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1.
Annu Rev Physiol ; 85: 317-337, 2023 02 10.
Artículo en Inglés | MEDLINE | ID: mdl-36347219

RESUMEN

Long-chain fatty acids (FAs) are components of plasma membranes and an efficient fuel source and also serve as metabolic regulators through FA signaling mediated by membrane FA receptors. Impaired tissue FA uptake has been linked to major complications of obesity, including insulin resistance, cardiovascular disease, and type 2 diabetes. Fatty acid interactions with a membrane receptor and the initiation of signaling can modify pathways related to nutrient uptake and processing, cell proliferation or differentiation, and secretion of bioactive factors. Here, we review the major membrane receptors involved in FA uptake and FA signaling. We focus on two types of membrane receptors for long-chain FAs: CD36 and the G protein-coupled FA receptors FFAR1 and FFAR4. We describe key signaling pathways and metabolic outcomes for CD36, FFAR1, and FFAR4 and highlight the parallels that provide insight into FA regulation of cell function.


Asunto(s)
Diabetes Mellitus Tipo 2 , Humanos , Transducción de Señal/fisiología , Receptores Acoplados a Proteínas G/metabolismo , Ácidos Grasos/metabolismo , Membrana Celular/metabolismo , Antígenos CD36/metabolismo
2.
Circ Res ; 128(3): 433-450, 2021 02 05.
Artículo en Inglés | MEDLINE | ID: mdl-33539224

RESUMEN

Lipid uptake and metabolism are central to the function of organs such as heart, skeletal muscle, and adipose tissue. Although most heart energy derives from fatty acids (FAs), excess lipid accumulation can cause cardiomyopathy. Similarly, high delivery of cholesterol can initiate coronary artery atherosclerosis. Hearts and arteries-unlike liver and adrenals-have nonfenestrated capillaries and lipid accumulation in both health and disease requires lipid movement from the circulation across the endothelial barrier. This review summarizes recent in vitro and in vivo findings on the importance of endothelial cell receptors and uptake pathways in regulating FAs and cholesterol uptake in normal physiology and cardiovascular disease. We highlight clinical and experimental data on the roles of ECs in lipid supply to tissues, heart, and arterial wall in particular, and how this affects organ metabolism and function. Models of FA uptake into ECs suggest that receptor-mediated uptake predominates at low FA concentrations, such as during fasting, whereas FA uptake during lipolysis of chylomicrons may involve paracellular movement. Similarly, in the setting of an intact arterial endothelial layer, recent and historic data support a role for receptor-mediated processes in the movement of lipoproteins into the subarterial space. We conclude with thoughts on the need to better understand endothelial lipid transfer for fuller comprehension of the pathophysiology of hyperlipidemia, and lipotoxic diseases such as some forms of cardiomyopathy and atherosclerosis.


Asunto(s)
Colesterol/metabolismo , Células Endoteliales/metabolismo , Proteínas de Transporte de Ácidos Grasos/metabolismo , Ácidos Grasos/metabolismo , Trastornos del Metabolismo de los Lípidos/metabolismo , Transcitosis , Animales , Antígenos CD36/metabolismo , Quilomicrones/metabolismo , Humanos , Trastornos del Metabolismo de los Lípidos/patología , Lipólisis , Tamaño de la Partícula
3.
Gastroenterology ; 161(3): 968-981.e12, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34004161

RESUMEN

BACKGROUND AND AIMS: Insulin resistance is a key factor in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). We evaluated the importance of subcutaneous abdominal adipose tissue (SAAT) inflammation and both plasma and SAAT-derived exosomes in regulating insulin sensitivity in people with obesity and NAFLD. METHODS: Adipose tissue inflammation (macrophage and T-cell content and expression of proinflammatory cytokines), liver and whole-body insulin sensitivity (assessed using a hyperinsulinemic-euglycemic clamp and glucose tracer infusion), and 24-hour serial plasma cytokine concentrations were evaluated in 3 groups stratified by adiposity and intrahepatic triglyceride (IHTG) content: (1) lean with normal IHTG content (LEAN; N = 14); (2) obese with normal IHTG content (OB-NL; N = 28); and (3) obese with NAFLD (OB-NAFLD; N = 28). The effect of plasma and SAAT-derived exosomes on insulin-stimulated Akt phosphorylation in human skeletal muscle myotubes and mouse primary hepatocytes was assessed in a subset of participants. RESULTS: Proinflammatory macrophages, proinflammatory CD4 and CD8 T-cell populations, and gene expression of several cytokines in SAAT were greater in the OB-NAFLD than the OB-NL and LEAN groups. However, with the exception of PAI-1, which was greater in the OB-NAFLD than the LEAN and OB-NL groups, 24-hour plasma cytokine concentration areas-under-the-curve were not different between groups. The percentage of proinflammatory macrophages and plasma PAI-1 concentration areas-under-the-curve were inversely correlated with both hepatic and whole-body insulin sensitivity. Compared with exosomes from OB-NL participants, plasma and SAAT-derived exosomes from the OB-NAFLD group decreased insulin signaling in myotubes and hepatocytes. CONCLUSIONS: Systemic insulin resistance in people with obesity and NAFLD is associated with increased plasma PAI-1 concentrations and both plasma and SAAT-derived exosomes. ClinicalTrials.gov number: NCT02706262 (https://clinicaltrials.gov/ct2/show/NCT02706262).


