RESUMO
BACKGROUND: This study constitutes a secondary analysis of a prospective cohort aiming to evaluate the potential correlation between nutritional risk and status at admission with the occurrence of post-discharge complications and hospital readmissions in children receiving care at high resource Centres. METHODS: Data was collected from 5 Canadian tertiary pediatric Centers between 2012 and 2016. Nutritional risk and status were evaluated at hospital admission with validated tools (STRONGkids and Subjective Global Nutrition Assessment [SGNA]) and anthropometric measurements. Thirty days after discharge, occurrence of post-discharge complications and hospital readmission were documented. RESULTS: A total of 360 participants were included in the study (median age, 6.1 years; median length of stay, 5 days). Following discharge, 24.1% experienced complications and 19.5% were readmitted to the hospital. The odds of experiencing complications were nearly tripled for participants with a high nutritional risk compared to a low risk (OR = 2.85; 95% CI [1.08-7.54]; P = 0.035) and those whose caregivers reported having a poor compared to a good appetite (OR = 2.96; 95% CI [1.59-5.50]; P < 0.001). According to SGNA, patients identified as malnourished had significantly higher odds of complications (OR, 1.92; 95% CI, 1.15-3.20; P = 0.013) and hospital readmission (OR, 1.95; 95% CI, 1.12-3.39; P = 0.017) than to those well-nourished. CONCLUSIONS: This study showed that complications and readmission post-discharge are common, and these are more likely to occur in malnourished children compared to their well-nourished counterparts. Enhancing nutritional care during admission, at discharge and in the community may be an area for future outcome optimization.
Assuntos
Avaliação Nutricional , Estado Nutricional , Alta do Paciente , Readmissão do Paciente , Humanos , Readmissão do Paciente/estatística & dados numéricos , Masculino , Feminino , Criança , Canadá/epidemiologia , Estudos Prospectivos , Pré-Escolar , Adolescente , Lactente , Fatores de Risco , Desnutrição/epidemiologia , Desnutrição/etiologia , Transtornos da Nutrição Infantil/epidemiologiaRESUMO
Biallelic pathogenic variants of the Sar1b gene cause chylomicron retention disease (CRD) whose central phenotype is the inability to secrete chylomicrons. Patients with CRD experience numerous clinical symptoms such as gastrointestinal, hepatic, neuromuscular, ophthalmic, and cardiological abnormalities. Recently, the production of mice expressing either a targeted deletion or mutation of Sar1b recapitulated biochemical and gastrointestinal defects associated with CRD. The present study was conducted to better understand little-known aspects of Sar1b mutations, including mouse embryonic development, lipid profile, and lipoprotein composition in response to high-fat diet, gut and liver cholesterol metabolism, sex-specific effects, and genotype-phenotype differences. Sar1b deletion and mutation produce a lethal phenotype in homozygous mice, which display intestinal lipid accumulation without any gross morphological abnormalities. On high-fat diet, mutant mice exhibit more marked abnormalities in body composition, adipose tissue and liver weight, plasma cholesterol, non-HDL cholesterol and polyunsaturated fatty acids than those on the regular Chow diet. Divergences were also noted in lipoprotein lipid composition, lipid ratios (serving as indices of particle size) and lipoprotein-apolipoprotein distribution. Sar1b defects significantly reduce gut cholesterol accumulation while altering key players in cholesterol metabolism. Noteworthy, variations were observed between males and females, and between Sar1b deletion and mutation phenotypes. Overall, mutant animal findings reveal the importance of Sar1b in several biochemical, metabolic and developmental processes.
Assuntos
Dieta Hiperlipídica , Desenvolvimento Embrionário , Proteínas Monoméricas de Ligação ao GTP , Animais , Feminino , Humanos , Masculino , Camundongos , Colesterol/metabolismo , Quilomícrons/metabolismo , Dieta Hiperlipídica/efeitos adversos , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , Proteínas Monoméricas de Ligação ao GTP/genéticaRESUMO
Chylomicron retention disease (CRD) is an autosomal recessive disorder associated with biallelic Sar1b mutations leading to defects in intracellular chylomicron (CM) trafficking and secretion. To date, a direct cause-effect relationship between CRD and Sar1b mutation has not been established, but genetically modified animal models provide an opportunity to elucidate unrecognized aspects of these mutations. To examine the physiological role and molecular mechanisms of Sar1b function, we generated mice expressing either a targeted deletion or mutation of human Sar1b using the CRISPR-Cas9 system. We found that deletion or mutation of Sar1b in mice resulted in late-gestation lethality of homozygous embryos. Moreover, compared with WT mice, heterozygotes carrying a single disrupted Sar1b allele displayed lower plasma levels of triglycerides, total cholesterol, and HDL-cholesterol, along with reduced CM secretion following gastric lipid gavage. Similarly, decreased expression of apolipoprotein B and microsomal triglyceride transfer protein was observed in correlation with the accumulation of mucosal lipids. Inefficient fat absorption in heterozygotes was confirmed via an increase in fecal lipid excretion. Furthermore, genetically modified Sar1b affected intestinal lipid homeostasis as demonstrated by enhanced fatty acid ß-oxidation and diminished lipogenesis through the modulation of transcription factors. This is the first reported mammalian animal model with human Sar1b genetic defects, which reproduces some of the characteristic CRD features and provides a direct cause-effect demonstration.
