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1.
Int J Mol Sci ; 20(13)2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31261740

RESUMO

In the presence of dietary lipids, both apolipoprotein A-IV (ApoA-IV) production and brown adipose tissue (BAT) thermogenesis are increased. The effect of dietary lipid-induced AproA-IV on BAT thermogenesis and energy expenditure remains unknown. In the present study, we hypothesized that ApoA-IV knockout (ApoA-IV-KO) mice exhibited decreased BAT thermogenesis to affect energy homeostasis. To test this hypothesis, BAT thermogenesis in wildtype (WT) and ApoA-IV-KO mice fed either a standard low-fat chow diet or a high-fat diet (HFD) was investigated. When fed a chow diet, energy expenditure and food intake were comparable between WT and ApoA-IV-KO mice. After 1 week of HFD consumption, ApoA-IV-KO mice had comparable energy intake but produced lower energy expenditure relative to their WT controls in the dark phase. After an acute feeding of dietary lipids or 1-week HFD feeding, ApoA-IV-KO mice produced lower levels of uncoupling protein 1 (UCP1) and exhibited reduced expression of thermogenic genes in the BAT compared with WT controls. In response to cold exposure, however, ApoA-IV-KO mice had comparable energy expenditure and BAT temperature relative to WT mice. Thus, ApoA-IV-KO mice exhibited reduced diet-induced BAT thermogenesis and energy expenditure.


Assuntos
Tecido Adiposo Marrom/metabolismo , Apolipoproteínas A/genética , Dieta Hiperlipídica , Termogênese , Tecido Adiposo Marrom/fisiologia , Animais , Apolipoproteínas A/deficiência , Gorduras na Dieta/metabolismo , Metabolismo Energético , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína Desacopladora 1/metabolismo
2.
Cells ; 8(4)2019 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-30959835

RESUMO

Apolipoprotein A-IV (apoA-IV) is a lipid-binding protein, which is primarily synthesized in the small intestine, packaged into chylomicrons, and secreted into intestinal lymph during fat absorption. In the circulation, apoA-IV is present on chylomicron remnants, high-density lipoproteins, and also in lipid-free form. ApoA-IV is involved in a myriad of physiological processes such as lipid absorption and metabolism, anti-atherosclerosis, platelet aggregation and thrombosis, glucose homeostasis, and food intake. ApoA-IV deficiency is associated with atherosclerosis and diabetes, which renders it as a potential therapeutic target for treatment of these diseases. While much has been learned about the physiological functions of apoA-IV using rodent models, the action of apoA-IV at the cellular and molecular levels is less understood, let alone apoA-IV-interacting partners. In this review, we will summarize the findings on the molecular function of apoA-IV and apoA-IV-interacting proteins. The information will shed light on the discovery of apoA-IV receptors and the understanding of the molecular mechanism underlying its mode of action.


Assuntos
Apolipoproteínas A/metabolismo , Aterosclerose/prevenção & controle , Diabetes Mellitus/prevenção & controle , Animais , Apolipoproteínas A/genética , Colesterol/metabolismo , Glucose/metabolismo , Homeostase , Humanos
3.
Pathology ; 51(2): 155-164, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30595508

RESUMO

Lipoprotein(a) [Lp(a)] is an apolipoprotein B (apoB)-containing plasma lipoprotein similar in structure to low-density lipoprotein (LDL). Lp(a) is more complex than LDL due to the presence of apolipoprotein(a) [apo(a)], a large glycoprotein sharing extensive homology with plasminogen, which confers some unique properties onto Lp(a) particles. ApoB and apo(a) are essential for the assembly and catabolism of Lp(a); however, other proteins associated with the particle may modify its metabolism. Lp(a) specifically carries a cargo of oxidised phospholipids (OxPL) bound to apo(a) which stimulates many proinflammatory pathways in cells of the arterial wall, a key property underlying its pathogenicity and association with cardiovascular disease (CVD). While the liver and kidney are the major tissues implicated in Lp(a) clearance, the pathways for Lp(a) uptake appear to be complex and are still under investigation. Biochemical studies have revealed an exceptional array of receptors that associate with Lp(a) either via its apoB, apo(a), or OxPL components. These receptors fall into five main categories, namely 'classical' lipoprotein receptors, toll-like and scavenger receptors, lectins, and plasminogen receptors. The roles of these receptors have largely been dissected by genetic manipulation in cells or mice, although their relative physiological importance for removal of Lp(a) from the circulation remains unclear. The LPA gene encoding apo(a) has an overwhelming effect on Lp(a) levels which precludes any clear associations between potential Lp(a) receptor genes and Lp(a) levels in population studies. Targeted approaches and the selection of unique Lp(a) phenotypes within populations has nevertheless allowed for some associations to be made. Few of the proposed Lp(a) receptors can specifically be manipulated with current drugs and, as such, it is not currently clear whether any of these receptors could provide relevant targets for therapeutic manipulation of Lp(a) levels. This review summarises the current status of knowledge about receptor-mediated pathways for Lp(a) catabolism.