Asunto(s)
Citocinas/sangre , Exosomas/metabolismo , Resistencia a la Insulina , Macrófagos/metabolismo , Células T de Memoria/metabolismo , Enfermedad del Hígado Graso no Alcohólico/sangre , Obesidad/sangre , Inhibidor 1 de Activador Plasminogénico/sangre , Grasa Subcutánea Abdominal/metabolismo , Adulto , Animales , Biomarcadores/sangre , Glucemia/metabolismo , Células Cultivadas , Exosomas/inmunología , Femenino , Hepatocitos/metabolismo , Humanos , Insulina/sangre , Hígado/metabolismo , Macrófagos/inmunología , Masculino , Células T de Memoria/inmunología , Ratones , Ratones Endogámicos C57BL , Fibras Musculares Esqueléticas/metabolismo , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/inmunología , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Obesidad/diagnóstico , Obesidad/inmunología , Obesidad/fisiopatología , Grasa Subcutánea Abdominal/inmunología , Técnicas de Cultivo de Tejidos
4.
Annu Rev Nutr ; 34: 281-303, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24850384

RESUMEN

CD36 (cluster of differentiation 36) is a scavenger receptor that functions in high-affinity tissue uptake of long-chain fatty acids (FAs) and contributes under excessive fat supply to lipid accumulation and metabolic dysfunction. This review describes recent evidence regarding the CD36 FA binding site and a potential mechanism for FA transfer. It also presents the view that CD36 and FA signaling coordinate fat utilization, a view that is based on newly identified CD36 actions that involve oral fat perception, intestinal fat absorption, secretion of the peptides cholecystokinin and secretin, regulation of hepatic lipoprotein output, activation of beta oxidation by muscle, and regulation of the production of the FA-derived bioactive eicosanoids. Thus abnormalities of fat metabolism and the associated pathology might involve dysfunction of CD36-mediated signal transduction in addition to the changes in FA uptake.


Asunto(s)
Antígenos CD36/metabolismo , Quilomicrones/metabolismo , Grasas de la Dieta/metabolismo , Ácidos Grasos no Esterificados/metabolismo , Lipoproteínas VLDL/metabolismo , Modelos Biológicos , Transducción de Señal , Animales , Sitios de Unión , Transporte Biológico , Antígenos CD36/sangre , Antígenos CD36/química , Quilomicrones/sangre , Ácidos Grasos no Esterificados/sangre , Humanos , Lipoproteínas VLDL/sangre , Conformación Proteica
6.
Diabetes ; 2024 Sep 12.
Artículo en Inglés | MEDLINE | ID: mdl-39264820

RESUMEN

Muscle sn-1,2-diacylglycerol (DAG) and C18:0 ceramide accumulation in sarcolemmal and mitochondrial compartments have been proposed to regulate muscle insulin sensitivity. Here, we evaluated whether weight loss-induced improvements in insulin sensitivity were associated with changes in muscle sn-1,2-DAG and ceramide content in people with obesity and type 2 diabetes. We measured skeletal muscle insulin sensitivity, assessed by using the hyperinsulinemic-euglycemic clamp procedure in conjunction with stable isotopically labeled glucose tracer infusion, and skeletal muscle sn-1,2-DAG and ceramide contents by using liquid chromatography-tandem mass spectrometry after subcellular fractionation and DAG isomer separation in 14 adults with obesity and type 2 diabetes before and after marked (18.6 ± 2.1%) weight loss. Whole-body insulin sensitivity doubled after weight loss. Sarcolemmal sn-1,2-DAG and C18:0 ceramide contents after weight loss were not different than values before weight loss. In contrast, mitochondrial/ER C18:0 ceramide content decreased by ∼20% after weight loss (from 2.16 ± 0.08 to 1.71 ± 0.13 nmol/g, P<0.005). These results suggest a decrease in muscle mitochondrial/ER C18:0 ceramide content could contribute to the beneficial effect of weight loss on skeletal muscle insulin sensitivity.

