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1.
Front Physiol ; 15: 1358625, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38426205

RESUMO

Lipid handling in the intestine is important for maintaining energy homeostasis and overall health. Mishandling of lipids in the intestine contributes to dyslipidemia and atherosclerotic cardiovascular diseases. Despite advances in this field over the past few decades, significant gaps remain. The gut hormone glucagon-like peptide-2 (GLP-2) has been shown to play pleotropic roles in the regulation of lipid handling in the intestine. Of note, GLP-2 exhibits unique actions on post-prandial lipid absorption and post-absorptive release of intestinally stored lipids. This review aims to summarize current knowledge in how GLP-2 regulates lipid processing in the intestine. Elucidating the mechanisms of GLP-2 regulation of intestinal lipid handling not only improves our understanding of GLP-2 biology, but also provides insights into how lipids are processed in the intestine, which offers opportunities for developing novel strategies towards prevention and treatment of dyslipidemia and atherosclerotic cardiovascular diseases.

2.
Arterioscler Thromb Vasc Biol ; 44(1): 192-201, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37970717

RESUMO

BACKGROUND: The gut hormone GLP-2 (glucagon-like peptide-2) plays important roles in lipid handling in the intestine. During postabsorptive stage, it releases preformed chylomicrons stored in the intestine, the underlying mechanisms of which are not well understood. Previous studies implicate the involvement of neural pathways in GLP-2's actions on lipid absorption in the intestine, but the role of such mechanisms in releasing postabsorptive lipid storage has not been established. METHODS: Here, in mesenteric lymph duct cannulated rats, we directly tested whether gut-brain neural communication mediates GLP-2's effects on postabsorptive lipid mobilization in the intestine. We performed total subdiaphragmatic vagotomy to disrupt the gut-brain neural communication and analyzed lipid output 5 hours after a lipid load in response to intraperitoneal GLP-2 or saline. RESULTS: Peripheral GLP-2 administration led to increased lymph lipid output and activation of proopiomelanocortin neurons in the arcuate nucleus of hypothalamus. Disruption of gut-brain neural communication via vagotomy blunted GLP-2's effects on promoting lipid release in the intestine. CONCLUSIONS: These results, for the first time, demonstrate a novel mechanism in which postabsorptive mobilization of intestinal lipid storage by GLP-2 enlists a gut-brain neural pathway.


Assuntos
Quilomícrons , Peptídeo 2 Semelhante ao Glucagon , Ratos , Animais , Peptídeo 2 Semelhante ao Glucagon/farmacologia , Quilomícrons/metabolismo , Encéfalo/metabolismo , Vias Neurais/metabolismo , Intestinos
3.
J Clin Endocrinol Metab ; 108(5): 1084-1092, 2023 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-36458872

RESUMO

CONTEXT: A portion of ingested fats are retained in the intestine for many hours before they are mobilized and secreted in chylomicron (CM) particles. Factors such as glucagon-like peptide-2 (GLP-2) and glucose can mobilize these stored intestinal lipids and enhance CM secretion. We have recently demonstrated in rodents that GLP-2 acutely enhances CM secretion by mechanisms that do not involve the canonical CM synthetic assembly and secretory pathways. OBJECTIVE: To further investigate the mechanism of GLP-2's potent intestinal lipid mobilizing effect, we examined intracellular cytoplasmic lipid droplets (CLDs) in intestinal biopsies of humans administered GLP-2 or placebo. DESIGN, SETTING, PATIENTS, AND INTERVENTIONS: A single dose of placebo or GLP-2 was administered subcutaneously 5 hours after ingesting a high-fat bolus. In 1 subset of participants, plasma samples were collected to quantify lipid and lipoprotein concentrations for 3 hours after placebo or GLP-2. In another subset, a duodenal biopsy was obtained 1-hour after placebo or GLP-2 administration for transmission electron microscopy and proteomic analysis. RESULTS: GLP-2 significantly increased plasma triglycerides by 46% (P = 0.009), mainly in CM-sized particles by 133% (P = 0.003), without reducing duodenal CLD size or number. Several proteins of interest were identified that require further investigation to elucidate their potential role in GLP-2-mediated CM secretion. CONCLUSIONS: Unlike glucose that mobilizes enterocyte CLDs and enhances CM secretion, GLP-2 acutely increased plasma CMs without significant mobilization of CLDs, supporting our previous findings that GLP-2 does not act directly on enterocytes to enhance CM secretion and most likely mobilizes secreted CMs in the lamina propria and lymphatics.