Assuntos
Hipobetalipoproteinemias , Síndromes de MalabsorçãoRESUMO
COVID-19 represents a novel infectious disease induced by SARS-CoV-2. It has to date affected 24,240,000 individuals and killed 2,735,805 people worldwide. The highly infectious virus attacks mainly the lung, causing fever, cough, and fatigue in symptomatic patients, but also pneumonia in severe cases. However, growing evidence highlights SARS-CoV-2-mediated extrarespiratory manifestations, namely, gastrointestinal (GI) and hepatic complications. The detection of 1) the virus in the GI system (duodenum, colon, rectum, anal region, and feces); 2) the high expression of additional candidate coreceptors/auxiliary proteins to facilitate the virus entry; 3) the abundant viral angiotensin-converting enzyme 2 receptor; 4) the substantial expression of host transmembrane serine protease 2, necessary to induce virus-cell fusion; 5) the viral replication in the intestinal epithelial cells; and 6) the primarily GI disorders in the absence of respiratory symptoms lead to increased awareness of the risk of disease transmission via the fecal-oral route. The objectives of this review are to provide a brief update of COVID-19 pathogenesis and prevalence, present a critical overview of its GI and liver complications that affect clinical COVID-19 outcomes, clarify associated mechanisms (notably microbiota-related), define whether gut/liver disorders occur more frequently among critically ill patients with COVID-19, determine the impact of COVID-19 on preexisting gut/liver complications and vice versa, and discuss the available strategies for prevention and treatment to improve prognosis of the patients. The novel SARS-CoV-2 can cause gastrointestinal and hepatobiliary manifestations. Metagenomics studies of virobiota in response to SARS-CoV-2 infection are necessary to highlight the contribution of bacterial microflora to COVID-19 phenotype, which is crucial for developing biomarkers and therapeutics.
Assuntos
COVID-19/virologia , Trato Gastrointestinal/virologia , Hepatopatias/virologia , SARS-CoV-2 , HumanosRESUMO
Much more serious than the previous severe acute respiratory syndrome (SARS) coronavirus (CoV) outbreaks, the novel SARS-CoV-2 infection has spread speedily, affecting 213 countries and causing â¼17,300,000 cases and â¼672,000 (â¼+1,500/day) deaths globally (as of July 31, 2020). The potentially fatal coronavirus disease (COVID-19), caused by air droplets and airborne as the main transmission modes, clearly induces a spectrum of respiratory clinical manifestations, but it also affects the immune, gastrointestinal, hematological, nervous, and renal systems. The dramatic scale of disorders and complications arises from the inadequacy of current treatments and absence of a vaccine and specific anti-COVID-19 drugs to suppress viral replication, inflammation, and additional pathogenic conditions. This highlights the importance of understanding the SARS-CoV-2 mechanisms of actions and the urgent need of prospecting for new or alternative treatment options. The main objective of the present review is to discuss the challenging issue relative to the clinical utility of plants-derived polyphenols in fighting viral infections. Not only is the strong capacity of polyphenols highlighted in magnifying health benefits, but the underlying mechanisms are also stressed. Finally, emphasis is placed on the potential ability of polyphenols to combat SARS-CoV-2 infection via the regulation of its molecular targets of human cellular binding and replication, as well as through the resulting host inflammation, oxidative stress, and signaling pathways.