7.
medRxiv ; 2024 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-38405702

RESUMEN

Dysfunction of endothelial insulin delivery to muscle associates with insulin resistance. CD36, a fatty acid transporter and modulator of insulin signaling is abundant in endothelial cells, especially in capillaries. Humans with inherited 50% reduction in CD36 expression have endothelial dysfunction but whether it is associated with insulin resistance is unclear. Using hyperinsulinemic/euglycemic clamps in Cd36-/- and wildtype mice, and in 50% CD36 deficient humans and matched controls we found that Cd36-/- mice have enhanced systemic glucose disposal despite unaltered transendothelial insulin transfer and reductions in microvascular perfusion and blood vessel compliance. Partially CD36 deficient humans also have better glucose disposal than controls with no capillary recruitment by insulin. CD36 knockdown in primary human-derived microvascular cells impairs insulin action on AKT, endothelial nitric oxide synthase, and nitric oxide release. Thus, insulin resistance of microvascular function in CD36 deficiency paradoxically associates with increased glucose utilization, likely through a remodeling of muscle gene expression.

8.
Biochem Biophys Res Commun ; 434(2): 388-93, 2013 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-23578663

RESUMEN

Expression of the hominoid-specific oncoprotein TBC1D3 promotes enhanced cell growth and proliferation by increased activation of signal transduction through several growth factors. Recently we documented the role of CUL7 E3 ligase in growth factors-induced ubiquitination and degradation of TBC1D3. Here we expanded our study to discover additional molecular mechanisms that control TBC1D3 protein turnover. We report that TBC1D3 is palmitoylated on two cysteine residues: 318 and 325. The expression of double palmitoylation mutant TBC1D3:C318/325S resulted in protein mislocalization and enhanced growth factors-induced TBC1D3 degradation. Moreover, ubiquitination of TBC1D3 via CUL7 E3 ligase complex was increased by mutating the palmitoylation sites, suggesting that depalmitoylation of TBC1D3 makes the protein more available for ubiquitination and degradation. The results reported here provide novel insights into the molecular mechanisms that govern TBC1D3 protein degradation. Dysregulation of these mechanisms in vivo could potentially result in aberrant TBC1D3 expression and promote oncogenesis.


Asunto(s)
Proteínas Activadoras de GTPasa/metabolismo , Regulación Neoplásica de la Expresión Génica , Lipoilación , Proteolisis , Proteínas Proto-Oncogénicas/metabolismo , Ubiquitinación , Membrana Celular/metabolismo , Proteínas Cullin/genética , Proteínas Cullin/metabolismo , Cisteína/metabolismo , Citosol/metabolismo , Electroforesis en Gel de Poliacrilamida , Proteínas Activadoras de GTPasa/genética , Células HeLa , Humanos , Microscopía Fluorescente , Complejos Multiproteicos/metabolismo , Unión Proteica , Transporte de Proteínas , Proteínas Proto-Oncogénicas/genética , Transfección
9.
FASEB J ; 26(11): 4733-42, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22815385

RESUMEN

CD36 has been linked to the etiology of insulin resistance and inflammation. We explored its function in regulating adipose tissue lipolysis, which influences fat accumulation by liver and muscle and overall metabolism. Knockdown of CD36 in differentiated 3T3-L1 adipocytes decreased lipolysis in response to 10 µM of the ß-adrenergic agonist isoproterenol (by 42%), 10 µM of the adenyl cyclase activator forskolin (by 32%), and 500 µM of the phosphodiesterase (PDE) inhibitor isobutylmethylxanthine (by 33%). All three treatments in the knockdown adipocytes were associated with significant decreases of cAMP levels and of the hormone-sensitive lipase (HSL) and perilipin phosphorylation. An important role for PDE was supported by the lack of inhibition of the lipolysis induced by the poorly hydrolyzable dibutyryl cAMP analog. An additional contributory mechanism was diminished activation of the Src-ERK1/2 pathway. Regulation of lipolysis and lipolytic signaling by CD36 was reproduced with adipose tissue from CD36(-/-) mice. The importance of surface CD36 in this regulation was suggested by the finding that the plasma membrane-impermeable CD36 inhibitor sulfo-N-succinimidyl oleate (20 µM) decreased lipolysis. Interestingly, isoproterenol induced CD36 internalization, and this process was blocked by HSL inhibition, suggesting feedback regulation of adipocyte lipolysis via CD36 trafficking.