Assuntos
Quilomícrons , Gotículas Lipídicas , Humanos , Quilomícrons/metabolismo , Triglicerídeos , Gotículas Lipídicas/metabolismo , Peptídeo 2 Semelhante ao Glucagon/farmacologia , Peptídeo 2 Semelhante ao Glucagon/metabolismo , Proteômica , Glucose
4.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1867(10): 159197, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35820577

RESUMO

Processing of dietary fats in the intestine is a highly regulated process that influences whole-body energy homeostasis and multiple physiological functions. Dysregulated lipid handling in the intestine leads to dyslipidemia and atherosclerotic cardiovascular disease. In intestinal enterocytes, lipids are incorporated into lipoproteins and cytoplasmic lipid droplets (CLDs). Lipoprotein synthesis and CLD metabolism are inter-connected pathways with multiple points of regulation. This review aims to highlight recent advances in the regulatory mechanisms of lipid processing in the enterocyte, with particular focus on CLDs. In-depth understanding of the regulation of lipid metabolism in the enterocyte may help identify therapeutic targets for the treatment and prevention of metabolic disorders.


Assuntos
Enterócitos , Gotículas Lipídicas , Citosol/metabolismo , Gorduras na Dieta/metabolismo , Enterócitos/metabolismo , Gotículas Lipídicas/metabolismo , Metabolismo dos Lipídeos/fisiologia
5.
Artigo em Inglês | MEDLINE | ID: mdl-35680083

RESUMO

BACKGROUND & AIMS: Dietary triglycerides (TG) retained in the intestine after a meal can be mobilized many hours later by glucagon-like peptide-2 (GLP-2) in humans and animal models, despite the well-documented absence of expression of the GLP-2 receptor on enterocytes. In this study, we examined the site of GLP-2 action to mobilize intestinal lipids and enhance chylomicron production. METHODS: In mesenteric lymph duct-cannulated rats, we assessed GLP-2-stimulated lymph flow rate, TG concentration, TG output, and apoB48 abundance 5 h after an intraduodenal lipid bolus, in the presence of a validated GLP-2 antagonist or vehicle. Additionally, the same GLP-2-stimulated parameters were examined in the presence or absence of cis-Golgi disruption by Brefeldin A (BFA). RESULTS: Compared to placebo, GLP-2 administration increased lymph flow by 2.8-fold (P < 0.001), cumulative lymph volume by 2.69-fold (P < 0.001) and total TG output 2-fold (P = 0.015). GLP-2 receptor antagonism markedly diminished GLP-2's ability to stimulate lymph flow, cumulative lymph volume and total TG output, demonstrating the dependence of GLP-2 stimulation of lymph flow and TG output on its receptor activation. In contrast, disruption of the cis-Golgi apparatus with Brefeldin A did not diminish the GLP-2-response of lymph flow i.e., increased lymph flow by 2.7-fold (P = 0.001), lymph volume by 2.9-fold (P = 0.001), and total TG output i.e., increased by 2.5-fold (P = 0.003). CONCLUSIONS: GLP-2 mobilizes enteral lipid at a site distal to the Golgi, acting via its receptor. Since GLP-2 receptors are not expressed on enterocytes, GLP-2 likely mobilizes intestinal lipid residing extracellularly, either in the lamina propria or in the lymphatics.


