígado/metabolismo , Masculino , RNA Mensageiro/metabolismo , Receptores de LDL/sangue , Receptores de LDL/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Triglicerídeos/sangue , Triglicerídeos/metabolismo , Regulação para Cima/efeitos dos fármacos
5.
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
6.
Biomed Pharmacother ; 139: 111668, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243630

RESUMO

Metabolic Syndrome (MetS) is a complex and multifactorial condition often characterised by obesity, hypertension, hyperlipidaemia, insulin resistance, glucose intolerance and fasting hyperglycaemia. Collectively, MetS can increase the risk of atherosclerotic-cardiovascular disease, which is the leading cause of death worldwide. However, no animal model currently exists to study MetS in the context of atherosclerosis. In this study we developed a pre-clinical mouse model that recapitulates the spectrum of MetS features while developing atherosclerosis. When BPHx mice were placed on a western type diet for 16 weeks, all the classical characteristics of MetS were observed. Comprehensive metabolic analyses and atherosclerotic imaging revealed BPHx mice to be obese and hypertensive, with elevated total plasma cholesterol and triglyceride levels, that accelerated atherosclerosis. Altogether, we demonstrate that the BPHx mouse has all the major components of MetS, and accelerates the development of atherosclerosis.


Assuntos
Aterosclerose/patologia , Dieta/efeitos adversos , Hipertensão/patologia , Síndrome Metabólica/patologia , Animais , Aterosclerose/sangue , Aterosclerose/metabolismo , Glicemia/metabolismo , Colesterol/sangue , Modelos Animais de Doenças , Feminino , Intolerância à Glucose/sangue , Intolerância à Glucose/metabolismo , Intolerância à Glucose/patologia , Hipercolesterolemia/sangue , Hipercolesterolemia/metabolismo , Hipercolesterolemia/patologia , Hiperglicemia/sangue , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Hiperlipidemias/sangue , Hiperlipidemias/metabolismo , Hiperlipidemias/patologia , Hipertensão/sangue , Hipertensão/metabolismo , Resistência à Insulina/fisiologia , Síndrome Metabólica/sangue , Síndrome Metabólica/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/sangue , Obesidade/metabolismo , Obesidade/patologia , Triglicerídeos/sangue
7.
J Oleo Sci ; 70(6): 837-848, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34078760

RESUMO

The current study was carried out to estimate the protective effect of methanolic extract of Chaetomorpha gracilis (MECG) against High Cholesterol Diet (HCD) induced erythrocyte damage in mice. The results of the in vitro assay showed that MECG have higher antioxidant capacities in the DPPH, TAC, ABTS, NBT, NO. inhibition assays. The HPLC analysis confirmed that this potential antioxidant seems to be due to the active compounds, in particular polyphenols, flavonoids. HCD promoted oxidative stress with a rise the level of malonaldehyde (MDA), advanced oxidation protein product (AOPP) levels and a significant decrease of the Vitamin C content, as well the antioxidant enzyme activities such as superoxide dismutase and glutathione peroxidase. In addition, HCD treatment caused significant lipid profile disorders via increase the cholesterol, triglycerides and LDL levels and reduction HDL-Ch level. A statistically significant decrease of Mg2+ and Ca2+ ATPase activities accompanied with a severe damage in the erythrocytes structure and hematological parameters alterations were also noted in hypercholesterolemic mice. Pre-treatment with MECG significantly restored biochemical markers and pathological lesions. It can be suggest that supplementation of MECG displays high potential to quench free radicals and attenuates high cholesterol diet induced erythrocytes oxidative stress and related damages.


Assuntos
Antioxidantes/uso terapêutico , Colesterol/farmacologia , Eritrócitos/efeitos dos fármacos , Hipercolesterolemia/prevenção & controle , Extratos Vegetais/uso terapêutico , Produtos da Oxidação Avançada de Proteínas/metabolismo , Animais , Ácido Ascórbico/metabolismo , Peso Corporal/efeitos dos fármacos , Clorófitas , Glutationa Peroxidase/metabolismo , Hipercolesterolemia/metabolismo , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
8.
Commun Biol ; 4(1): 564, 2021 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-33980978