Assuntos
Apolipoproteínas A/metabolismo , Doenças Cardiovasculares/metabolismo , Lipoproteína(a)/metabolismo , Receptores de Lipoproteínas/metabolismo , Receptores Depuradores/metabolismo , Animais , Apolipoproteínas A/genética , Estudo de Associação Genômica Ampla , Humanos , Rim/metabolismo , Lectinas/metabolismo , Lipoproteína(a)/genética , Fígado/metabolismo , Camundongos , Oxirredução , Fosfolipídeos/metabolismo , Plasminogênio/metabolismo , Receptores de Lipoproteínas/genética
4.
Gene ; 684: 76-81, 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30367981

RESUMO

BACKGROUND AND PURPOSES: Stroke is a leading cause of death and serious disability worldwide. Now, evidences indicate that dyslipidemia may play an important role in stroke. APOA1 and APOA5 involve in lipid metabolism. In this study, we investigated the association of APOA1 rs670 and APOA5 rs662799 with different stroke subtypes in the Han Chinese population of Taiwan. METHODS: A total of 1751 participants, including 459 control subjects, 606 large artery atherosclerosis (LAA), 339 small vessel occlusion (SVO), and 347 hypertensive intracranial hemorrhage (HICH), were enrolled. The presence of rs670 and rs662799 was analyzed through polymerase chain react ion and matrix-assisted laser desorption/ionization-time-of-flight-mass spectrometry. RESULTS: Notably, the frequency of the rs662799 C allele was significantly lower in the SVO patients than in the controls (24.36% vs. 29.74%, P = 0.024). The frequencies of heterozygote TC [odd ratio (OR) = 0.732, 95% confidence interval (CI) = 0.544-0.984, P = 0.038] and TC + CC (OR = 0.719, 95% CI = 0.542-0.953, P = 0.022) genotypes were significantly lower in the SVO patients than in the controls. In addition, triglyceride levels in individuals carrying the rs662799 TC + CC genotype were significantly higher than in those carrying the TT genotype, especially in older age, female, and body mass index (BMI) ≥ 25 groups. On the contrary, the low-density lipoprotein-cholesterol (LDL-C) was significantly lower in rs662799 TC + CC genotype than TT genotype. The BMI was significantly lower in subjects with rs662799 TC + CC genotype than those with TT genotype, especially in older age and female. High-density lipoprotein-cholesterol (HDL-C) levels were higher in individuals carrying the rs670 GG genotype than in those carrying the AG + AA genotype, especially in BMI < 25 group. Logistic regression analysis showed that the rs662799 C allele (TC + CC) was an independent protective factor for SVO after adjustment for conventional risk factors (OR = 0.709, 95% CI = 0.526-0.956; P = 0.024). CONCLUSION: GG genotype of rs670 is correlated with high serum HDL-C levels, whereas TC + CC genotype of rs662799 is associated with high serum triglyceride and low LDL and BMI levels. In addition, the rs662799 C allele (TC + CC) is an independent protective factor for SVO in the Han Chinese population in Taiwan.


Assuntos
Apolipoproteína A-I/genética , Apolipoproteína A-V/genética , Acidente Vascular Cerebral/genética , Idoso , Alelos , Apolipoproteína A-I/fisiologia , Apolipoproteína A-V/metabolismo , Apolipoproteínas A/genética , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Grupos Étnicos/genética , Feminino , Frequência do Gene/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Acidente Vascular Cerebral/classificação , Taiwan
5.
Artigo em Inglês | MEDLINE | ID: mdl-30352313

RESUMO

Apolipoprotein A-IV is lipid-binding protein, which is synthesized by the intestine and secreted into mesenteric lymph. ApoA-IV is correlated with chylomicrons and high density lipoprotein, but a large portion is free-lipoprotein, in circulation. Studies showed that apoA-IV has anti-inflammatory and anti-oxidative properties, and is able to mediate reverse cholesterol transport, which suggest that it may has anti-atherosclerotic effects and be related to protection from atherosclerotic cardiovascular disease. This article focus on current studies and the possible anti-atherogenic mechanism related to apoA-IV, in order to provide a new therapeutic target for atherosclerotic cardiovascular diseases.


Assuntos
Apolipoproteínas A/metabolismo , Aterosclerose/metabolismo , Metabolismo dos Lipídeos/genética , Transporte Proteico/genética , Apolipoproteínas A/genética , Aterosclerose/genética , Aterosclerose/patologia , Colesterol , Humanos , Mucosa Intestinal/metabolismo , Lipoproteínas HDL/genética , Lipoproteínas HDL/metabolismo , Ligação Proteica/genética
6.
Nat Commun ; 9(1): 3608, 2018 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-30190457

RESUMO

Platelet αIIbß3 integrin and its ligands are essential for thrombosis and hemostasis, and play key roles in myocardial infarction and stroke. Here we show that apolipoprotein A-IV (apoA-IV) can be isolated from human blood plasma using platelet ß3 integrin-coated beads. Binding of apoA-IV to platelets requires activation of αIIbß3 integrin, and the direct apoA-IV-αIIbß3 interaction can be detected using a single-molecule Biomembrane Force Probe. We identify that aspartic acids 5 and 13 at the N-terminus of apoA-IV are required for binding to αIIbß3 integrin, which is additionally modulated by apoA-IV C-terminus via intra-molecular interactions. ApoA-IV inhibits platelet aggregation and postprandial platelet hyperactivity. Human apoA-IV plasma levels show a circadian rhythm that negatively correlates with platelet aggregation and cardiovascular events. Thus, we identify apoA-IV as a novel ligand of αIIbß3 integrin and an endogenous inhibitor of thrombosis, establishing a link between lipoprotein metabolism and cardiovascular diseases.