Assuntos
Quilomícrons , Peptídeo 2 Semelhante ao Glucagon , Animais , Brefeldina A , Quilomícrons/metabolismo , Enterócitos/metabolismo , Peptídeo 2 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 2 , Intestinos , Ratos , Triglicerídeos/metabolismo
6.
Curr Opin Lipidol ; 33(3): 175-184, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35258031

RESUMO

PURPOSE OF REVIEW: Lymphatics are known to have active, regulated pumping by smooth muscle cells that enhance lymph flow, but whether active regulation of lymphatic pumping contributes significantly to the rate of appearance of chylomicrons (CMs) in the blood circulation (i.e., CM production rate) is not currently known. In this review, we highlight some of the potential mechanisms by which lymphatics may regulate CM production. RECENT FINDINGS: Recent data from our lab and others are beginning to provide clues that suggest a more active role of lymphatics in regulating CM appearance in the circulation through various mechanisms. Potential contributors include apolipoproteins, glucose, glucagon-like peptide-2, and vascular endothelial growth factor-C, but there are likely to be many more. SUMMARY: The digested products of dietary fats absorbed by the small intestine are re-esterified and packaged by enterocytes into large, triglyceride-rich CM particles or stored temporarily in intracellular cytoplasmic lipid droplets. Secreted CMs traverse the lamina propria and are transported via lymphatics and then the blood circulation to liver and extrahepatic tissues, where they are stored or metabolized as a rich energy source. Although indirect data suggest a relationship between lymphatic pumping and CM production, this concept requires more experimental evidence before we can be sure that lymphatic pumping contributes significantly to the rate of CM appearance in the blood circulation.


Assuntos
Quilomícrons , Vasos Linfáticos , Quilomícrons/metabolismo , Gorduras na Dieta/metabolismo , Humanos , Vasos Linfáticos/metabolismo , Triglicerídeos/metabolismo , Fator C de Crescimento do Endotélio Vascular/metabolismo
7.
Commun Biol ; 5(1): 132, 2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-35169231

RESUMO

Atherosclerosis is a chronic inflammatory condition in which macrophages play a major role. Janus kinase 2 (JAK2) is a pivotal molecule in inflammatory and metabolic signaling, and Jak2V617F activating mutation has recently been implicated with enhancing clonal hematopoiesis and atherosclerosis. To determine the essential in vivo role of macrophage (M)-Jak2 in atherosclerosis, we generate atherosclerosis-prone ApoE-null mice deficient in M-Jak2. Contrary to our expectation, these mice exhibit increased plaque burden with no differences in macrophage proliferation, recruitment or bone marrow clonal expansion. Notably, M-Jak2-deficient bone marrow derived macrophages show a significant defect in cholesterol efflux. Pharmacologic JAK2 inhibition with ruxolitinib also leads to defects in cholesterol efflux and accelerates atherosclerosis. Liver X receptor agonist abolishes the efflux defect and attenuates the accelerated atherosclerosis that occurs with M-Jak2 deficiency. Macrophages of individuals with the Jak2V617F mutation show increased efflux which is normalized when treated with a JAK2 inhibitor. Together, M-Jak2-deficiency leads to accelerated atherosclerosis primarily through defects in cholesterol efflux from macrophages.


Assuntos
Aterosclerose , Colesterol , Janus Quinase 2 , Animais , Aterosclerose/enzimologia , Aterosclerose/genética , Aterosclerose/metabolismo , Colesterol/metabolismo , Janus Quinase 2/deficiência , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL
8.
Annu Rev Nutr ; 41: 79-104, 2021 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-34283920

RESUMO

Dietary fat absorption is required for health but also contributes to hyperlipidemia and metabolic disease when dysregulated. One step in the process of dietary fat absorption is the formation of cytoplasmic lipid droplets (CLDs) in small intestinal enterocytes; these CLDs serve as dynamic triacylglycerol storage organelles that influence the rate at which dietary fat is absorbed. Recent studies have uncovered novel factors regulating enterocyte CLD metabolism that in turn influence the absorption of dietary fat. These include peroxisome proliferator-activated receptor α activation, compartmentalization of different lipid pools, the gut microbiome, liver X receptor and farnesoid X receptor activation, obesity, and physiological factors stimulating CLD mobilization. Understanding how enterocyte CLD metabolism is regulated is key in modulating the absorption of dietary fat in the prevention of hyperlipidemia and its associated metabolic disorders.