Asunto(s)
Adipocitos/metabolismo , Antígenos CD36/metabolismo , Lipólisis/fisiología , Células 3T3-L1 , Adipocitos/efectos de los fármacos , Animales , AMP Cíclico/genética , AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/genética , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Ácidos Grasos no Esterificados/metabolismo , Regulación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Glicerol/metabolismo , Isoproterenol/farmacología , Ratones , Hidrolasas Diéster Fosfóricas/genética , Hidrolasas Diéster Fosfóricas/metabolismo , Transporte de Proteínas/fisiología , ARN Interferente Pequeño , Transducción de Señal
10.
J Lipid Res ; 53(4): 709-17, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22315395

RESUMEN

The FA translocase cluster of differentiation 36 (CD36) facilitates FA uptake by the myocardium, and its surface recruitment in cardiomyocytes is induced by insulin, AMP-dependent protein kinase (AMPK), or contraction. Dysfunction of CD36 trafficking contributes to disordered cardiac FA utilization and promotes progression to disease. The Akt substrate 160 (AS160) Rab GTPase-activating protein (GAP) is a key regulator of vesicular trafficking, and its activity is modulated via phosphorylation. Our study documents that AS160 mediates insulin or AMPK-stimulated surface translocation of CD36 in cardiomyocytes. Knock-down of AS160 redistributes CD36 to the surface and abrogates its translocation by insulin or the AMPK agonist 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR). Conversely, overexpression of a phosphorylation-deficient AS160 mutant (AS160 4P) suppresses the stimulated membrane recruitment of CD36. The AS160 substrate Rab8a GTPase is shown via overexpression and knock-down studies to be specifically involved in insulin/AICAR-induced CD36 membrane recruitment. Our findings directly demonstrate AS160 regulation of CD36 trafficking. In myocytes, the AS160 pathway also mediates the effect of insulin, AMPK, or contraction on surface recruitment of the glucose transporter GLUT4. Thus, AS160 constitutes a point of convergence for coordinating physiological regulation of CD36 and GLUT4 membrane recruitment.


Asunto(s)
Antígenos CD36/metabolismo , Proteínas Activadoras de GTPasa/metabolismo , Insulina/farmacología , Miocitos Cardíacos/efectos de los fármacos , Proteínas de Unión al GTP rab/metabolismo , Adenilato Quinasa/metabolismo , Animales , Antígenos CD36/genética , Línea Celular Tumoral , Membrana Celular/enzimología , Membrana Celular/metabolismo , Activación Enzimática , Proteínas Activadoras de GTPasa/genética , Humanos , Sistema de Señalización de MAP Quinasas , Ratones , Miocitos Cardíacos/metabolismo , Transporte de Proteínas , Interferencia de ARN , Transfección , Proteínas de Unión al GTP rab/genética
11.
J Biol Chem ; 285(10): 6879-90, 2010 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-20037159

RESUMEN

The role played by long chain fatty acids (LCFA) in promoting energy expenditure is confounded by their dual function as substrates for oxidation and as putative classic uncouplers of mitochondrial oxidative phosphorylation. LCFA analogs of the MEDICA (MEthyl-substituted DICarboxylic Acids) series are neither esterified into lipids nor beta-oxidized and may thus simulate the uncoupling activity of natural LCFA in vivo, independently of their substrate role. Treatment of rats or cell lines with MEDICA analogs results in low conductance gating of the mitochondrial permeability transition pore (PTP), with 10-40% decrease in the inner mitochondrial membrane potential. PTP gating by MEDICA analogs is accounted for by inhibition of Raf1 expression and kinase activity, resulting in suppression of the MAPK/RSK1 and the adenylate cyclase/PKA transduction pathways. Suppression of RSK1 and PKA results in a decrease in phosphorylation of their respective downstream targets, Bad(Ser-112) and Bad(Ser-155). Decrease in Bad(Ser-112, Ser-155) phosphorylation results in increased binding of Bad to mitochondrial Bcl2 with concomitant displacement of Bax, followed by PTP gating induced by free mitochondrial Bax. Low conductance PTP gating by LCFA/MEDICA may account for their thyromimetic calorigenic activity in vivo.