RESUMO

The risks of non-alcoholic fatty liver disease (NAFLD) include obese and non-obese stresses such as chronic hepatitis C virus (HCV) infection, but the regulatory determinants remain obscure. Apolipoprotein J (ApoJ) served as an ER-Golgi contact-site chaperone near lipid droplet (LD), facilitating HCV virion production. We hypothesized an interplay between hepatic ApoJ, cholesterol esterification and lipid deposit in response to NAFLD inducers. Exposures of HCV or free-fatty acids exhibited excess LDs along with increased ApoJ expression, whereas ApoJ silencing alleviated hepatic lipid accumulation. Both stresses could concomitantly disperse Golgi, induce closer ApoJ and sterol O-acyltransferase 2 (SOAT2) contacts via the N-terminal intrinsically disordered regions, and increase cholesteryl-ester. Furthermore, serum ApoJ correlated positively with cholesterol and low-density lipoprotein levels in normal glycaemic HCV patients, NAFLD patients and in mice with steatosis. Taken together, hepatic ApoJ might activate SOAT2 to supply cholesteryl-ester for lipid loads, thus providing a therapeutic target of stress-induced steatosis.


Assuntos
Clusterina/metabolismo , Metabolismo dos Lipídeos/fisiologia , Esterol O-Aciltransferase/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Colesterol/metabolismo , Ésteres do Colesterol/metabolismo , Clusterina/fisiologia , Esterificação , Fígado Gorduroso/metabolismo , Feminino , Hepatite C Crônica/metabolismo , Humanos , Hipercolesterolemia/metabolismo , Gotículas Lipídicas/metabolismo , Lipídeos/fisiologia , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Esterol O-Aciltransferase/fisiologia
9.
Nutrients ; 13(4)2021 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-33917704

RESUMO

Impaired triglyceride-rich lipoprotein plasma catabolism is considered the most important factor for hypertriglyceridemia development. The aim of this study was to evaluate the impact of hypercholesterolemia and hypertriglyceridemia on the efficiency of lipoprotein lipase (LPL)-mediated very-low-density lipoprotein (VLDL)-triglyceride lipolysis and the role of high-density lipoprotein (HDL) in this process. Subjects with no history of cardiovascular disease (CVD) and untreated with lipid-lowering agents were recruited into the study and divided into normolipidemic, hypercholesterolemic, and hyperlipidemic groups. VLDL was isolated from serum and incubated with LPL in the absence or presence of HDL. For the hypercholesterolemic and hyperlipidemic groups, a significantly lower percentage of hydrolyzed VLDL-triglyceride was achieved compared to the normolipidemic group (p < 0.01). HDL enhanced the lipolysis efficiency in the hypercholesterolemic and hyperlipidemic groups on average by ~7% (p < 0.001). The lowest electrophoretic mobility of the VLDL remnants indicating the most effective lipolysis was obtained in the normolipidemic group (p < 0.05). HDL presence significantly reduced the electrophoretic mobility of the VLDL remnants for the hypercholesterolemic and hyperlipidemic groups (p < 0.05). The results of our study indicate that VLDL obtained from hypercholesterolemic and hyperlipidemic subjects are more resistant to lipolysis and are additional evidence of the need for early implementation of hypocholesterolemic treatment, already in asymptomatic CVD subjects.


Assuntos
Hipercolesterolemia/metabolismo , Hipertrigliceridemia/metabolismo , Lipólise , Lipoproteínas HDL/metabolismo , Lipoproteínas VLDL/metabolismo , Adulto , Apolipoproteínas E/sangue , Feminino , Humanos , Hipercolesterolemia/sangue , Hipertrigliceridemia/sangue , Lipoproteínas HDL/sangue , Lipoproteínas VLDL/sangue , Masculino , Pessoa de Meia-Idade , Triglicerídeos/sangue , Adulto Jovem
10.
J Med Chem ; 64(8): 4396-4409, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33821652

RESUMO

Multiple diseases are at some point associated with altered endothelial function, and endothelial dysfunction (ED) contributes to their pathophysiology. Biochemical changes of the dysfunctional endothelium are linked to various cellular organelles, including the mitochondria, endoplasmic reticulum, and nucleus, so organelle-specific insight is needed for better understanding of endothelial pathobiology. Raman imaging, which combines chemical specificity with microscopic resolution, has proved to be useful in detecting biochemical changes in ED at the cellular level. However, the detection of spectroscopic markers associated with specific cell organelles, while desirable, cannot easily be achieved by Raman imaging without labeling. This critical review summarizes the current advances in Raman-based analysis of ED, with a focus on a new approach involving molecular Raman reporters that could facilitate the study of biochemical changes in cellular organelles. Finally, imaging techniques based on both conventional spontaneous Raman scattering and the emerging technique of stimulated Raman scattering are discussed.