Assuntos
Gorduras na Dieta , Gotículas Lipídicas , Gorduras na Dieta/metabolismo , Enterócitos/metabolismo , Humanos , Gotículas Lipídicas/metabolismo , Metabolismo dos Lipídeos/fisiologia , Triglicerídeos/metabolismo
10.
Endocr Rev ; 42(6): 815-838, 2021 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-33743013

RESUMO

Plasma triglyceride-rich lipoproteins (TRL), particularly atherogenic remnant lipoproteins, contribute to atherosclerotic cardiovascular disease. Hypertriglyceridemia may arise in part from hypersecretion of TRLs by the liver and intestine. Here we focus on the complex network of hormonal, nutritional, and neuronal interorgan communication that regulates secretion of TRLs and provide our perspective on the relative importance of these factors. Hormones and peptides originating from the pancreas (insulin, glucagon), gut [glucagon-like peptide 1 (GLP-1) and 2 (GLP-2), ghrelin, cholecystokinin (CCK), peptide YY], adipose tissue (leptin, adiponectin) and brain (GLP-1) modulate TRL secretion by receptor-mediated responses and indirectly via neural networks. In addition, the gut microbiome and bile acids influence lipoprotein secretion in humans and animal models. Several nutritional factors modulate hepatic lipoprotein secretion through effects on the central nervous system. Vagal afferent signaling from the gut to the brain and efferent signals from the brain to the liver and gut are modulated by hormonal and nutritional factors to influence TRL secretion. Some of these factors have been extensively studied and shown to have robust regulatory effects whereas others are "emerging" regulators, whose significance remains to be determined. The quantitative importance of these factors relative to one another and relative to the key regulatory role of lipid availability remains largely unknown. Our understanding of the complex interorgan regulation of TRL secretion is rapidly evolving to appreciate the extensive hormonal, nutritional, and neural signals emanating not only from gut and liver but also from the brain, pancreas, and adipose tissue.


Assuntos
Peptídeo 1 Semelhante ao Glucagon , Lipoproteínas , Animais , Glucagon , Humanos , Redes Neurais de Computação , Nutrientes
11.
Front Cardiovasc Med ; 7: 100, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32582769

RESUMO

There is consistent, unequivocal and reproducible epidemiological evidence derived from diverse populations that various indices of glycemia (fasting plasma glucose, post-prandial or post oral glucose challenge plasma glucose, HbA1c) are associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD), even in the prediabetic state. Furthermore, there is abundant experimental evidence demonstrating that hyperglycemia per se accelerates and aggravates the atherosclerotic process, providing biological plausibility to the concept that hyperglycemia is causally related or a true risk factor for ASCVD. Two studies in particular, DCCT and UKPDS, that enrolled a younger cohort of patients with type 1 diabetes or an older cohort with newly diagnosed type 2 diabetes, respectively, showed trends toward a reduction in ASCVD. The reductions in ASCVD reached statistical significance only after prolonged follow up, and when differences in HbA1c were no longer maintained (referred to by some as a "legacy effect"). More recent studies in those with established type 2 diabetes, in which glycemic control was improved by a variety of strategies, failed to demonstrate reductions in ASCVD. The gap in evidence supporting hyperglycemia as a true causative risk factor for ASCVD or simply a risk marker for some other confounding causative factor is discussed in this review. We conclude that hyperglycemia does appear to be at least partially causative of ASCVD (i.e., an ASCVD risk factor). We discuss how this evidence can be incorporated into an overall therapeutic strategy to prevent ASCVD in those with prediabetes and established diabetes.