Assuntos
Infecções por Coronavirus/prevenção & controle , Pandemias/prevenção & controle , Fitoterapia/métodos , Pneumonia Viral/prevenção & controle , Polifenóis/uso terapêutico , Prevenção Primária/métodos , Betacoronavirus/fisiologia , COVID-19 , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/história , História do Século XXI , Humanos , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , Pandemias/história , Pneumonia Viral/epidemiologia , Pneumonia Viral/história , Polifenóis/farmacologia , SARS-CoV-2 , Replicação Viral/efeitos dos fármacosRESUMO
PURPOSE OF REVIEW: Chylomicron retention disease (CRD) is an autosomic recessive disorder, in which intestinal fat malabsorption is the main cause of diverse severe manifestations. The specific molecular defect was identified in 2003 and consists of mutations in the SAR1B or SARA2 gene encoding for intracellular SAR1B GTPase protein. The aim of this review is first to provide an update of the recent biochemical, genetic and clinical findings, and second to discuss novel mechanisms related to hallmark symptoms. RECENT FINDINGS: CRD patients present with SAR1B mutations, which disable the formation of coat protein complex II and thus blocks the transport of chylomicron cargo from the endoplasmic reticulum to the Golgi. Consequently, there is a total absence of chylomicron and apolipoprotein B-48 in the blood circulation following a fat meal, accompanied by a deficiency in liposoluble vitamins and essential fatty acids. The recent discovery of Transport and Golgi organization and Transport and Golgi organization-like proteins may explain the intriguing export of large chylomicron, exceeding coat protein complex II size. Hypocholesterolemia could be accounted for by a decrease in HDL cholesterol, likely a reflection of limited production of intestinal HDL in view of reduced ATP-binding cassette family A protein 1 and apolipoprotein A-I protein. In experimental studies, the paralog SAR1A compensates for the lack of the SAR1B GTPase protein. SUMMARY: Molecular testing for CRD is recommended to distinguish the disease from other congenital fat malabsorptions, and to early define molecular aberrations, accelerate treatment, and prevent complications.
Assuntos
HDL-Colesterol/metabolismo , Quilomícrons/metabolismo , Hipobetalipoproteinemias/metabolismo , Mucosa Intestinal/metabolismo , Metabolismo dos Lipídeos/genética , Síndromes de Malabsorção/metabolismo , Proteínas Monoméricas de Ligação ao GTP/genética , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Apolipoproteína A-I/genética , Apolipoproteína A-I/metabolismo , Apolipoproteína B-48/genética , Apolipoproteína B-48/metabolismo , Vesículas Revestidas pelo Complexo de Proteína do Envoltório/genética , Vesículas Revestidas pelo Complexo de Proteína do Envoltório/metabolismo , Retículo Endoplasmático/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Regulação da Expressão Gênica , Complexo de Golgi/metabolismo , Humanos , Hipobetalipoproteinemias/diagnóstico , Hipobetalipoproteinemias/genética , Hipobetalipoproteinemias/patologia , Mucosa Intestinal/patologia , Síndromes de Malabsorção/diagnóstico , Síndromes de Malabsorção/genética , Síndromes de Malabsorção/patologia , Proteínas Monoméricas de Ligação ao GTP/metabolismo , MutaçãoRESUMO
Genetic defects in SAR1B GTPase inhibit chylomicron (CM) trafficking to the Golgi and result in a huge intraenterocyte lipid accumulation with a failure to release CMs and liposoluble vitamins into the blood circulation. The central aim of this study is to test the hypothesis that SAR1B deletion (SAR1B-/- ) disturbs enterocyte lipid homeostasis (e.g., FA ß-oxidation and lipogenesis) while promoting oxidative stress and inflammation. Another issue is to compare the impact of SAR1B-/- to that of its paralogue SAR1A-/- and combined SAR1A-/- /B-/- To address these critical issues, we have generated Caco-2/15 cells with a knockout of SAR1A, SAR1B, or SAR1A/B genes. SAR1B-/- results in lipid homeostasis disruption, reflected by enhanced mitochondrial FA ß-oxidation and diminished lipogenesis in intestinal absorptive cells via the implication of PPARα and PGC1α transcription factors. Additionally, SAR1B-/- cells, which mimicked enterocytes of CM retention disease, spontaneously disclosed inflammatory and oxidative characteristics via the implication of NF-κB and NRF2. In most conditions, SAR1A-/- cells showed a similar trend, albeit less dramatic, but synergetic effects were observed with the combined defects of the two SAR1 paralogues. In conclusion, SAR1B and its paralogue are needed not only for CM trafficking but also for lipid homeostasis, prooxidant/antioxidant balance, and protection against inflammatory processes.