Assuntos
Endotélio/química , Análise Espectral Raman , Vasos Sanguíneos/química , Vasos Sanguíneos/metabolismo , Núcleo Celular/química , Núcleo Celular/metabolismo , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patologia , Retículo Endoplasmático/química , Retículo Endoplasmático/metabolismo , Endotélio/metabolismo , Endotélio/fisiopatologia , Humanos , Hipercolesterolemia/metabolismo , Hipercolesterolemia/patologia , Mitocôndrias/química , Mitocôndrias/metabolismo , Sondas Moleculares/química , Sondas Moleculares/metabolismo
11.
Int J Mol Sci ; 22(5)2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33807969

RESUMO

Sitosterolemia is a lipid disorder characterized by the accumulation of dietary xenosterols in plasma and tissues caused by mutations in either ABCG5 or ABCG8. ABCG5 ABCG8 encodes a pair of ABC half transporters that form a heterodimer (G5G8), which then traffics to the surface of hepatocytes and enterocytes and promotes the secretion of cholesterol and xenosterols into the bile and the intestinal lumen. We review the literature from the initial description of the disease, the discovery of its genetic basis, current therapy, and what has been learned from animal, cellular, and molecular investigations of the transporter in the twenty years since its discovery. The genomic era has revealed that there are far more carriers of loss of function mutations and likely pathogenic variants of ABCG5 ABCG8 than previously thought. The impact of these variants on G5G8 structure and activity are largely unknown. We propose a classification system for ABCG5 ABCG8 mutants based on previously published systems for diseases caused by defects in ABC transporters. This system establishes a framework for the comprehensive analysis of disease-associated variants and their impact on G5G8 structure-function.


Assuntos
Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Colesterol/metabolismo , Hipercolesterolemia , Enteropatias , Erros Inatos do Metabolismo Lipídico , Lipoproteínas , Mutação , Fitosteróis/efeitos adversos , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/história , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/história , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Enterócitos/metabolismo , Enterócitos/patologia , Hepatócitos/metabolismo , Hepatócitos/patologia , História do Século XXI , Humanos , Hipercolesterolemia/genética , Hipercolesterolemia/história , Hipercolesterolemia/metabolismo , Hipercolesterolemia/patologia , Enteropatias/genética , Enteropatias/história , Enteropatias/metabolismo , Enteropatias/patologia , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/história , Erros Inatos do Metabolismo Lipídico/metabolismo , Erros Inatos do Metabolismo Lipídico/patologia , Lipoproteínas/genética , Lipoproteínas/história , Lipoproteínas/metabolismo , Fitosteróis/genética , Fitosteróis/história , Fitosteróis/metabolismo
12.
Am J Physiol Endocrinol Metab ; 320(5): E989-E998, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33843281

RESUMO

Cardiovascular effects of glucagon-like peptide-1 receptor (GLP-1R) agonist therapies are potentially mediated by anti-inflammatory effects on atherosclerosis. Our study demonstrates that 68Ga-NODAGA-exendin-4, a radioligand specifically targeting GLP-1R, detects GLP-1R expression in inflamed atherosclerotic lesions in nondiabetic and diabetic hypercholesterolemic mice. Immunofluorescence staining suggests that GLP-1R is primarily localized in M2 macrophages in lesions. This study describes a new potential tool that may have translational relevance for studies of pharmacological modification of GLP-1R signaling in atherosclerosis.