Asunto(s)
Ácidos Grasos , Activación del Canal Iónico/fisiología , Mitocondrias Hepáticas/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Animales , Línea Celular , Ácidos Grasos/química , Ácidos Grasos/metabolismo , Humanos , Masculino , Mitocondrias Hepáticas/ultraestructura , Poro de Transición de la Permeabilidad Mitocondrial , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-raf/genética , Proteínas Proto-Oncogénicas c-raf/metabolismo , Ratas , Proteína Letal Asociada a bcl/genética , Proteína Letal Asociada a bcl/metabolismo
12.
Atherosclerosis ; 329: 1-8, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-34130222

RESUMEN

Lipids released from circulating lipoproteins by intravascular action of lipoprotein lipase (LpL) reach parenchymal cells in tissues with a non-fenestrated endothelium by transfer through or around endothelial cells. The actions of LpL are controlled at multiple sites, its synthesis and release by myocytes and adipocytes, its transit and association with the endothelial cell luminal surface, and finally its activation and inhibition by a number of proteins and by its product non-esterified fatty acids. Multiple pathways mediate endothelial transit of lipids into muscle and adipose tissues. These include movement of fatty acids via the endothelial cell fatty acid transporter CD36 and movement of whole or partially LpL-hydrolyzed lipoproteins via other apical endothelial cell receptors such as SR-B1and Alk1. Lipids also likely change the barrier function of the endothelium and operation of the paracellular pathway around endothelial cells. This review summarizes in vitro and in vivo support for the key role of endothelial cells in delivery of lipids and highlights incompletely understood processes that are the focus of active investigation.


Asunto(s)
Células Endoteliales , Ácidos Grasos no Esterificados , Endotelio , Ácidos Grasos , Humanos , Lipoproteína Lipasa , Lipoproteínas , Triglicéridos
13.
Cell Metab ; 33(9): 1853-1868.e11, 2021 09 07.
Artículo en Inglés | MEDLINE | ID: mdl-34418352

RESUMEN

Adipocytes undergo intense energetic stress in obesity resulting in loss of mitochondrial mass and function. We have found that adipocytes respond to mitochondrial stress by rapidly and robustly releasing small extracellular vesicles (sEVs). These sEVs contain respiration-competent, but oxidatively damaged mitochondrial particles, which enter circulation and are taken up by cardiomyocytes, where they trigger a burst of ROS. The result is compensatory antioxidant signaling in the heart that protects cardiomyocytes from acute oxidative stress, consistent with a preconditioning paradigm. As such, a single injection of sEVs from energetically stressed adipocytes limits cardiac ischemia/reperfusion injury in mice. This study provides the first description of functional mitochondrial transfer between tissues and the first vertebrate example of "inter-organ mitohormesis." Thus, these seemingly toxic adipocyte sEVs may provide a physiological avenue of potent cardio-protection against the inevitable lipotoxic or ischemic stresses elicited by obesity.


Asunto(s)
Adipocitos , Vesículas Extracelulares , Adipocitos/metabolismo , Animales , Vesículas Extracelulares/metabolismo , Ratones , Mitocondrias/metabolismo , Mitocondrias Cardíacas , Miocitos Cardíacos/metabolismo , Estrés Oxidativo
14.
Commun Biol ; 4(1): 1247, 2021 11 02.
Artículo en Inglés | MEDLINE | ID: mdl-34728772