Assuntos
Homeostase , Mucosa Intestinal/enzimologia , Metabolismo dos Lipídeos , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Estresse Oxidativo , Antioxidantes/metabolismo , Células CACO-2 , Ácidos Graxos/metabolismo , Regulação Enzimológica da Expressão Gênica , Técnicas de Inativação de Genes , Humanos , Inflamação/enzimologia , Inflamação/metabolismo , Inflamação/patologia , Peroxidação de Lipídeos , Proteínas Monoméricas de Ligação ao GTP/deficiência , Proteínas Monoméricas de Ligação ao GTP/genética , Perilipina-2/genética , Perilipina-2/metabolismoRESUMO
OBJECTIVE: To assess the prevalence, causes, and consequences of malnutrition, as well as the evolution of nutritional status, in Canadian pediatric health care institutions. STUDY DESIGN: In this multicenter prospective cohort study, a total of 371 patients were recruited from pediatric hospitals in 5 Canadian provinces. Subjects were aged 1 month to 18 years; admitted to a medical, surgical, or oncology ward; and had a planned hospital stay of >48 hours. Data on demographics, medical condition, anthropometric measures, and dietary intake were collected. The Screening Tool Risk on Nutritional Status and Growth (STRONGkids) and Subjective Global Nutritional Assessment (SGNA) were applied at admission. Malnutrition was defined as a weight-for-age, height-for-age, body mass index-for-age, or weight-for-length/height z score <-2 SD. RESULTS: Among 307 subjects (median age, 5.3 years; median length of stay, 5 days), 19.5% were malnourished on admission. Both STRONGkids and SGNA classifications were associated with baseline nutritional status. Mean weight-for-age z score was lower at discharge compared with admission (-0.14 vs -0.09; P < .01), and nearly one-half of all patients lost weight during their hospital stay. Only one-half of the children who were malnourished or screened as high risk of malnutrition were visited by a dietitian during their stay. The percentage of patients who lost weight during hospitalization was significantly greater in the group not visited by a dietitian (76.5 vs 23.5%; P < .01). CONCLUSION: Nutritional status deterioration and malnutrition are common in hospitalized Canadian children. Screening tools, anthropometric measurements, and dietitian consultation should be used to establish adequate nutritional support.
Assuntos
Hospitais Pediátricos/estatística & dados numéricos , Desnutrição/epidemiologia , Inquéritos Nutricionais/métodos , Estado Nutricional , Medição de Risco/métodos , Adolescente , Índice de Massa Corporal , Canadá/epidemiologia , Criança , Criança Hospitalizada/estatística & dados numéricos , Pré-Escolar , Feminino , Seguimentos , Humanos , Tempo de Internação/tendências , Masculino , Desnutrição/diagnóstico , Prevalência , Estudos Prospectivos , Fatores de RiscoRESUMO
BACKGROUND: Understanding the specific mechanisms of rare autosomal disorders has greatly expanded insights into the complex processes regulating intestinal fat transport. Sar1B GTPase is one of the critical proteins governing chylomicron secretion by the small intestine, and its mutations lead to chylomicron retention disease, despite the presence of Sar1A paralog. OBJECTIVE: The central aim of this work is to examine the cause-effect relationship between Sar1B expression and chylomicron output and to determine whether Sar1B is obligatory for normal high-density lipoprotein biogenesis. APPROACH AND RESULTS: The SAR1B gene was totally silenced in Caco-2/15 cells using the zinc finger nuclease technique. SAR1B deletion resulted in significantly decreased secretion of triglycerides (≈40%), apolipoprotein B-48 (≈57%), and chylomicron (≈34.5%). The absence of expected chylomicron production collapse may be because of the compensatory SAR1A elevation observed in our experiments. Therefore, a double knockout of SAR1A and SAR1B was engineered in Caco-2/15 cells, which led to almost complete inhibition of triglycerides, apolipoprotein B-48, and chylomicron output. Further experiments with labeled cholesterol revealed the downregulation of high-density lipoprotein biogenesis in cells deficient in SAR1B or with the double knockout of the 2 SAR1 paralogs. Similarly, there was a fall in the movement of labeled cholesterol from cells to basolateral medium containing apolipoprotein A-I, thereby limiting newly synthesized high-density lipoprotein in genetically modified cells. The decreased cholesterol efflux was associated with impaired expression of ABCA1 (ATP-binding cassette subfamily A member 1). CONCLUSIONS: These findings demonstrate that the deletion of the 2 SAR1 isoforms is required to fully eliminate the secretion of chylomicron in vitro. They also underscore the limited high-density lipoprotein production by the intestinal cells in response to SAR1 knockout.
Assuntos
Quilomícrons/metabolismo , Enterócitos/enzimologia , Técnicas de Silenciamento de Genes , Hipobetalipoproteinemias/enzimologia , Mucosa Intestinal/enzimologia , Síndromes de Malabsorção/enzimologia , Proteínas Monoméricas de Ligação ao GTP/deficiência , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Apolipoproteína B-48/metabolismo , Células CACO-2 , Colesterol/metabolismo , Regulação Enzimológica da Expressão Gênica , Inativação Gênica , Humanos , Hipobetalipoproteinemias/genética , Síndromes de Malabsorção/genética , Proteínas Monoméricas de Ligação ao GTP/genética , Transfecção , Triglicerídeos/metabolismoRESUMO
Hypertension (HT) is among the major components of the metabolic syndrome, i.e., obesity, dyslipidemia, and hyperglycemia/insulin resistance. It represents a significant health problem with foremost risks for chronic cardiovascular disease and a significant cause of morbidity and mortality worldwide. Therefore, it is not surprising that this disorder constitutes a serious public health concern. Although multiple studies have stressed the multifactorial nature of HT, the pathogenesis remains largely unknown. However, if we want to reduce the global prevalence of HT, restrain the number of deaths (currently 9.4 million/year in the world), and alleviate the socio-economic burden, a deeper insight into the mechanisms is urgently needed in order to define new meaningful therapeutic targets. Recently, the role of epigenetics in the development of various complex diseases has attracted much attention. In the present review, we provide a critical update on the available literature and ongoing research regarding the epigenetic modifications of genes involved in several pathways of elevated blood pressure, especially those linked to the vascular epithelium. This review also focuses on the role of microRNA (miRNA) in the regulation of gene expression associated with HT and of fetal programming mediating susceptibility to HT in adulthood.