12.
Artigo em Inglês | MEDLINE | ID: mdl-32231641

RESUMO

Type 2 diabetes (T2D) is associated with increased risk of cardiovascular disease (CVD). In insulin resistant states such as the metabolic syndrome, overproduction and impaired clearance of liver-derived very-low-density lipoproteins and gut-derived chylomicrons (CMs) contribute to hypertriglyceridemia and elevated atherogenic remnant lipoproteins. Although ingested fat is the major stimulus of CM secretion, intestinal lipid handling and ultimately CM secretory rate is determined by numerous additional regulatory inputs including nutrients, hormones and neural signals that fine tune CM secretion during fasted and fed states. Insulin resistance and T2D represent perturbed metabolic states in which intestinal sensitivity to key regulatory hormones such as insulin, leptin and glucagon-like peptide-1 (GLP-1) may be altered, contributing to increased CM secretion. In this review, we describe the evidence from human and animal models demonstrating increased CM secretion in insulin resistance and T2D and discuss the molecular mechanisms underlying these effects. Several novel compounds are in various stages of preclinical and clinical investigation to modulate intestinal CM synthesis and secretion. Their efficacy, safety and therapeutic utility are discussed. Similarly, the effects of currently approved lipid modulating therapies such as statins, ezetimibe, fibrates, and PCSK9 inhibitors on intestinal CM production are discussed. The intricacies of intestinal CM production are an active area of research that may yield novel therapies to prevent atherosclerotic CVD in insulin resistance and T2D.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Dislipidemias/etiologia , Intestinos/fisiologia , Animais , Aterosclerose/complicações , Aterosclerose/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Dislipidemias/metabolismo , Humanos , Resistência à Insulina/fisiologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/fisiologia
13.
Diabetes Obes Metab ; 21(11): 2535-2541, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31364232

RESUMO

AIM: To test the hypothesis that gut hormone glucagon-like peptide-2 (GLP-2) mobilizes intestinal triglyceride (TG) stores and stimulates chylomicron secretion by a nitric oxide (NO)-dependent mechanism in humans. METHODS: In a randomized, single-blind, cross-over study, 10 healthy male volunteers ingested a high-fat formula followed, 7 hours later, by one of three treatments: NO synthase inhibitor L-NG -monomethyl arginine acetate (L-NMMA) + GLP-2 analogue teduglutide, normal saline + teduglutide, or L-NMMA + placebo. TG in plasma and lipoprotein fractions were measured, along with measurement of blood flow in superior mesenteric and coeliac arteries using Doppler ultrasound in six participants. RESULTS: Teduglutide rapidly increased mesenteric blood flow and TG concentrations in plasma, in TG-rich lipoproteins, and most robustly in chylomicrons. L-NMMA significantly attenuated teduglutide-induced enhancement of mesenteric blood flow but not TG mobilization and chylomicron secretion. CONCLUSIONS: GLP-2 mobilization of TG stores and stimulation of chylomicron secretion from the small intestine appears to be independent of systemic NO in humans.


Assuntos
Peptídeo 2 Semelhante ao Glucagon/metabolismo , Mucosa Intestinal/metabolismo , Lipoproteínas/metabolismo , Óxido Nítrico/metabolismo , Triglicerídeos/metabolismo , Artéria Celíaca/diagnóstico por imagem , Quilomícrons/química , Quilomícrons/metabolismo , Humanos , Mucosa Intestinal/efeitos dos fármacos , Lipoproteínas/sangue , Masculino , Artéria Mesentérica Superior/diagnóstico por imagem , Pessoa de Meia-Idade , Peptídeos/farmacologia , Método Simples-Cego , Triglicerídeos/sangue , Ultrassonografia Doppler
14.
Arterioscler Thromb Vasc Biol ; 39(8): 1565-1573, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31294621