RESUMEN

The gastric epithelium is often exposed to injurious elements and failure of appropriate healing predisposes to ulcers, hemorrhage, and ultimately cancer. We examined the gastric function of CD36, a protein linked to disease and homeostasis. We used the tamoxifen model of gastric injury in mice null for Cd36 (Cd36-/-), with Cd36 deletion in parietal cells (PC-Cd36-/-) or in endothelial cells (EC-Cd36-/-). CD36 expresses on corpus ECs, on PC basolateral membranes, and in gastrin and ghrelin cells. Stomachs of Cd36-/- mice have altered gland organization and secretion, more fibronectin, and inflammation. Tissue respiration and mitochondrial efficiency are reduced. Phospholipids increased and triglycerides decreased. Mucosal repair after injury is impaired in Cd36-/- and EC-Cd36-/-, not in PC-Cd36-/- mice, and is due to defect of progenitor differentiation to PCs, not of progenitor proliferation or mature PC dysfunction. Relevance to humans is explored in the Vanderbilt BioVu using PrediXcan that links genetically-determined gene expression to clinical phenotypes, which associates low CD36 mRNA with gastritis, gastric ulcer, and gastro-intestinal hemorrhage. A CD36 variant predicted to disrupt an enhancer site associates (p < 10-17) to death from gastro-intestinal hemorrhage in the UK Biobank. The findings support role of CD36 in gastric tissue repair, and its deletion associated with chronic diseases that can predispose to malignancy.


Asunto(s)
Antígenos CD36/genética , Mucosa Gástrica/metabolismo , Gastritis/genética , Hemorragia Gastrointestinal/genética , Úlcera Gástrica/genética , Animales , Antígenos CD36/metabolismo , Células Endoteliales/metabolismo , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL
15.
Diabetes ; 67(7): 1272-1284, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29748289

RESUMEN

During reduced energy intake, skeletal muscle maintains homeostasis by rapidly suppressing insulin-stimulated glucose utilization. Loss of this adaptation is observed with deficiency of the fatty acid transporter CD36. A similar loss is also characteristic of the insulin-resistant state where CD36 is dysfunctional. To elucidate what links CD36 to muscle glucose utilization, we examined whether CD36 signaling might influence insulin action. First, we show that CD36 deletion specific to skeletal muscle reduces expression of insulin signaling and glucose metabolism genes. It decreases muscle ceramides but impairs glucose disposal during a meal. Second, depletion of CD36 suppresses insulin signaling in primary-derived human myotubes, and the mechanism is shown to involve functional CD36 interaction with the insulin receptor (IR). CD36 promotes tyrosine phosphorylation of IR by the Fyn kinase and enhances IR recruitment of P85 and downstream signaling. Third, pretreatment for 15 min with saturated fatty acids suppresses CD36-Fyn enhancement of IR phosphorylation, whereas unsaturated fatty acids are neutral or stimulatory. These findings define mechanisms important for muscle glucose metabolism and optimal insulin responsiveness. Potential human relevance is suggested by genome-wide analysis and RNA sequencing data that associate genetically determined low muscle CD36 expression to incidence of type 2 diabetes.


Asunto(s)
Antígenos CD36/fisiología , Glucosa/metabolismo , Insulina/metabolismo , Músculo Esquelético/metabolismo , Receptor de Insulina/metabolismo , Animales , Antígenos CD36/genética , Células CHO , Metabolismo de los Hidratos de Carbono/genética , Células Cultivadas , Cricetinae , Cricetulus , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/genética , Femenino , Humanos , Resistencia a la Insulina/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Transducción de Señal/genética
16.
J Clin Invest ; 128(10): 4329-4342, 2018 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-30047927

RESUMEN

Movement of circulating fatty acids (FAs) to parenchymal cells requires their transfer across the endothelial cell (EC) barrier. The multiligand receptor cluster of differentiation 36 (CD36) facilitates tissue FA uptake and is expressed in ECs and parenchymal cells such as myocytes and adipocytes. Whether tissue uptake of FAs is dependent on EC or parenchymal cell CD36, or both, is unknown. Using a cell-specific deletion approach, we show that EC, but not parenchymal cell, CD36 deletion increased fasting plasma FAs and postprandial triglycerides. EC-Cd36-KO mice had reduced uptake of radiolabeled long-chain FAs into heart, skeletal muscle, and brown adipose tissue; these uptake studies were replicated using [11C]palmitate PET scans. High-fat diet-fed EC-CD36-deficient mice had improved glucose tolerance and insulin sensitivity. Both EC and cardiomyocyte (CM) deletion of CD36 reduced heart lipid droplet accumulation after fasting, but CM deletion did not affect heart glucose or FA uptake. Expression in the heart of several genes modulating glucose metabolism and insulin action increased with EC-CD36 deletion but decreased with CM deletion. In conclusion, EC CD36 acts as a gatekeeper for parenchymal cell FA uptake, with important downstream effects on glucose utilization and insulin action.