Assuntos
Pressão Sanguínea/genética , Epigênese Genética , Hipertensão/genética , MicroRNAs/genética , Endotélio Vascular/fisiopatologia , Humanos , Hipertensão/tratamento farmacológicoRESUMO
Cystic fibrosis (CF)-related diabetes (CFRD) has become a critical complication that seriously affects the clinical outcomes of CF patients. Although CFRD has emerged as the most common nonpulmonary complication of CF, little is known about its etiopathogenesis. Additionally, whether oxidative stress (OxS), a common feature of CF and diabetes, influences CFRD pathophysiology requires clarification. The main objective of this study was to shed light on the role of the cystic fibrosis transmembrane conductance regulator (CFTR) in combination with OxS in insulin secretion from pancreatic ß-cells. CFTR silencing was accomplished in MIN6 cells by stable expression of small hairpin RNAs (shRNA), and glucose-induced insulin secretion was evaluated in the presence and absence of the valuable prooxidant system iron/ascorbate (Fe/Asc; 0.075/0.75 mM) along with or without the antioxidant Trolox (1 mM). Insulin output from CFTR-silenced MIN6 cells was significantly reduced (â¼ 70%) at basal and at different glucose concentrations compared with control Mock cells. Furthermore, CFTR silencing rendered MIN6 cells more sensitive to OxS as evidenced by both increased lipid peroxides and weakened antioxidant defense, especially following incubation with Fe/Asc. The decreased insulin secretion in CFTR-silenced MIN6 cells was associated with high levels of NF-κB (the major participant in inflammatory responses), raised apoptosis, and diminished ATP production in response to the Fe/Asc challenge. However, these defects were alleviated by the addition of Trolox, thereby pointing out the role of OxS in aggravating the effects of CFTR deficiency. Our findings indicate that CFTR deficiency in combination with OxS may contribute to endocrine cell dysfunction and insulin secretion, which at least in part may explain the development of CFRD.
Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Glucose/metabolismo , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Estresse Oxidativo/genética , RNA Mensageiro/metabolismo , Difosfato de Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Western Blotting , Catalase/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Cromanos/farmacologia , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Técnicas de Silenciamento de Genes , Inativação Gênica , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Células HEK293 , Humanos , Secreção de Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Ferro/farmacologia , Peroxidação de Lipídeos/genética , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Superóxido Dismutase/metabolismo , Oligoelementos/farmacologiaRESUMO
Sar1B GTPase is a key component of Coat protein complex II (COPII)-coated vesicles that bud from the endoplasmic reticulum to export newly synthesized proteins. The aims of this study were to determine whether Sar1B responds to lipid regulation and to evaluate its role in cholesterol (CHOL) homeostasis. The influence of lipids on Sar1B protein expression was analyzed in Caco-2/15 cells by Western blot. Our results showed that the presence of CHOL (200 µM) and oleic acid (0.5 mM), bound to albumin, increases Sar1B protein expression. Similarly, supplementation of the medium with micelles composed of taurocholate with monooleylglycerol or oleic acid also stimulated Sar1B expression, but the addition of CHOL (200 µM) to micelle content did not modify its regulation. On the other hand, overexpression of Sar1B impacted on CHOL transport and metabolism in view of the reduced cellular CHOL content along with elevated secretion when incubated with oleic acid-containing micelles for 24 h, thereby disclosing induced CHOL transport. This was accompanied with higher secretion of free- and esterified-CHOL within chylomicrons, which was not the case when oleic acid was replaced with monooleylglycerol or when albumin-bound CHOL was given alone. The aforementioned cellular CHOL depletion was accompanied with a low phosphorylated/non phosphorylated HMG-CoA reductase ratio, indicating elevated enzymatic activity. Combination of Sar1B overexpression with micelle incubation led to reduction in intestinal CHOL transporters (NPC1L1, SR-BI) and metabolic regulators (PCSK9 and LDLR). The present work showed that Sar1B is regulated in a time- and concentration-dependent manner by dietary lipids, suggesting an adaptation to alimentary lipid flux. Our data also suggest that Sar1B overexpression contributes to regulation of CHOL transport and metabolism by facilitating rapid uptake and transport of CHOL.