RESUMO

OBJECTIVE: Dietary triglycerides are partially retained in the intestine within intracellular or extracellular compartments, which can be rapidly mobilized in response to several stimuli, including glucose and GLP-2 (glucagon-like peptide-2). To elucidate the mechanism of intestinal lipid mobilization, this study examined the patterns and time course of lymph flow and triglycerides after glucose and GLP-2 treatment in rats. Approach and Results: Lymph flow, triglyceride concentration, and triglyceride output were assessed in mesenteric lymph duct-cannulated rats in response to an intraduodenal (i.d.) lipid bolus followed 5 hours later by either (1) i.d. saline+intraperitoneal (i.p.) saline (placebo), (2) i.d. glucose plus i.p. saline, (3) i.d. saline+i.p. GLP-2, or (4) i.d. glucose+i.p. GLP-2. GLP-2 and glucose administered alone or in combination stimulated total triglyceride output to a similar extent, but the timing and pattern of stimulation differed markedly. Whereas GLP-2 rapidly increased lymph flow with no effect on lymph triglyceride concentration or triglyceride:apoB48 (apolipoprotein B48) ratio (a surrogate marker of chylomicron size) compared with placebo, glucose transiently decreased lymph flow followed by delayed stimulation of lymph flow and increased lymph triglyceride concentration and triglyceride:apoB48 ratio. CONCLUSIONS: Glucose and GLP-2 robustly enhanced intestinal triglyceride output in rats but with different effects on lymph flow, lymph triglyceride concentration, and chylomicron size. GLP-2 stimulated triglyceride output primarily by enhancing lymph flow with no effect on chylomicron size, whereas glucose mobilized intestinal triglycerides, stimulating secretion of larger chylomicrons. This suggests that these 2 stimuli mobilize intestinal lipid by different mechanisms.


Assuntos
Peptídeo 2 Semelhante ao Glucagon/farmacologia , Glucose/farmacologia , Mucosa Intestinal/metabolismo , Triglicerídeos/metabolismo , Animais , Apolipoproteína B-48/análise , Quilomícrons/metabolismo , Linfa/efeitos dos fármacos , Linfa/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley
15.
Cell Mol Gastroenterol Hepatol ; 7(3): 487-501, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30819663

RESUMO

Rapid and efficient digestion and absorption of dietary triglycerides and other lipids by the intestine, the packaging of those lipids into lipoprotein chylomicron (CM) particles, and their secretion via the lymphatic duct into the blood circulation are essential in maintaining whole-body lipid and energy homeostasis. Biosynthesis and assembly of CMs in enterocytes is a complex multistep process that is subject to regulation by intracellular signaling pathways as well as by hormones, nutrients, and neural factors extrinsic to the enterocyte. Dysregulation of this process has implications for health and disease, contributing to dyslipidemia and a potentially increased risk of atherosclerotic cardiovascular disease. There is increasing recognition that, besides intracellular regulation of CM assembly and secretion, regulation of postassembly pathways also plays important roles in CM secretion. This review examines recent advances in our understanding of the regulation of CM secretion in relation to mobilization of intestinal lipid stores, drawing particular attention to post-assembly regulatory mechanisms, including intracellular trafficking of triglycerides in enterocytes, CM mobilization from the lamina propria, and regulated transport of CM by intestinal lymphatics.


Assuntos
Quilomícrons/metabolismo , Animais , Transporte Biológico , Quilomícrons/biossíntese , Gorduras na Dieta/metabolismo , Humanos , Metabolismo dos Lipídeos , Linfa/metabolismo , Mucosa/metabolismo
16.
Cell Mol Gastroenterol Hepatol ; 7(2): 313-337, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30704982