Assuntos
Aterosclerose/metabolismo , Diabetes Mellitus Experimental/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Acetatos/farmacocinética , Animais , Apolipoproteínas B/genética , Apolipoproteínas B/metabolismo , Aterosclerose/complicações , Aterosclerose/diagnóstico , Aterosclerose/genética , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/diagnóstico , Diabetes Mellitus Experimental/genética , Exenatida/farmacocinética , Feminino , Radioisótopos de Gálio/farmacocinética , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Compostos Heterocíclicos com 1 Anel/farmacocinética , Hipercolesterolemia/complicações , Hipercolesterolemia/diagnóstico , Hipercolesterolemia/genética , Hipercolesterolemia/metabolismo , Fator de Crescimento Insulin-Like II/genética , Fator de Crescimento Insulin-Like II/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Tomografia por Emissão de Pósitrons/métodos , Receptores de LDL/genética , Receptores de LDL/metabolismo
13.
J Biol Chem ; 296: 100697, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33895138

RESUMO

Down syndrome critical region (DSCR)-1 functions as a feedback modulator for calcineurin-nuclear factor for activated T cell (NFAT) signals, which are crucial for cell proliferation and inflammation. Stable expression of DSCR-1 inhibits pathological angiogenesis and septic inflammation. DSCR-1 also plays a critical role in vascular wall remodeling associated with aneurysm development that occurs primarily in smooth muscle cells. Besides, Dscr-1 deficiency promotes the M1-to M2-like phenotypic switch in macrophages, which correlates to the reduction of denatured cholesterol uptakes. However, the distinct roles of DSCR-1 in cholesterol and lipid metabolism are not well understood. Here, we show that loss of apolipoprotein (Apo) E in mice with chronic hypercholesterolemia induced Dscr-1 expression in the liver and aortic atheroma. In Dscr-1-null mice fed a high-fat diet, oxidative- and endoplasmic reticulum (ER) stress was induced, and sterol regulatory element-binding protein (SREBP) 2 production in hepatocytes was stimulated. This exaggerated ApoE-/--mediated nonalcoholic fatty liver disease (NAFLD) and subsequent hypercholesterolemia. Genome-wide screening revealed that loss of both ApoE and Dscr-1 resulted in the induction of immune- and leukocyte activation-related genes in the liver compared with ApoE deficiency alone. However, expressions of inflammation-activated markers and levels of monocyte adhesion were suspended upon induction of the Dscr-1 null background in the aortic endothelium. Collectively, our study shows that the combined loss of Dscr-1 and ApoE causes metabolic dysfunction in the liver but reduces atherosclerotic plaques, thereby leading to a dramatic increase in serum cholesterol and the formation of sporadic vasculopathy.


Assuntos
Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Proteínas de Ligação ao Cálcio/deficiência , Colesterol/metabolismo , Deleção de Genes , Hipercolesterolemia/genética , Proteínas Musculares/deficiência , Animais , Proteínas de Ligação ao Cálcio/genética , Regulação da Expressão Gênica , Hepatócitos/metabolismo , Hipercolesterolemia/metabolismo , Camundongos , Proteínas Musculares/genética , Fenótipo
14.
J Agric Food Chem ; 69(15): 4453-4463, 2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33844520

RESUMO

Hypercholesterolemia is often considered to be a major risk factor for atherosclerosis, and medium-chain fatty acids have been found to reduce the total cholesterol (TC) level and maintain low-density lipoprotein cholesterol (LDL-c) stability. However, we unexpectedly found that the levels of TC and LDL-c were increased in obese rats treated with high-dose lauric triglycerides (LT). The study aimed to investigate the effect and mechanism of LT on cholesterol metabolism in obese rats. Our results showed that LT intervention could reduce cholesterol biosynthesis by downregulating the expression of HMG-CoA reductase in obese rats. LT increased the expression levels of PPARγ1, LXRα, ABCA1, and ABCG8 in the liver. These results indicated that LT could improve the lipid transfer and bile acid efflux. However, LT significantly increased the expression of PCSK 9, resulting in accelerated degradation of LDLR, thus reducing the transport of very LDL (VLDL) and LDL to the liver. Together with the increased expression of NPC1L1 protein, LT impaired the uptake of VLDL/LDL by the liver and increased the reabsorption of sterols, leading to an increase in the levels of TC and LDL-c in obese rats.