Assuntos
Colesterol/metabolismo , Retículo Endoplasmático/metabolismo , Metabolismo dos Lipídeos/genética , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Transporte Biológico/genética , Vesículas Revestidas pelo Complexo de Proteína do Envoltório/metabolismo , Células CACO-2 , Quilomícrons/metabolismo , Regulação da Expressão Gênica , Homeostase , Humanos , Mucosa Intestinal/metabolismo , Proteínas Monoméricas de Ligação ao GTP/biossíntese , Ácido Oleico/metabolismoRESUMO
BACKGROUND/AIMS: Sar1b GTPase (Sar1b) represents an obligatory component of COPII vesicles that bud from the endoplasmic reticulum to transport proteins to the Golgi apparatus. Its genetic mutations lead to a severe disorder known as chylomicron retention disease. Despite growing knowledge on Sar1b, little is known about it tissue distribution and regulation, which constitute the aims of the present study. We aimed to determine the Sar1b tissue distribution and modulation by a high-fat diet and gene forcing using transgenic mice in comparison to wild-type mice. Methods : The expression pattern of Sar1b was studied in different organs of wild-type and Sar1b transgenic mice by qRT-PCR and Western blot. The effect of transgenesis and insulin resistance induced by a 12-week high-fat diet on Sar1b gene expression was also assessed by qRT-PCR. RESULTS: Evaluation of Sar1b mRNA revealed the skeletal muscle as the tissue with the highest Sar1b expression, followed by the heart and liver, the organs composing the digestive tract, the brain and finally the lung and the adipose tissue. Sar1b protein expression levels follow a similar pattern among the organs, except for its lower expression in the heart. While the high-fat diet did not exert any significant alterations, Sar1b transgenic mice displayed higher gene expression in the liver, ileum, jejunum, proximal and distal colon compared to wild-type mice. CONCLUSION: Our study supports the importance of Sar1b in organs involved in lipid transport and/or calcium trafficking such as the liver, intestine, skeletal muscle and heart.
Assuntos
Dieta Hiperlipídica , Regulação Enzimológica da Expressão Gênica/genética , Proteínas Monoméricas de Ligação ao GTP/genética , Transcriptoma/genética , Animais , Western Blotting , Células CACO-2 , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Resistência à Insulina/genética , Mucosa Intestinal/metabolismo , Fígado/metabolismo , Masculino , Camundongos Transgênicos , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Músculo Esquelético/metabolismo , Miocárdio/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcriptoma/efeitos dos fármacosRESUMO
Over the past three decades, significant efforts have been focused on unraveling congenital intestinal disorders that disrupt the absorption of dietary lipids and fat-soluble vitamins. The primary goal has been to gain deeper insights into intra-enterocyte sites, molecular steps, and crucial proteins/regulatory pathways involved, while simultaneously identifying novel therapeutic targets and diagnostic tools. This research not only delves into specific and rare malabsorptive conditions, such as chylomicron retention disease (CRD), but also contributes to our understanding of normal physiology through the utilization of cutting-edge cellular and animal models alongside advanced research methodologies. This review elucidates how modern techniques have facilitated the decoding of CRD gene defects, the identification of dysfunctional cellular processes, disease regulatory mechanisms, and the essential role of coat protein complex II-coated vesicles and cargo receptors in chylomicron trafficking and endoplasmic reticulum (ER) exit sites. Moreover, experimental approaches have shed light on the multifaceted functions of SAR1B GTPase, wherein loss-of-function mutations not only predispose individuals to CRD but also exacerbate oxidative stress, inflammation, and ER stress, potentially contributing to clinical complications associated with CRD. In addition to dissecting the primary disease pathology, genetically modified animal models have emerged as invaluable assets in exploring various ancillary aspects, including responses to environmental challenges such as dietary alterations, gender-specific disparities in disease onset and progression, and embryonic lethality or developmental abnormalities. In summary, this comprehensive review provides an in-depth and contemporary analysis of CRD, offering a meticulous examination of the CRD current landscape by synthesizing the latest research findings and advancements in the field.