RESUMO

BACKGROUND & AIMS: The small intestine regulates plasma triglyceride (TG) concentration. Within enterocytes, dietary TGs are packaged into chylomicrons (CMs) for secretion or stored temporarily in cytoplasmic lipid droplets (CLDs) until further mobilization. We and others have shown that oral and intravenous glucose enhances CM particle secretion in human beings, however, the mechanisms through which this occurs are incompletely understood. METHODS: Two separate cohorts of participants ingested a high-fat liquid meal and, 5 hours later, were assigned randomly to ingest either a glucose solution or an equivalent volume of water. In 1 group (N = 6), plasma and lipoprotein TG responses were assessed in a randomized cross-over study. In a separate group (N = 24), duodenal biopsy specimens were obtained 1 hour after ingestion of glucose or water. Ultrastructural and proteomic analyses were performed on duodenal biopsy specimens. RESULTS: Compared with water, glucose ingestion increased circulating TGs within 30 minutes, mainly in the CM fraction. It decreased the total number of CLDs and the proportion of large-sized CLDs within enterocytes. We identified 2919 proteins in human duodenal tissue, 270 of which are related to lipid metabolism and 134 of which were differentially present in response to glucose compared with water ingestion. CONCLUSIONS: Oral glucose mobilizes TGs stored within enterocyte CLDs to provide substrate for CM synthesis and secretion. Future studies elucidating the underlying signaling pathways may provide mechanistic insights that lead to the development of novel therapeutics for the treatment of hypertriglyceridemia.


Assuntos
Glucose/administração & dosagem , Intestinos/química , Triglicerídeos/metabolismo , Administração Oral , Adulto , Biópsia , Quilomícrons/metabolismo , Dieta Hiperlipídica , Duodeno/patologia , Enterócitos/metabolismo , Enterócitos/ultraestrutura , Jejum , Feminino , Ontologia Genética , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/ultraestrutura , Metabolismo dos Lipídeos/genética , Lipoproteínas VLDL/metabolismo , Masculino , Pessoa de Meia-Idade , Triglicerídeos/sangue
17.
Front Physiol ; 10: 1604, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-32063861

RESUMO

Intestinal handling of dietary triglycerides has important implications for health and disease. Following digestion in the intestinal lumen, absorption, and re-esterification of fatty acids and monoacylglycerols in intestinal enterocytes, triglycerides are packaged into lipoprotein particles (chylomicrons) for secretion or into cytoplasmic lipid droplets for transient or more prolonged storage. Despite the recognition of prolonged retention of triglycerides in the post-absorptive phase and subsequent release from the intestine in chylomicron particles, the underlying regulatory mechanisms remain poorly understood. Chylomicron secretion involves multiple steps, including intracellular assembly and post-assembly transport through cellular organelles, the lamina propria, and the mesenteric lymphatics before being released into the circulation. Contrary to the long-held view that the intestinal lymphatic vasculature acts mainly as a passive conduit, it is increasingly recognized to play an active and regulatory role in the rate of chylomicron release into the circulation. Here, we review the latest advances in understanding the role of lymphatics in intestinal lipid handling and chylomicron secretion. We highlight emerging evidence that oral glucose and the gut hormone glucagon-like peptide-2 mobilize retained enteral lipid by differing mechanisms to promote the secretion of chylomicrons via glucose possibly by mobilizing cytoplasmic lipid droplets and via glucagon-like peptide-2 possibly by targeting post-enterocyte secretory mechanisms. We discuss other potential regulatory factors that are the focus of ongoing and future research. Regulation of lymphatic pumping and function is emerging as an area of great interest in our understanding of the integrated absorption of dietary fat and chylomicron secretion and potential implications for whole-body metabolic health.