Asunto(s)
Antígenos CD36/metabolismo , Células Endoteliales/metabolismo , Ácidos Grasos/metabolismo , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Animales , Transporte Biológico Activo/genética , Antígenos CD36/genética , Células Endoteliales/patología , Ácidos Grasos/genética , Glucosa/genética , Glucosa/metabolismo , Humanos , Resistencia a la Insulina , Ratones , Ratones Noqueados , Miocardio/patología , Miocitos Cardíacos/patología , Especificidad de Órganos
17.
J Clin Invest ; 125(2): 787-95, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25555214

RESUMEN

BACKGROUND. Obesity is associated with insulin resistance and increased intrahepatic triglyceride (IHTG) content, both of which are key risk factors for diabetes and cardiovascular disease. However, a subset of obese people does not develop these metabolic complications. Here, we tested the hypothesis that people defined by IHTG content and insulin sensitivity as "metabolically normal obese" (MNO), but not those defined as "metabolically abnormal obese" (MAO), are protected from the adverse metabolic effects of weight gain. METHODS. Body composition, multiorgan insulin sensitivity, VLDL apolipoprotein B100 (apoB100) kinetics, and global transcriptional profile in adipose tissue were evaluated before and after moderate (~6%) weight gain in MNO (n = 12) and MAO (n = 8) subjects with a mean BMI of 36 ± 4 kg/m2 who were matched for BMI and fat mass. RESULTS. Although the increase in body weight and fat mass was the same in both groups, hepatic, skeletal muscle, and adipose tissue insulin sensitivity deteriorated, and VLDL apoB100 concentrations and secretion rates increased in MAO, but not MNO, subjects. Moreover, biological pathways and genes associated with adipose tissue lipogenesis increased in MNO, but not MAO, subjects. CONCLUSIONS. These data demonstrate that MNO people are resistant, whereas MAO people are predisposed, to the adverse metabolic effects of moderate weight gain and that increased adipose tissue capacity for lipogenesis might help protect MNO people from weight gain-induced metabolic dysfunction. TRIAL REGISTRATION. ClinicalTrials.gov NCT01184170. FUNDING. This work was supported by NIH grants UL1 RR024992 (Clinical Translational Science Award), DK 56341 (Nutrition and Obesity Research Center), DK 37948 and DK 20579 (Diabetes Center Grant), and UL1 TR000450 (KL2 Award); a Central Society for Clinical and Translational Research Early Career Development Award; and by grants from the Longer Life Foundation and the Kilo Foundation.


Asunto(s)
Tejido Adiposo , Adiposidad , Índice de Masa Corporal , Resistencia a la Insulina , Lipogénesis , Obesidad , Tejido Adiposo/metabolismo , Tejido Adiposo/fisiopatología , Adulto , Apolipoproteína B-100/sangre , Femenino , Humanos , Lipoproteínas VLDL/sangre , Masculino , Persona de Mediana Edad , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatología , Obesidad/sangre , Obesidad/fisiopatología
18.
Diabetes ; 64(2): 353-9, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25157091

RESUMEN

Increases in muscle energy needs activate AMPK and induce sarcolemmal recruitment of the fatty acid (FA) translocase CD36. The resulting rises in FA uptake and FA oxidation are tightly correlated, suggesting coordinated regulation. We explored the possibility that membrane CD36 signaling might influence AMPK activation. We show, using several cell types, including myocytes, that CD36 expression suppresses AMPK, keeping it quiescent, while it mediates AMPK activation by FA. These dual effects reflect the presence of CD36 in a protein complex with the AMPK kinase LKB1 (liver kinase B1) and the src kinase Fyn. This complex promotes Fyn phosphorylation of LKB1 and its nuclear sequestration, hindering LKB1 activation of AMPK. FA interaction with CD36 dissociates Fyn from the protein complex, allowing LKB1 to remain cytosolic and activate AMPK. Consistent with this, CD36(-/-) mice have constitutively active muscle and heart AMPK and enhanced FA oxidation of endogenous triglyceride stores. The molecular mechanism described, whereby CD36 suppresses AMPK, with FA binding to CD36 releasing this suppression, couples AMPK activation to FA availability and would be important for the maintenance of cellular FA homeostasis. Its dysfunction might contribute to the reported association of CD36 variants with metabolic complications of obesity in humans.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Antígenos CD36/metabolismo , Ácidos Grasos/metabolismo , Proteínas Quinasas Activadas por AMP/genética , Animales , Línea Celular , Activación Enzimática , Regulación de la Expresión Génica , Lipoproteínas LDL , Masculino , Ratones , Ratones Noqueados , Fibras Musculares Esqueléticas/metabolismo , Mioblastos/metabolismo , Oxidación-Reducción , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Transporte de Proteínas , Proteínas Proto-Oncogénicas c-fyn , Triglicéridos
19.
PLoS One ; 7(2): e31225, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22348058