Assuntos
Apolipoproteínas A/metabolismo , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Trombose/metabolismo , Adulto , Animais , Apolipoproteínas A/genética , Apolipoproteínas A/farmacologia , Ácido Aspártico/metabolismo , Sítios de Ligação , Ritmo Circadiano/fisiologia , Modelos Animais de Doenças , Humanos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/farmacologia , Período Pós-Prandial , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacologia , Trombose/tratamento farmacológico
7.
PLoS One ; 13(8): e0201618, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30067832

RESUMO

Mouse and rabbit are frequently employed species for atherosclerosis research. With respect to modeling human atherosclerosis, it has been observed that variations in phenotype under commonly used atherogenic conditions are partial or no congruence between two species. However, genome-wide molecular variations are still lacking. To understand the differences between rabbit and mouse in developing atherosclerosis, here from aspect of orthologs, we compared the genome-wide expression profiles of two species under the same atherosclerosis driven factors: high-fat diet or LDLR deficiency. Our results illuminated that: 1) LDLR-deficiency induced different gene expression changes in rabbit and mouse. WHHL rabbit had more significantly differential expressed genes and the most of genes were down-regulated. 2) Some genes and functions were commonly dysregulated in high-fat fed rabbit and mouse models, such as lipid metabolism and inflammation process. However, high-fat intake in rabbit produced more differentially expressed genes and more serious functional effects. 3) Specific differential expression genes were revealed for rabbit and mouse related with high-fat intake. In the aspect of lipoprotein metabolism, APOA4 and APOB was the major responding gene in rabbit and mice, respectively. The expression change of APOA4 and APOB in human atherosclerosis was more similar to rabbit, and therefore rabbit might be a better animal model for investigating human lipoprotein metabolism related diseases. In conclusion, our comparative transcriptome analysis revealed species-specific expression regulation that could partially explain the different phenotypes between rabbit and mouse, which was helpful for model selection to study atherosclerosis.


Assuntos
Apolipoproteínas A/genética , Apolipoproteínas B/genética , Aterosclerose/genética , Dieta Hiperlipídica/efeitos adversos , Perfilação da Expressão Gênica/métodos , Receptores de LDL/deficiência , Animais , Aterosclerose/etiologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Metabolismo dos Lipídeos , Camundongos , Coelhos , Análise de Sequência de RNA , Especificidade da Espécie
8.
Elife ; 72018 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-29916366

RESUMO

How host and microbial factors combine to structure gut microbial communities remains incompletely understood. Redox potential is an important environmental feature affected by both host and microbial actions. We assessed how antibiotics, which can impact host and microbial function, change redox state and how this contributes to post-antibiotic succession. We showed gut redox potential increased within hours of an antibiotic dose in mice. Host and microbial functioning changed under treatment, but shifts in redox potentials could be attributed specifically to bacterial suppression in a host-free ex vivo human gut microbiota model. Redox dynamics were linked to blooms of the bacterial family Enterobacteriaceae. Ecological succession to pre-treatment composition was associated with recovery of gut redox, but also required dispersal from unaffected gut communities. As bacterial competition for electron acceptors can be a key ecological factor structuring gut communities, these results support the potential for manipulating gut microbiota through managing bacterial respiration.


Assuntos
Antibacterianos/farmacologia , Enterobacteriaceae/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/efeitos dos fármacos , Animais , Apolipoproteínas A/genética , Apolipoproteínas A/metabolismo , Enterobacteriaceae/genética , Enterobacteriaceae/isolamento & purificação , Fezes/microbiologia , Microbioma Gastrointestinal/genética , Trato Gastrointestinal/microbiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Lipocalina-2/genética , Lipocalina-2/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/genética , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Oxirredução , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo
9.
Physiol Behav ; 188: 11-17, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29378187

RESUMO

Cholecystokinin (CCK) and apolipoprotein A-IV (ApoA-IV) are gastrointestinal peptides that play an important role in controlling energy homeostasis. Lymphatic ApoA-IV and plasma CCK secretion are mediated via a chylomicron formation-dependent pathway during a dietary lipid infusion. Given their similar roles as satiating proteins, the present study examines how the two peptides interact in their function. Specifically, this study sought to understand how ApoA-IV regulates CCK secretion. For this purpose, Cck gene expression in the small intestines of ApoA-IV knockout (ApoA-IV-KO) and wild-type (WT) mice were compared under an array of feeding conditions. When fed with a chow or high-fat diet (HFD), basal levels of Cck transcripts were significantly reduced in the duodenum of ApoA-IV-KO mice compared to WT mice. Furthermore, after an oral gavage of a lipid mixture, Cck gene expression in the duodenum was significantly reduced in ApoA-IV-KO mice relative to the change seen in WT mice. To determine the mechanism by which ApoA-IV modulates Cck gene expression, STC-1 cells were transfected with predesigned mouse lysophosphatidic acid receptor 5 (LPAR5) small interfering RNA (siRNA) to knockdown Lpar5 gene expression. In this in-vitro study, mouse recombinant ApoA-IV protein increased Cck gene expression in enteroendocrine STC-1 cells and stimulated CCK release from the STC-1 cells. However, the levels of CCK protein and Cck expression were attenuated when Lpar5 was knocked down in the STC-1 cells. Together these observations suggest that dietary lipid-induced ApoA-IV is associated with Cck synthesis in the duodenum and that ApoA-IV protein directly enhances CCK release through the activation of a LPAR5-dependent pathway.