18.
Diabetes Obes Metab ; 20(7): 1751-1754, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29536605

RESUMO

The effects of intranasal insulin on the regulation of endogenous glucose production (EGP) in individuals with insulin resistance were assessed in a single-blind, crossover study. Overweight or obese insulin-resistant men (n = 7; body mass index 35.4 ± 4.4 kg/m2 , homeostatic model assessment of insulin resistance 5.6 ± 1.6) received intranasal spray of either 40 IU insulin lispro or placebo in 2 randomized visits. Acute systemic spillover of intranasal insulin into the circulation was matched with a 30-minute intravenous infusion of insulin lispro in the nasal placebo arm. EGP was assessed under conditions of a pancreatic clamp with a primed, constant infusion of glucose tracer. Under these experimental conditions, compared with placebo, intranasal administration of insulin did not significantly affect plasma glucose concentrations, EGP or glucose disposal in overweight/obese, insulin-resistant men, in contrast to our previous study, in which an equivalent dose of intranasal insulin significantly suppressed EGP in lean, insulin-sensitive men. Insulin resistance is probably associated with impairment in centrally mediated insulin suppression of EGP.


Assuntos
Glicemia/metabolismo , Hipoglicemiantes/administração & dosagem , Insulina Lispro/administração & dosagem , Resistência à Insulina , Obesidade/metabolismo , Administração Intranasal , Adulto , Estudos Cross-Over , Gluconeogênese , Técnica Clamp de Glucose , Humanos , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Sobrepeso/metabolismo , Método Simples-Cego
19.
Can J Cardiol ; 34(5): 595-604, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29459241

RESUMO

Despite the effectiveness of low-density lipoprotein (LDL)-lowering strategies for the treatment of diabetic dyslipidemia, significant residual risk of atherosclerotic cardiovascular disease remains. Residual risk might in part be explained by lipid abnormalities that go beyond LDL cholesterol elevation, collectively termed the "atherogenic dyslipidemia complex (ADC)," consisting of hypertriglyceridemia, elevated small dense LDL particles, reduced high-density lipoprotein cholesterol, and high-density lipoprotein particle numbers, increased remnant lipoproteins, and postprandial hyperlipidemia. In this review, we briefly discuss the pathophysiology of the typical dyslipidemia that occurs in insulin-resistant states including obesity, the metabolic syndrome, and type 2 diabetes. Lipid-modifying strategies including lifestyle modification, ezetimibe, statins, fibrates, niacin, and cholesteryl ester transfer protein inhibitors in treating ADC are discussed. With the advent of novel therapies involving antisense oligonucleotides and monoclonal antibodies, new targets can be specifically downregulated to potentially promote lipoprotein clearance or suppress production. We review novel approaches currently undergoing clinical testing and we speculate on their suitability for use in treating ADC for the prevention of atherosclerotic cardiovascular disease. In addition, future targets that might be considered for therapeutic development are discussed.


Assuntos
Aterosclerose/metabolismo , Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Dislipidemias , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/terapia , Desenvolvimento de Medicamentos , Dislipidemias/metabolismo , Dislipidemias/fisiopatologia , Dislipidemias/terapia , Humanos , Resistência à Insulina , Administração dos Cuidados ao Paciente/métodos
20.
Trends Endocrinol Metab ; 29(3): 151-163, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29306629

RESUMO

Dietary lipid absorption and lipoprotein secretion by the gut are important in maintaining whole-body energy homeostasis and have significant implications for health and disease. The processing of dietary lipids, including storage within and subsequent mobilization and transport from enterocyte cytoplasmic lipid droplets or other intestinal lipid storage pools (including the secretary pathway, lamina propria and lymphatics) and secretion of chylomicrons, involves coordinated steps that are subject to various controls. This review summarizes recent advances in our understanding of the mechanisms that underlie lipid storage and mobilization by small intestinal enterocytes and the intestinal lymphatic vasculature. Therapeutic targeting of lipid processing by the gut may provide opportunities for the treatment and prevention of dyslipidemia, and for improving health status.


Assuntos
Mucosa Intestinal/metabolismo , Intestino Delgado/metabolismo , Metabolismo dos Lipídeos/fisiologia , Triglicerídeos/metabolismo , Animais , Gorduras na Dieta/metabolismo , Enterócitos/metabolismo , Humanos , Absorção Intestinal/fisiologia
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