Assuntos
Hipercolesterolemia , Metabolismo dos Lipídeos , Animais , LDL-Colesterol/metabolismo , Hipercolesterolemia/metabolismo , Fígado/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Obesidade/genética , Obesidade/metabolismo , Ratos , Triglicerídeos/metabolismo
15.
J Am Soc Nephrol ; 32(6): 1371-1388, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33758009

RESUMO

BACKGROUND: Dyslipidemia is an important risk factor in CKD. The liver clears triglyceride-rich lipoproteins (TRL) via LDL receptor (LDLR), LDLR-related protein-1 (LRP-1), and heparan sulfate proteoglycans (HSPGs), mostly syndecan-1. HSPGs also facilitate LDLR degradation by proprotein convertase subtilisin/kexin type 9 (PCSK9). Progressive renal failure affects the structure and activity of hepatic lipoprotein receptors, PCSK9, and plasma cholesterol. METHODS: Uninephrectomy- and aging-induced CKD in normotensive Wistar rats and hypertensive Munich-Wistar-Frömter (MWF) rats. RESULTS: Compared with 22-week-old sex- and strain-matched rats, 48-week-old uninephrectomized Wistar-CKD and MWF-CKD rats showed proteinuria, increased plasma creatinine, and hypercholesterolemia (all P<0.05), which were most apparent in hypertensive MWF-CKD rats. Hepatic PCSK9 expression increased in both CKD groups (P<0.05), with unusual sinusoidal localization, which was not seen in 22-week-old rats. Heparan sulfate (HS) disaccharide analysis, staining with anti-HS mAbs, and mRNA expression of HS polymerase exostosin-1 (Ext-1), revealed elongated HS chains in both CKD groups. Solid-phase competition assays showed that the PCSK9 interaction with heparin-albumin (HS-proteoglycan analogue) was critically dependent on polysaccharide chain length. VLDL binding to HS from CKD livers was reduced (P<0.05). Proteinuria and plasma creatinine strongly associated with plasma cholesterol, PCSK9, and HS changes. CONCLUSIONS: Progressive CKD induces hepatic HS elongation, leading to increased interaction with PCSK9. This might reduce hepatic lipoprotein uptake and thereby induce dyslipidemia in CKD. Therefore, PCSK9/HS may be a novel target to control dyslipidemia.


Assuntos
Envelhecimento , Proteoglicanas de Heparan Sulfato/metabolismo , Hipercolesterolemia/metabolismo , Fígado/metabolismo , Pró-Proteína Convertase 9/metabolismo , Insuficiência Renal Crônica/metabolismo , Animais , Colesterol/sangue , Creatinina/sangue , Dissacarídeos/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Proteoglicanas de Heparan Sulfato/análogos & derivados , Hipercolesterolemia/complicações , Hipertensão/complicações , Hipertensão/metabolismo , Lipoproteínas VLDL/metabolismo , Masculino , N-Acetilglucosaminiltransferases/genética , Nefrectomia , Pró-Proteína Convertase 9/genética , Ratos Wistar , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/fisiopatologia , Sindecana-1/genética , Sindecana-1/metabolismo
16.
Biochem Biophys Res Commun ; 553: 1-8, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33752091

RESUMO

BACKGROUND AND AIMS: Hypercholesterolemia is characterized by the elevation of plasma total cholesterol level, especially low-density lipoprotein (LDL) cholesterol. This disease is usually caused by a mutation in genes such as LDL receptor, apolipoprotein B, or proprotein convertase subtilisin/kexin type 9. However, a considerable number of patients with hypercholesterolemia do not have any mutation in these candidate genes. In this study, we examined the difference in the metabolic level between patients with hypercholesterolemia and healthy subjects, and screened the potential biomarkers for this disease. METHODS: Analysis of plasma metabolomics in hypercholesterolemia patients and healthy controls was performed by gas chromatography-mass spectrometry and metabolic correlation networks were constructed using Gephi-0.9.2. RESULTS: First, metabolic profile analysis confirmed the distinct metabolic footprints between the patients and the healthy ones. The potential biomarkers screened by orthogonal partial least-squares discrimination analysis included l-lactic acid, cholesterol, phosphoric acid, d-glucose, urea, and d-allose (Variable importance in the projection > 1). Second, arginine and methionine metabolism were significantly perturbed in hypercholesterolemia patients. Finally, we identified that l-lactic acid, l-lysine, l-glutamine, and l-cysteine had high scores of centrality parameters in the metabolic correlation network. CONCLUSION: Plasma l-lactic acid could be used as a sensitive biomarker for hypercholesterolemia. In addition, arginine biosynthesis and cysteine and methionine metabolism were profoundly altered in patients with hypercholesterolemia.