Assuntos
Antioxidantes/farmacologia , Apolipoproteínas A/farmacologia , Colecistocinina/metabolismo , Duodeno/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Animais , Apolipoproteínas A/deficiência , Apolipoproteínas A/genética , Linhagem Celular Transformada , Colecistocinina/genética , Gorduras na Dieta/administração & dosagem , Relação Dose-Resposta a Droga , Duodeno/metabolismo , Regulação da Expressão Gênica/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Mensageiro/metabolismo , Receptores de Ácidos Lisofosfatídicos/metabolismo , Fatores de Tempo , Triglicerídeos/sangue
10.
Cell Biol Int ; 42(3): 313-323, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29064597

RESUMO

High concentrations of plasma lipoprotein(a) [Lp(a)] have been inferred to be an independent risk factor for cardiovascular and cerebrovascular diseases, such as coronary artery diseases, restenosis, and stroke. Apolipoprotein(a) [apo(a)] is one of the most important components of Lp(a) and contributes greatly to the increased concentration of plasma Lp(a). As a critical positive transacting factor of apo(a) gene, Ets1 has been proven as a target gene of several miRNAs, such as miR-193b, miR-125b-5p, miR-200b, miR-1, and miR-499. In this study, a series of experiments on miRNAs and relative miRNAs inhibitor delivered HepG2 cells were conducted, and two miRNAs that downregulate the apo(a) by targeting the 3'-UTR of Ets1 were identified. Results showed that apo(a) and Ets1 were differentially expressed in SMMC7721 and HepG2 cell lines. Meanwhile, apo(a) and Ets1 were inversely correlated with several hepatic endogenous miRNAs, such as miR-125b-5p, miR-23b-3p, miR-26a-5p, and miR-423-5p, which were predicted to bind to Ets1. Results show that miR-125b-5p and miR-23b-3p mimics could inhibit the synthesis of apo(a) by directly targeting Ets1 in HepG2, thereby reducing the plasma Lp (a) concentration.


Assuntos
Apolipoproteínas A/biossíntese , MicroRNAs/metabolismo , Proteína Proto-Oncogênica c-ets-1/metabolismo , Regiões 3' não Traduzidas , Apolipoproteínas A/genética , Apolipoproteínas A/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Regulação para Baixo , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , MicroRNAs/genética , Proteína Proto-Oncogênica c-ets-1/genética
11.
J Biol Chem ; 293(6): 2091-2101, 2018 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-29263093

RESUMO

We previously found that 17ß-estradiol (E2) stimulates apolipoprotein A-IV (apoA-IV) gene expression in the nucleus of the solitary tract (NTS) of lean ovariectomized (OVX) rodents. Here we report that in the NTS of high-fat diet-induced obese (DIO) rats, the apoA-IV mRNA level is significantly reduced and that the estrogenic effects on apoA-IV gene expression and food intake are impaired. E2 regulates apoA-IV gene expression through its nuclear receptor α (ERα), which requires co-activators, such as steroid receptor coactivator-1 (SRC-1), to facilitate the transcription of targeted genes. Interestingly, SRC-1 gene expression is significantly reduced in DIO OVX rats. SRC-1 is colocalized with apoA-IV in the cells of the NTS and E2 treatment enhances the recruitment of ERα and SRC-1 to the estrogen response element at the apoA-V promoter, implying the participation of SRC-1 in E2's stimulatory effect on apoA-IV gene expression. Using small hairpin RNA (shRNA), which was validated in cultured neuronal cells, we found that SRC-1 gene knockdown specifically in the NTS significantly diminished E2's anorectic action, leading to increased food intake and body weight. More importantly, the stimulatory effect of E2 on apoA-IV gene expression in the NTS was significantly attenuated in SRC-1 knockdown rats. These results collectively demonstrate the critical roles of NTS SRC-1 in mediating E2's actions on food intake and apoA-IV gene expression and suggest that reduced levels of endogenous SRC-1 and apoA-IV expression are responsible for the impaired E2's anorectic action in obese females.


Assuntos
Apolipoproteínas A/genética , Estradiol/metabolismo , Estrogênios/metabolismo , Coativador 1 de Receptor Nuclear/genética , Obesidade/genética , Núcleo Solitário/metabolismo , Animais , Apolipoproteínas A/metabolismo , Dieta Hiperlipídica/efeitos adversos , Ingestão de Alimentos , Feminino , Inativação Gênica , Humanos , Coativador 1 de Receptor Nuclear/metabolismo , Obesidade/metabolismo , Obesidade/fisiopatologia , Ovariectomia , Ratos , Ratos Long-Evans
12.
Mol Vis ; 24: 801-817, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30713420