RESUMO
There is currently a growing interest in the use of nutraceuticals as a means of preventing the development of complex diseases. Given the considerable health potential of milk-derived peptides, the aim of this study was to investigate the protective effects of glycomacropeptide (GMP) on metabolic syndrome. Particular emphasis was placed on the potential mechanisms mitigating cardiometabolic disorders in high-fat, high-fructose diet-fed mice in the presence of GMP or Bipro, an isocaloric control. The administration of GMP for 12 weeks reduced obesity, hyperglycemia and hyperinsulinemia caused by a high-fat, high-fructose diet, resulting in a decline in insulin resistance. GMP also lessened systemic inflammation, as indicated by decreased circulating inflammatory cytokines. In the intestinal and hepatic tissues, GMP improved homeostasis by increasing insulin sensitivity and attenuating high-fat, high-fructose-induced inflammation, oxidative stress and endoplasmic reticulum stress. Biochemical and histological analyses revealed improved hepatic steatosis and fatty acid composition in the livers of high-fat, high-fructose diet-fed mice treated with GMP compared to Bipro. A trend toward a decrease in bile acids without any marked changes in intestinal microbiota composition characterized GMP-treated animals compared to those administered Bipro. GMP offers considerable potential for fighting metabolic syndrome-related components and complications given its beneficial effects on risk factors such as inflammation, oxidative stress and endoplasmic reticulum stress without involving the intestinal microbiota.
Assuntos
Caseínas , Hiperinsulinismo , Resistência à Insulina , Síndrome Metabólica , Fragmentos de Peptídeos , Animais , Camundongos , Síndrome Metabólica/metabolismo , Fígado/metabolismo , Inflamação/metabolismo , Dieta Hiperlipídica/efeitos adversos , Hiperinsulinismo/metabolismo , Frutose/metabolismo , Camundongos Endogâmicos C57BLRESUMO
We have recently shown that a high glucose (HG) concentration raised intestinal cholesterol (CHOL) transport and metabolism in intestinal epithelial cells. The objective of the present work is to determine whether the stimulus for increased CHOL absorption by glucose originates from the apical site (corresponding to the intestinal lumen) or from the basolateral site (related to blood circulation). We tackled this issue by using differentiated Caco-2/15 cells. Only basolateral medium, supplemented with 25 mmol/L glucose, stimulated [(14)C]-CHOL uptake via the up-regulation of the critical CHOL transporter NPC1L1 protein, as confirmed by its specific ezetimibe inhibitor that abolished the rise in glucose-mediated CHOL capture. No significant changes were noted in SR-BI and CD36. Elevated CHOL uptake was associated with an increase in the transcription factors SREBP-2, LXR-ß, and ChREBP, along with a fall in RXR-α. Interestingly, although the HG concentration in the apical medium caused modest changes in CHOL processing, its impact was synergetic with that of the basolateral medium. Our results suggest that HG concentration influences positively intestinal CHOL uptake when present in the basolateral medium. In addition, excessive consumption of diets containing high levels of carbohydrates may strengthen intestinal CHOL uptake in metabolic syndrome, thereby contributing to elevated levels of circulating CHOL and, consequently, the risk of developing type 2 diabetes and cardiovascular disease.
Assuntos
Colesterol/metabolismo , Enterócitos/efeitos dos fármacos , Glucose/farmacologia , Proteínas de Membrana/genética , Anticolesterolemiantes/farmacologia , Azetidinas/farmacologia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Transporte Biológico , Antígenos CD36/genética , Antígenos CD36/metabolismo , Células CACO-2 , Radioisótopos de Carbono , Diferenciação Celular , Polaridade Celular , Enterócitos/citologia , Enterócitos/metabolismo , Ezetimiba , Regulação da Expressão Gênica , Glucose/metabolismo , Humanos , Receptores X do Fígado , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras , Receptores Nucleares Órfãos/genética , Receptores Nucleares Órfãos/metabolismo , Receptor X Retinoide alfa/genética , Receptor X Retinoide alfa/metabolismo , Receptores Depuradores Classe B/genética , Receptores Depuradores Classe B/metabolismo , Transdução de Sinais , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismoRESUMO
Milk-derived bioactive proteins have increasingly gained attention and consideration throughout the world due to their high-quality amino acids and multiple health-promoting attributes. Apparently, being at the forefront of functional foods, these bioactive proteins are also suggested as potential alternatives for the management of various complex diseases. In this review, we will focus on lactoferrin (LF) and osteopontin (OPN), two multifunctional dairy proteins, as well as to their naturally occurring bioactive LF-OPN complex. While describing their wide variety of physiological, biochemical, and nutritional functionalities, we will emphasize their specific roles in the perinatal period. Afterwards, we will evaluate their ability to control oxidative stress, inflammation, gut mucosal barrier, and intestinal microbiota in link with cardiometabolic disorders (CMD) (obesity, insulin resistance, dyslipidemia, and hypertension) and associated complications (diabetes and atherosclerosis). This review will not only attempt to highlight the mechanisms of action, but it will critically discuss the potential therapeutic applications of the underlined bioactive proteins in CMD.