Assuntos
Biomarcadores/sangue , Biomarcadores/metabolismo , Hipercolesterolemia/sangue , Hipercolesterolemia/metabolismo , Metabolômica , Adolescente , Adulto , Arginina/metabolismo , Estudos de Casos e Controles , Colesterol/metabolismo , Cisteína/metabolismo , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Glucose/metabolismo , Glutamina/metabolismo , Humanos , Ácido Láctico/sangue , Ácido Láctico/metabolismo , Lisina/metabolismo , Masculino , Metionina/metabolismo , Pessoa de Meia-Idade , Ácidos Fosfóricos/metabolismo , Ureia/metabolismo , Adulto Jovem
17.
Am J Physiol Cell Physiol ; 320(6): C943-C955, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33689479

RESUMO

Endothelial cell (EC) migration is critical for healing arterial injuries, such as those that occur with angioplasty. Impaired re-endothelialization following arterial injury contributes to vessel thrombogenicity, intimal hyperplasia, and restenosis. Oxidized lipid products, including lysophosphatidylcholine (lysoPC), induce canonical transient receptor potential 6 (TRPC6) externalization leading to increased [Ca2+]i, activation of calpains, and alterations of the EC cytoskeletal structure that inhibit migration. The p110α and p110δ catalytic subunit isoforms of phosphatidylinositol 3-kinase (PI3K) regulate lysoPC-induced TRPC6 externalization in vitro. The goal of this study was to assess the in vivo relevance of those in vitro findings to arterial healing following a denuding injury in hypercholesterolemic mice treated with pharmacologic inhibitors of the p110α and p110δ isoforms of PI3K and a general PI3K inhibitor. Pharmacologic inhibition of the p110α or the p110δ isoform of PI3K partially preserves healing in hypercholesterolemic male mice, similar to a general PI3K inhibitor. Interestingly, the p110α, p110δ, and the general PI3K inhibitor do not improve arterial healing after injury in hypercholesterolemic female mice. These results indicate a potential new role for isoform-specific PI3K inhibitors in male patients following arterial injury/intervention. The results also identify significant sex differences in the response to PI3K inhibition in the cardiovascular system, where female sex generally has a cardioprotective effect. This study provides a foundation to investigate the mechanism for the sex differences in response to PI3K inhibition to develop a more generally applicable treatment option.


Assuntos
Domínio Catalítico/fisiologia , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Hipercolesterolemia/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Cicatrização/fisiologia , Animais , Bovinos , Linhagem Celular , Células Endoteliais/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Isoformas de Proteínas/metabolismo , Transdução de Sinais/fisiologia
18.
Mol Cells ; 44(2): 116-125, 2021 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-33658436

RESUMO

Cardiovascular diseases (CVDs) are the most common cause of death in patients with nonalcoholic fatty liver disease (NAFLD) and dyslipidemia is considered at least partially responsible for the increased CVD risk in NAFLD patients. The aim of the present study is to understand how hepatic de novo lipogenesis influences hepatic cholesterol content as well as its effects on the plasma lipid levels. Hepatic lipogenesis was induced in mice by feeding a fat-free/high-sucrose (FF/HS) diet and the metabolic pathways associated with cholesterol were then analyzed. Both liver triglyceride and cholesterol contents were significantly increased in mice fed an FF/HS diet. Activation of fatty acid synthesis driven by the activation of sterol regulatory element binding protein (SREBP)-1c resulted in the increased liver triglycerides. The augmented cholesterol content in the liver could not be explained by an increased cholesterol synthesis, which was decreased by the FF/HS diet. HMGCoA reductase protein level was decreased in mice fed an FF/HS diet. We found that the liver retained more cholesterol through a reduced excretion of bile acids, a reduced fecal cholesterol excretion, and an increased cholesterol uptake from plasma lipoproteins. Very low-density lipoproteintriglyceride and -cholesterol secretion were increased in mice fed an FF/HS diet, which led to hypertriglyceridemia and hypercholesterolemia in Ldlr-/- mice, a model that exhibits a more human like lipoprotein profile. These findings suggest that dietary cholesterol intake and cholesterol synthesis rates cannot only explain the hypercholesterolemia associated with NAFLD, and that the control of fatty acid synthesis should be considered for the management of dyslipidemia.