RESUMO

Purpose: Pseudoexfoliation (PEX) syndrome is an age-related progressive disease of the extracellular matrix with ocular manifestations. PEX is clinically diagnosed by the presence of extracellular exfoliative deposits on the anterior surface of the ocular lens. PEX syndrome is a major risk factor for developing glaucoma, the leading cause of irreversible blindness in the world, and is often associated with the development of cataract. PEX reportedly coexists with Alzheimer disease and increases the risk of heart disease and stroke. PEX material deposited on the anterior surface of the ocular lens is highly proteinaceous, complex, and insoluble, making deciphering the protein composition of the material challenging. Thus, to date, only a small proportion of the protein composition of PEX material is known. The aim of this study was to decipher the protein composition of pathological PEX material deposited on the ocular lens in patients and advance the understanding of pathophysiology of PEX syndrome. Methods: Liquid-chromatography and tandem mass spectrometry (LC-MS/MS) was employed to discover novel proteins in extracts of neat PEX material surgically isolated from patients (n = 4) with PEX syndrome undergoing cataract surgery. A sub-set of the identified proteins was validated with immunohistochemistry using lens capsule specimens from independent patients (n=3); lens capsules from patients with cataract but without PEX syndrome were used as controls (n=4). Expression of transcripts of the validated proteins in the human lens epithelium was analyzed with reverse transcription PCR (RT-PCR). Functional relationships among the proteins identified in this study and genes and proteins previously implicated in the disease were bioinformatically determined using InnateDB. Results: Peptides corresponding to 66 proteins, including ten proteins previously known to be present in PEX material, were identified. Thirteen newly identified proteins were chosen for validation. Of those proteins, 12 were found to be genuine components of the material. The novel protein constituents include apolipoproteins (APOA1 and APOA4), stress response proteins (CRYAA and PRDX2), and blood-related proteins (fibrinogen and hemoglobin subunits), including iron-free hemoglobin. The gene expression data suggest that the identified stress-response proteins and hemoglobin are contributed by the lens epithelium and apolipoproteins and fibrinogen by the aqueous humor to the PEX material. Pathway analysis of the identified novel protein constituents and genes or proteins previously implicated in the disease reiterated the involvement of extracellular matrix organization and degradation, elastic fiber formation, and complement cascade in PEX syndrome. Network analysis suggested a central role of fibronectin in the pathophysiology of the disease. The identified novel protein constituents of PEX material also shed light on the molecular basis of the association of PEX syndrome with heart disease, stroke, and Alzheimer disease. Conclusions: This study expands the understanding of the protein composition of pathological PEX material deposited on the ocular lens in patients with PEX syndrome and provides useful insights into the pathophysiology of this disease. This study together with the previous study by our group (Sharma et al. Experimental Eye Research 2009;89(4):479-85) demonstrate that using neat PEX material, devoid of the underlying lens capsule, for proteomics analysis is an effective approach for deciphering the protein composition of complex and highly insoluble extracellular pathological ocular deposits present in patients with PEX syndrome.


Assuntos
Catarata/metabolismo , Síndrome de Exfoliação/metabolismo , Cápsula do Cristalino/química , Agregados Proteicos , Agregação Patológica de Proteínas/metabolismo , Idoso , Idoso de 80 Anos ou mais , Apolipoproteína A-I/química , Apolipoproteína A-I/genética , Apolipoproteína A-I/metabolismo , Apolipoproteínas A/química , Apolipoproteínas A/genética , Apolipoproteínas A/metabolismo , Catarata/genética , Catarata/patologia , Cristalinas/química , Cristalinas/genética , Cristalinas/metabolismo , Tecido Elástico/química , Tecido Elástico/metabolismo , Tecido Elástico/patologia , Síndrome de Exfoliação/genética , Síndrome de Exfoliação/patologia , Matriz Extracelular/química , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Feminino , Fibrinogênio/química , Fibrinogênio/genética , Fibrinogênio/metabolismo , Expressão Gênica , Hemoglobinas/química , Hemoglobinas/genética , Hemoglobinas/metabolismo , Humanos , Cápsula do Cristalino/metabolismo , Cápsula do Cristalino/patologia , Masculino , Peroxirredoxinas/química , Peroxirredoxinas/genética , Peroxirredoxinas/metabolismo , Agregação Patológica de Proteínas/genética , Agregação Patológica de Proteínas/patologia , Espectrometria de Massas em Tandem
13.
Lipids Health Dis ; 16(1): 223, 2017 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-29178936

RESUMO

BACKGROUND: Lipoprotein(a) [LP(a)] is implicated as a common and independent risk factor for cardiovascular diseases. The therapeutic options currently available for reducing plasma LP(a) concentrations are limited. Diallyl disulphide (DADS), the main component of garlic, regulates lipid metabolism in hepatocytes and adipocytes through ERK1/2 signalling. This study aimed to assess the effect of DADS on apolipoprotein(a) [apo(a)] in HepG2 cells. We also determined the effects of DADS on apo(a) expression and secretion in HepG2 cells as well as the underlying mechanisms. METHODS: We examined the role of DADS on apo(a) expression in HepG2 cells by treating cell with different concentrations of DADS (10, 20, 40 and 80 µg/mL) for 24 h or treating cells with 40 µg/mL DADS for 0, 6, 12, 24 and 48 h. Then we used quantitative real-time PCR to analysis apo(a) mRNA levels, used Western blot to analysis apo(a) protein levels and used enzyme-linked immunosorbent assay to test apo(a) secreted levels. To farther determined the role of DADS, we applied Transfection of small interfering RNA to knockdown ELK-1levels and applied PD98059, a specific inhibitor of ERK1/2, to block ERK1/2 signal. RESULTS: The results show DADS inhibited apo(a) at both the mRNA and protein levels in HepG2 cells in a dose-dependent manner. DADS-mediated inhibition of apoa(a) expression in HepG2 cells was attenuated when the cells were cultured in medium containing PD98059 (ERK1/2 inhibitor) or were transfected with siRNAs against MEK1 or ELK-1. Overexpression of apo(a) yielded similar results. CONCLUSIONS: This study reveals that DADS can downregulate apo(a) expression in a dose-dependent manner via the MEK-ERK12-ELK-1 pathway.