RESUMEN

Insulin/IGF-1 signaling plays a pivotal role in the regulation of cellular homeostasis through its control of glucose metabolism as well as due to its effects on cell proliferation. Aberrant regulation of insulin signaling has been repeatedly implicated in uncontrolled cell growth and malignant transformations. TBC1D3 is a hominoid specific gene previously identified as an oncogene in breast and prostate cancers. Our efforts to identify the molecular mechanisms of TBC1D3-induced oncogenesis revealed the role of TBC1D3 in insulin/IGF-1 signaling pathway. We document here that TBC1D3 intensifies insulin/IGF-1-induced signal transduction through intricate, yet elegant fine-tuning of signaling mechanisms. We show that TBC1D3 expression substantially delayed ubiquitination and degradation of insulin receptor substrate-1 (IRS-1). This effect is achieved through suppression of serine phosphorylation at S636/639, S307 and S312 of IRS-1, which are key phosphorylation sites required for IRS-1 degradation. Furthermore, we report that the effect of TBC1D3 on IRS-1:S636/639 phosphorylation is mediated through TBC1D3-induced activation of protein phosphatase 2A (PP2A), followed by suppression of T389 phosphorylation on p70 S6 kinase (S6K). TBC1D3 specifically interacts with PP2A regulatory subunit B56γ, indicating that TBC1D3 and PP2A B56γ operate jointly to promote S6K:T389 dephosphorylation. These findings suggest that TBC1D3 plays an unanticipated and potentially unique role in the fine-tuning of insulin/IGF-1 signaling, while providing novel insights into the regulation of tumorigenesis by a hominoid-specific protein.


Asunto(s)
Proteínas Activadoras de GTPasa/genética , Proteínas Sustrato del Receptor de Insulina/metabolismo , Insulina/metabolismo , Proteolisis , Proteínas Proto-Oncogénicas/genética , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Transducción de Señal , Proteínas Activadoras de GTPasa/metabolismo , Humanos , Fosforilación , Proteína Fosfatasa 2/metabolismo , Proteínas Proto-Oncogénicas/metabolismo
20.
PLoS One ; 7(9): e46485, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23029530

RESUMEN

Expression of the hominoid-specific TBC1D3 oncoprotein enhances growth factor receptor signaling and subsequently promotes cellular proliferation and survival. Here we report that TBC1D3 is degraded in response to growth factor signaling, suggesting that TBC1D3 expression is regulated by a growth factor-driven negative feedback loop. To gain a better understanding of how TBC1D3 is regulated, we studied the effects of growth factor receptor signaling on TBC1D3 post-translational processing and turnover. Using a yeast two-hybrid screen, we identified CUL7, the scaffolding subunit of the CUL7 E3 ligase complex, as a TBC1D3-interacting protein. We show that CUL7 E3 ligase ubiquitinates TBC1D3 in response to serum stimulation. Moreover, TBC1D3 recruits F-box 8 (Fbw8), the substrate recognition domain of CUL7 E3 ligase, in pull-down experiments and in an in vitro assay. Importantly, alkaline phosphatase treatment of TBC1D3 suppresses its ability to recruit Fbw8, indicating that TBC1D3 phosphorylation is critical for its ubiquitination and degradation. We conclude that serum- and growth factor-stimulated TBC1D3 ubiquitination and degradation are regulated by its interaction with CUL7-Fbw8.


Asunto(s)
Proteínas Cullin/metabolismo , Proteínas F-Box/metabolismo , Proteínas Activadoras de GTPasa/metabolismo , Procesamiento Proteico-Postraduccional , Proteolisis , Proteínas Proto-Oncogénicas/metabolismo , Células HeLa , Humanos , Péptidos y Proteínas de Señalización Intercelular/fisiología , Leupeptinas/farmacología , Fosforilación , Inhibidores de Proteasoma/farmacología , Unión Proteica , Técnicas del Sistema de Dos Híbridos , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitinación
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