Assuntos
Colesterol/metabolismo , Lipogênese , Fígado/metabolismo , Animais , Células Cultivadas , Ésteres do Colesterol/metabolismo , Dieta , Sacarose na Dieta , Ácidos Graxos/metabolismo , Fígado Gorduroso/sangue , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Comportamento Alimentar , Hepatócitos/metabolismo , Hipercolesterolemia/sangue , Hipercolesterolemia/metabolismo , Gotículas Lipídicas/metabolismo , Lipoproteínas/sangue , Masculino , Camundongos Endogâmicos C57BL , Receptores de LDL/metabolismo , Triglicerídeos/metabolismo
19.
Ann Agric Environ Med ; 28(1): 81-88, 2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33775071

RESUMO

INTRODUCTION: Increased serum cholesterol levels constitute one of the main risk factors for cardiovascular diseases. Statins are a major method for reducing the levels which also lower the risk of cardiovascular events. However, these valuable drugs cannot be used in all patients who need them due to contraindications and intolerance. In such cases, help can be sought from nutraceutics that reduce the serum cholesterol concentration. Since there are numerous products of this type available at drugstores, registered as supplements, there seems to be a need to demonstrate their effectiveness in preventing cardiovascular diseases induced by atherosclerosis. In literature, increasingly more attention is drawn to red yeast rice, Armolipid, berberine and bergamot. BRIEF DESCRIPTION: This article presents knowledge about these nutraceutics based on clinical studies and expert statements relating to their use. The results of clinical studies and metaanalyses have shown that nutraceutics with cholesterol lowering properties, red yeast rice and Armolipid are the most favourable for reducing cardiovascular events. However, the evidence of benefits of berberine and bergamot is not so conclusive. CONCLUSIONS: Red yeast rice products and Armolipid may be used as an alternative treatment in statin intolerant patients, especially in combination with ezetimibe. These nutraceutics can be also considered, as an adjunct to diet therapy in primary prevention of cardiovascular diseases in patients with mild and moderate hypercholesterolaemia. The opinion of experts on berberine and bergamot is ambiguous.


Assuntos
Berberina/administração & dosagem , Produtos Biológicos/administração & dosagem , Hipercolesterolemia/tratamento farmacológico , Hipolipemiantes/administração & dosagem , Extratos Vegetais/administração & dosagem , Colesterol/metabolismo , Citrus/química , Ensaios Clínicos como Assunto , Suplementos Nutricionais/análise , Humanos , Hipercolesterolemia/metabolismo
20.
Drug Deliv ; 28(1): 408-421, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33594923

RESUMO

Native nanostructured lipoproteins such as low- and high-density lipoproteins (LDL and HDL) are powerful tools for the targeted delivery of drugs and imaging agents. While the cellular recognition of well-known HDL-based carriers occurs via interactions with an HDL receptor, the selective delivery and uptake of LDL particles by target cells are more complex. The most well-known mode of LDL-based delivery is via the interaction between apolipoprotein B (Apo-B) - the main protein of LDL - and the low-density lipoprotein receptor (LDLR). LDLR is expressed in the liver, adipocytes, and macrophages, and thus selectively delivers LDL carriers to these cells and tissues. Moreover, the elevated expression of LDLR in tumor cells indicates a role for LDL in the targeted delivery of chemotherapy drugs. In addition, chronic inflammation associated with hypercholesterolemia (i.e., high levels of endogenous LDL) can be abated by LDL carriers, which outcompete the deleterious oxidized LDL for uptake by macrophages. In this case, synthetic LDL nanocarriers act as 'eat-me' signals and exploit mechanisms of native LDL uptake for targeted drug delivery and imaging. Lastly, recent studies have shown that the delivery of LDL-based nanocarriers to macrophages via fluid-phase pinocytosis is a promising tool for atherosclerosis imaging. Hence, the present review summarizes the use of natural and synthetic LDL-based carriers for drug delivery and imaging and discusses various mechanisms of targeting.


Assuntos
Lipoproteínas LDL/química , Lipoproteínas LDL/farmacologia , Animais , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Portadores de Fármacos/química , Humanos , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/metabolismo , Lipoproteínas HDL/metabolismo , Lipoproteínas LDL/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Nanomedicina/métodos , Receptores de Lipoproteínas/metabolismo
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