Assuntos
Compostos Alílicos/farmacologia , Apolipoproteínas A/genética , Expressão Gênica/efeitos dos fármacos , Hipolipemiantes/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sulfetos/farmacologia , Apolipoproteínas A/metabolismo , Sítios de Ligação , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática , Células Hep G2 , Humanos , MAP Quinase Quinase 1/metabolismo , Fosforilação , Regiões Promotoras Genéticas , Processamento de Proteína Pós-Traducional , Proteínas Elk-1 do Domínio ets/metabolismo
14.
Acta Diabetol ; 54(11): 1031-1038, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28866807

RESUMO

AIMS: Inverse relationships have been described between the largely genetically determined levels of serum/plasma lipoprotein(a) [Lp(a)], type 2 diabetes (T2D) and fasting insulin. Here, we aimed to evaluate the nature of these relationships with respect to causality. METHODS: We tested whether we could replicate the recent negative findings on causality between Lp(a) and T2D by employing the Mendelian randomization (MR) approach using cross-sectional data from three independent cohorts, Berlin Aging Study II (BASE-II; n = 2012), LIFE-Adult (n = 3281) and LIFE-Heart (n = 2816). Next, we explored another frequently discussed hypothesis in this context: Increasing insulin levels during the course of T2D disease development inhibits hepatic Lp(a) synthesis and thereby might explain the inverse Lp(a)-T2D association. We used two fasting insulin-associated variants, rs780094 and rs10195252, as instrumental variables in MR analysis of n = 4937 individuals from BASE-II and LIFE-Adult. We further investigated causality of the association between fasting insulin and Lp(a) by combined MR analysis of 12 additional SNPs in LIFE-Adult. RESULTS: While an Lp(a)-T2D association was observed in the combined analysis (meta-effect of OR [95% CI] = 0.91 [0.87-0.96] per quintile, p = 1.3x10-4), we found no evidence of causality in the Lp(a)-T2D association (p = 0.29, fixed effect model) when using the variant rs10455872 as the instrumental variable in the MR analyses. Likewise, no evidence of a causal effect of insulin on Lp(a) levels was found. CONCLUSIONS: While these results await confirmation in larger cohorts, the nature of the inverse Lp(a)-T2D association remains to be elucidated.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Insulina/sangue , Lipoproteína(a)/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Apolipoproteínas A/genética , Estudos de Casos e Controles , Estudos de Coortes , Estudos Transversais , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Jejum/sangue , Feminino , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Adulto Jovem
15.
Sci Rep ; 7(1): 8734, 2017 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-28821713

RESUMO

Apolipoprotein A-IV (apoA-IV) has been observed to be associated with lipids, kidney function, adiposity- and diabetes-related parameters. To assess the causal relationship of apoA-IV with these phenotypes, we conducted bidirectional Mendelian randomization (MR) analyses using publicly available summary-level datasets from GWAS consortia on apoA-IV concentrations (n = 13,813), kidney function (estimated glomerular filtration rate (eGFR), n = 133,413), lipid traits (HDL cholesterol, LDL cholesterol, triglycerides, n = 188,577), adiposity-related traits (body-mass-index (n = 322,206), waist-hip-ratio (n = 210,088)) and fasting glucose (n = 133,010). Main analyses consisted in inverse-variance weighted and multivariable MR, whereas MR-Egger regression and weighted median estimation were used as sensitivity analyses. We found that eGFR is likely to be causal on apoA-IV concentrations (53 SNPs; causal effect estimate per 1-SD increase in eGFR = -0.39; 95% CI = [-0.54, -0.24]; p-value = 2.4e-07). Triglyceride concentrations were also causally associated with apoA-IV concentrations (40 SNPs; causal effect estimate per 1-SD increase in triglycerides = -0.06; 95% CI = [-0.08, -0.04]; p-value = 4.8e-07), independently of HDL-C and LDL-C concentrations (causal effect estimate from multivariable MR = -0.06; 95% CI = [-0.10, -0.02]; p-value = 0.0014). Evaluating the inverse direction of causality revealed a possible causal association of apoA-IV on HDL-cholesterol (2 SNPs; causal effect estimate per one percent increase in apoA-IV = -0.40; 95% CI = [-0.60, -0.21]; p-value = 5.5e-05).


Assuntos
Apolipoproteínas A/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Característica Quantitativa Herdável , Adiposidade , Apolipoproteínas A/metabolismo , Biomarcadores , Glicemia , Jejum , Estudos de Associação Genética/métodos , Taxa de Filtração Glomerular , Humanos , Lipídeos/sangue , Análise da Randomização Mendeliana , Fenótipo , Polimorfismo de Nucleotídeo Único
16.
Sci Rep ; 7(1): 8856, 2017 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-28821873

RESUMO

Apo-A4 expression was increased in tissues from chronic kidney disease (CKD) patients compared to that in normal kidney tissue. We determined the association of apo-A4 and its regulatory signals following acute kidney injury and elucidated the effects of apo-A4 on cell signaling pathways related to kidney injury in vitro and in vivo. Tumor necrosis factor (TNF)-α, which causes inflammatory cell injury, induced significantly increased expression of apo-A4 protein levels, and these levels were related to pro-inflammatory acute kidney injury in human kidney cells. Apo-A4 expression was also increased in experimented rat kidney tissues after ischemic reperfusion injury. The expression of tumor necrosis factor receptor (TNFR) 2 was increased in both kidney cell lines and experimented rat kidney tissues following acute kidney injury. The expression of apo-A4 and TNFR2 was increased upon treatment with TNF-α. Immunohistochemistry revealed positive apo-A4 and TNFR2 staining in ischemic reperfusion injury rat kidneys compared with levels in the sham operation kidneys. After neutralization of TNF-α, NF-κB expression was only observed in the cytoplasm by immunofluorescence. Therefore, the apo-A4 expression is increased by stimulation of injured kidney cells with TNF-α and that these effects occur via a TNFR2-NFκB complex.