Assuntos
Doenças Cardiovasculares , Lactoferrina , Gravidez , Feminino , Humanos , Lactoferrina/farmacologia , Lactoferrina/metabolismo , Osteopontina/farmacologia , Inflamação , Obesidade , Proteínas do Leite/metabolismo , Doenças Cardiovasculares/prevenção & controleRESUMO
Significance: Metabolic syndrome (MetS) prevalence continues to grow and represents a serious public health issue worldwide. This multifactorial condition carries the risk of hastening the development of type 2 diabetes (T2D), non-alcoholic fatty liver disease (NAFLD), and cardiovascular diseases (CVD). Another troubling aspect of MetS is the requirement of poly-pharmacological therapy not devoid of side effects. Therefore, there is an urgent need for prospecting alternative nutraceuticals as effective therapeutic agents for MetS. Recent Advances: Currently, there is an increased interest in understanding the regulation of metabolic derangements by specialized pro-resolving lipid mediators (SPMs), especially those derived from the long chain n-3 polyunsaturated fatty acids. Critical Issues: The SPMs are recognized as efficient modulators that are capable of inhibiting the production of pro-inflammatory cytokines, blocking neutrophil activation/recruitment, and inducing non-phlogistic (anti-inflammatory) activation of macrophage engulfment and removal of apoptotic inflammatory cells and debris. The aim of the present review is precisely to first underline key concepts relative to SPM functions before focusing on their status and actions on MetS components (e.g., obesity, glucose dysmetabolism, hyperlipidemia, hypertension) and complications such as T2D, NAFLD, and CVD. Future Directions: Valuable data from preclinical and clinical investigations have emphasized the SPM functions and influence on oxidative stress- and inflammation-related MetS. Despite these promising findings obtained without compromising host defense, additional efforts are needed to evaluate their potential therapeutic applications and further develop practical tools to monitor their bioavailability to cope with cardiometabolic disorders. Antioxid. Redox Signal. 37, 54-83.
Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Ácidos Graxos Ômega-3 , Síndrome Metabólica , Hepatopatia Gordurosa não Alcoólica , Doenças Cardiovasculares/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Ácidos Graxos Ômega-3/uso terapêutico , Humanos , Inflamação/metabolismo , Mediadores da Inflamação , Síndrome Metabólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológicoRESUMO
While the prevalence of metabolic syndrome (MetS) is steadily increasing worldwide, no optimal pharmacotherapy is readily available to address its multifaceted risk factors and halt its complications. This growing challenge mandates the development of other future curative directions. The purpose of the present study is to investigate the efficacy of cranberry proanthocyanidins (PACs) in improving MetS pathological conditions and liver complications; C57BL/6J mice were fed either a standard chow or a high fat/high sucrose (HFHS) diet with and without PACs (200 mg/kg), delivered by daily gavage for 12 weeks. Our results show that PACs lowered HFHS-induced obesity, insulin resistance, and hyperlipidemia. In conjunction, PACs lessened circulatory markers of oxidative stress (OxS) and inflammation. Similarly, the anti-oxidative and anti-inflammatory capacities of PACs were noted in the liver in association with improved hepatic steatosis. Inhibition of lipogenesis and stimulation of beta-oxidation could account for PACs-mediated decline of fatty liver as evidenced not only by the expression of rate-limiting enzymes but also by the status of AMPKα (the key sensor of cellular energy) and the powerful transcription factors (PPARα, PGC1α, SREBP1c, ChREBP). Likewise, treatment with PACs resulted in the downregulation of critical enzymes of liver gluconeogenesis, a process contributing to increased rates of glucose production in type 2 diabetes. Our findings demonstrate that PACs prevented obesity and improved insulin resistance likely via suppression of OxS and inflammation while diminishing hyperlipidemia and fatty liver disease, as clear evidence for their strength of fighting the cluster of MetS abnormalities.
RESUMO
During the last two decades, a large body of information on the events responsible for intestinal fat digestion and absorption has been accumulated. In particular, many groups have extensively focused on the absorptive phase in order to highlight the critical "players" and the main mechanisms orchestrating the assembly and secretion of chylomicrons (CM) as essential vehicles of alimentary lipids. The major aim of this article is to review understanding derived from basic science and clinical conditions associated with impaired packaging and export of CM. We have particularly insisted on inborn metabolic pathways in humans as well as on genetically modified animal models (recapitulating pathological features). The ultimate goal of this approach is that "experiments of nature" and in vivo model strategy collectively allow gaining novel mechanistic insight and filling the gap between the underlying genetic defect and the apparent clinical phenotype. Thus, uncovering the cause of disease contributes not only to understanding normal physiologic pathway, but also to capturing disorder onset, progression, treatment and prognosis.