Assuntos
Apolipoproteínas A/metabolismo , Células Epiteliais/metabolismo , Inflamação/metabolismo , NF-kappa B/metabolismo , Receptores Tipo II do Fator de Necrose Tumoral/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo , Animais , Apolipoproteínas A/genética , Linhagem Celular , Células Cultivadas , Células Epiteliais/efeitos dos fármacos , Expressão Gênica , Humanos , Inflamação/etiologia , Inflamação/patologia , Túbulos Renais/citologia , Túbulos Renais/metabolismo , Masculino , Camundongos , Modelos Biológicos , Insuficiência Renal/etiologia , Insuficiência Renal/metabolismo , Insuficiência Renal/patologia , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia
17.
Lipids Health Dis ; 16(1): 116, 2017 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-28610615

RESUMO

BACKGROUND: Given the characteristic atherogenic dyslipidemia of south Indian population and crucial role of APOA1, APOC3, APOA4 and APOA5 genes clustered in 11q23.3 chromosomal region in regulating lipoprotein metabolism and cholesterol homeostasis, a large number of recently identified variants are to be explored for their role in regulating the serum lipid parameters among south Indians. METHODS: Using fluidigm SNP genotyping platform, a prioritized set of 96 SNPs of the 11q23.3 chromosomal region were genotyped on 516 individuals from Hyderabad, India, and its vicinity and aged >45 years. RESULTS: The linear regression analysis of the individual lipid traits viz., TC, LDLC, HDLC, VLDL and TG with each of the 78 SNPs that confirm to HWE and with minor allele frequency > 1%, suggests 23 of those to be significantly associated (p ≤ 0.05) with at least one of these quantitative traits. Most importantly, the variant rs632153 is involved in elevating TC, LDLC, TG and VLDLs and probably playing a crucial role in the manifestation of dyslipidemia. Additionally, another three SNPs rs633389, rs2187126 and rs1263163 are found risk conferring to dyslipidemia by elevating LDLC and TC levels in the present population. Further, the ROC (receiver operating curve) analysis for the risk scores and dyslipidemia status yielded a significant area under curve (AUC) = 0.675, suggesting high discriminative power of the risk variants towards the condition. The interaction analysis suggests rs10488699-rs2187126 pair of the BUD13 gene to confer significant risk (Interaction odds ratio = 14.38, P = 7.17 × 105) towards dyslipidemia by elevating the TC levels (ß = 37.13, p = 6.614 × 105). On the other hand, the interaction between variants of APOA1 gene and BUD13 and/or ZPR1 regulatory genes at this region are associated with elevated TG and VLDL. CONCLUSION: The variants at 11q23.3 chromosomal region seem to determine the quantitative lipid traits and in turn dyslipidemia in the population of Hyderabad. Particularly, the variants rs632153, rs633389, rs2187126 and rs1263163 might be risk conferring to dyslipidemia by elevating LDLC and TC levels, while the variants of APOC3 and APOA1 genes might be the genetic determinants of elevated triglycerides in the present population.


Assuntos
Cromossomos Humanos Par 11/genética , Dislipidemias/genética , Locos de Características Quantitativas/genética , Apolipoproteína A-I/genética , Apolipoproteína A-V/genética , Apolipoproteínas A/genética , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Genótipo , Haplótipos/genética , Humanos , Índia , Masculino , Polimorfismo de Nucleotídeo Único/genética
18.
J Lipid Res ; 58(9): 1834-1844, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28512139

RESUMO

High lipoprotein (a) [Lp(a)] concentrations are an independent risk factor for cardiovascular outcomes. Concentrations are strongly influenced by apo(a) kringle IV repeat isoforms. We aimed to identify genetic loci associated with Lp(a) concentrations using data from five genome-wide association studies (n = 13,781). We identified 48 independent SNPs in the LPA and 1 SNP in the APOE gene region to be significantly associated with Lp(a) concentrations. We also adjusted for apo(a) isoforms to identify loci affecting Lp(a) levels independently from them, which resulted in 31 SNPs (30 in the LPA, 1 in the APOE gene region). Seven SNPs showed a genome-wide significant association with coronary artery disease (CAD) risk. A rare SNP (rs186696265; MAF ∼1%) showed the highest effect on Lp(a) and was also associated with increased risk of CAD (odds ratio = 1.73, P = 3.35 × 10-30). Median Lp(a) values increased from 2.1 to 91.1 mg/dl with increasing number of Lp(a)-increasing alleles. We found the APOE2-determining allele of rs7412 to be significantly associated with Lp(a) concentrations (P = 3.47 × 10-10). Each APOE2 allele decreased Lp(a) by 3.34 mg/dl corresponding to ∼15% of the population's mean values. Performing a gene-based test of association, including suspected Lp(a) receptors and regulators, resulted in one significant association of the TLR2 gene with Lp(a) (P = 3.4 × 10-4). In summary, we identified a large number of independent SNPs in the LPA gene region, as well as the APOE2 allele, to be significantly associated with Lp(a) concentrations.


Assuntos
Apolipoproteínas A/metabolismo , Estudo de Associação Genômica Ampla/métodos , Lipoproteína(a)/genética , Lipoproteína(a)/metabolismo , Animais , Apolipoproteínas A/genética , Humanos , Polimorfismo de Nucleotídeo Único , Isoformas de Proteínas/metabolismo , Caracteres Sexuais
19.
FASEB J ; 31(6): 2548-2561, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28246167

RESUMO

The molecular mechanism of stress-induced hepatic steatosis is not well known. Human leucine zipper protein (LZIP) regulates the expression of genes involved in inflammation, cell migration, and stress response. The aim of this study was to determine the regulatory role of LZIP in stress-induced hepatic steatosis. We used a microarray analysis to identify LZIP-induced genes involved in hepatic lipid metabolism. LZIP increased the expression of apolipoprotein A-IV (APOA4) mRNA. In the presence of stress inducer, APOA4 promoter analysis was performed, and LZIP-induced lipid accumulation was monitored in mouse primary cells and human tissues. Under Golgi stress conditions, LZIP underwent proteolytic cleavage and was phosphorylated by AKT to protect against proteasome degradation. The stabilized N-terminal LZIP was translocated to the nucleus, where it directly bound to the APOA4 promoter, leading to APOA4 induction. LZIP-induced APOA4 expression resulted in increased absorption of surrounding free fatty acids. LZIP also promoted hepatic steatosis in mouse liver. Both LZIP and APOA4 were highly expressed in human steatosis samples. Our findings indicate that LZIP is a novel modulator of APOA4 expression and hepatic lipid metabolism. LZIP might be a therapeutic target for developing treatment strategies for hepatic steatosis and related metabolic diseases.-Kang, M., Kim, J., An, H.-T., Ko, J. Human leucine zipper protein promotes hepatic steatosis via induction of apolipoprotein A-IV.


Assuntos
Apolipoproteínas A/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Fígado Gorduroso/metabolismo , Apolipoproteínas A/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Fígado Gorduroso/genética , Regulação da Expressão Gênica/fisiologia , Complexo de Golgi/fisiologia , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Metabolismo dos Lipídeos/genética , Metabolismo dos Lipídeos/fisiologia , Mutação , Ácido Oleico/metabolismo , Fosforilação , Plasmídeos , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Estresse Fisiológico
20.
J Gastroenterol ; 52(8): 940-954, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28062946

RESUMO

BACKGROUND: Palmitic acid is an important risk factor for the pathogenesis of non-alcoholic steatohepatitis (NASH), but changes in palmitic acid intestinal absorption in NASH are unclear. The aim of this study was to clarify changes in palmitic acid intestinal absorption and their association with the pathogenesis of NASH. METHODS: A total of 106 participants were recruited to the study, of whom 33 were control subjects (control group), 32 were patients with NASH Brunt stage 1-2 [early NASH (e-NASH)], and 41 were patients with NASH Brunt stage 3-4 [advanced NASH (a-NASH)]. 13C-labeled palmitate was administered directly into the duodenum of all participants by gastrointestinal endoscopy. Breath 13CO2 levels were measured to quantify palmitic acid absorption, and serum Apolipoprotein B-48 (ApoB-48) concentrations were measured after a test meal to quantify absorbed chylomicrons. Expressions of fatty acid (FA) transporters were also examined. The associations of breath 13CO2 levels with hepatic steatosis, fibrosis and insulin resistance was evaluated using laboratory data, elastography results and liver histology findings. RESULTS: Overall, 13CO2 excretion was significantly higher in e-NASH patients than in the control subjects and a-NASH patients (P < 0.01). e-NASH patients had higher serum ApoB-48 levels, indicating increased palmitic acid transport via chylomicrons in these patients. Jejunal mRNA and protein expressions of microsomal triglyceride transfer protein and cluster of differentiation 36 were also increased in both NASH patient groups. The 13CO2 excretion of e-NASH patients was significantly correlated with the degree of hepatic steatosis, fibrosis and insulin resistance (P = 0.005, P < 0.001, P = 0.019, respectively). CONCLUSIONS: Significantly upregulated palmitic acid absorption by activation of its transporters was evident in patients with NASH, and clinical progression of NASH was related to palmitic acid absorption. These dietary changes are associated with the onset and progression of NASH.


Assuntos
Apolipoproteína B-48/sangue , Absorção Intestinal , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Ácidos Palmíticos/metabolismo , Adulto , Idoso , Apolipoproteína B-48/genética , Apolipoproteína B-48/metabolismo , Apolipoproteínas A/genética , Apolipoproteínas A/metabolismo , Testes Respiratórios , Antígenos CD36/genética , Antígenos CD36/metabolismo , Radioisótopos de Carbono , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Estudos de Casos e Controles , Caveolina 1/genética , Quilomícrons/metabolismo , Endorribonucleases/genética , Proteínas de Transporte de Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Feminino , Peptídeos Semelhantes ao Glucagon/sangue , Humanos , Resistência à Insulina , Jejuno/metabolismo , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/patologia , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Proteínas Monoméricas de Ligação ao GTP/genética , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Proteínas Serina-Treonina Quinases/genética , RNA Mensageiro/metabolismo
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