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1.
Diabetologia ; 64(8): 1850-1865, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34014371

RESUMEN

AIMS/HYPOTHESIS: Adipocytes are critical cornerstones of energy metabolism. While obesity-induced adipocyte dysfunction is associated with insulin resistance and systemic metabolic disturbances, adipogenesis, the formation of new adipocytes and healthy adipose tissue expansion are associated with metabolic benefits. Understanding the molecular mechanisms governing adipogenesis is of great clinical potential to efficiently restore metabolic health in obesity. Here we investigate the role of heart and neural crest derivatives-expressed 2 (HAND2) in adipogenesis. METHODS: Human white adipose tissue (WAT) was collected from two cross-sectional studies of 318 and 96 individuals. In vitro, for mechanistic experiments we used primary adipocytes from humans and mice as well as human multipotent adipose-derived stem (hMADS) cells. Gene silencing was performed using siRNA or genetic inactivation in primary adipocytes from loxP and or tamoxifen-inducible Cre-ERT2 mouse models with Cre-encoding mRNA or tamoxifen, respectively. Adipogenesis and adipocyte metabolism were measured by Oil Red O staining, quantitative PCR (qPCR), microarray, glucose uptake assay, western blot and lipolysis assay. A combinatorial RNA sequencing (RNAseq) and ChIP qPCR approach was used to identify target genes regulated by HAND2. In vivo, we created a conditional adipocyte Hand2 deletion mouse model using Cre under control of the Adipoq promoter (Hand2AdipoqCre) and performed a large panel of metabolic tests. RESULTS: We found that HAND2 is an obesity-linked white adipocyte transcription factor regulated by glucocorticoids that was necessary but insufficient for adipocyte differentiation in vitro. In a large cohort of humans, WAT HAND2 expression was correlated to BMI. The HAND2 gene was enriched in white adipocytes compared with brown, induced early in differentiation and responded to dexamethasone (DEX), a typical glucocorticoid receptor (GR, encoded by NR3C1) agonist. Silencing of NR3C1 in hMADS cells or deletion of GR in a transgenic conditional mouse model results in diminished HAND2 expression, establishing that adipocyte HAND2 is regulated by glucocorticoids via GR in vitro and in vivo. Furthermore, we identified gene clusters indirectly regulated by the GR-HAND2 pathway. Interestingly, silencing of HAND2 impaired adipocyte differentiation in hMADS and primary mouse adipocytes. However, a conditional adipocyte Hand2 deletion mouse model using Cre under control of the Adipoq promoter did not mirror these effects on adipose tissue differentiation, indicating that HAND2 was required at stages prior to Adipoq expression. CONCLUSIONS/INTERPRETATION: In summary, our study identifies HAND2 as a novel obesity-linked adipocyte transcription factor, highlighting new mechanisms of GR-dependent adipogenesis in humans and mice. DATA AVAILABILITY: Array data have been submitted to the GEO database at NCBI (GSE148699).


Asunto(s)
Adipocitos/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Regulación de la Expresión Génica/fisiología , Glucocorticoides/farmacología , Obesidad/genética , Factores de Transcripción/genética , Adipogénesis/fisiología , Tejido Adiposo Pardo/metabolismo , Adulto , Anciano , Animales , Estudios Transversales , Femenino , Silenciador del Gen , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Reacción en Cadena en Tiempo Real de la Polimerasa , Transducción de Señal , Adulto Joven
2.
EMBO Rep ; 20(11): e48552, 2019 11 05.
Artículo en Inglés | MEDLINE | ID: mdl-31559673

RESUMEN

Aberrant activity of the glucocorticoid (GC)/glucocorticoid receptor (GR) endocrine system has been linked to obesity-related metabolic dysfunction. Traditionally, the GC/GR axis has been believed to play a crucial role in adipose tissue formation and function in both, white (WAT) and brown adipose tissue (BAT). While recent studies have challenged this notion for WAT, the contribution of GC/GR signaling to BAT-dependent energy homeostasis remained unknown. Here, we have generated and characterized a BAT-specific GR-knockout mouse (GRBATKO ), for the first time allowing to genetically interrogate the metabolic impact of BAT-GR. The HPA axis in GRBATKO mice was intact, as was the ability of mice to adapt to cold. BAT-GR was dispensable for the adaptation to fasting-feeding cycles and the development of diet-induced obesity. In obesity, glucose and lipid metabolism, insulin sensitivity, and food intake remained unchanged, aligning with the absence of changes in thermogenic gene expression. Together, we demonstrate that the GR in UCP1-positive BAT adipocytes plays a negligible role in systemic metabolism and BAT function, thereby opposing a long-standing paradigm in the field.


Asunto(s)
Adipocitos Marrones/metabolismo , Metabolismo Energético , Homeostasis , Receptores de Glucocorticoides/metabolismo , Animales , Peso Corporal , Respuesta al Choque por Frío , Ayuno , Ratones , Ratones Noqueados
3.
Proc Natl Acad Sci U S A ; 111(11): E1043-52, 2014 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-24591600

RESUMEN

Physical activity increases energy metabolism in exercising muscle. Whether acute exercise elicits metabolic changes in nonexercising muscles remains unclear. We show that one of the few genes that is more highly induced in nonexercising muscle than in exercising human muscle during acute exercise encodes angiopoietin-like 4 (ANGPTL4), an inhibitor of lipoprotein lipase-mediated plasma triglyceride clearance. Using a combination of human, animal, and in vitro data, we show that induction of ANGPTL4 in nonexercising muscle is mediated by elevated plasma free fatty acids via peroxisome proliferator-activated receptor-δ, presumably leading to reduced local uptake of plasma triglyceride-derived fatty acids and their sparing for use by exercising muscle. In contrast, the induction of ANGPTL4 in exercising muscle likely is counteracted via AMP-activated protein kinase (AMPK)-mediated down-regulation, promoting the use of plasma triglycerides as fuel for active muscles. Our data suggest that nonexercising muscle and the local regulation of ANGPTL4 via AMPK and free fatty acids have key roles in governing lipid homeostasis during exercise.


Asunto(s)
Angiopoyetinas/metabolismo , Ejercicio Físico/fisiología , Homeostasis/fisiología , Metabolismo de los Lípidos/fisiología , Músculo Esquelético/fisiología , Adulto , Proteína 4 Similar a la Angiopoyetina , Angiopoyetinas/sangre , Angiopoyetinas/fisiología , Ácidos Grasos/metabolismo , Técnica del Anticuerpo Fluorescente , Humanos , Masculino , Análisis por Micromatrices , Persona de Mediana Edad
4.
J Biol Chem ; 289(28): 19279-93, 2014 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-24876382

RESUMEN

Peroxisome proliferator-activated receptors (PPARs) play major roles in the regulation of hepatic lipid metabolism through the control of numerous genes involved in processes such as lipid uptake and fatty acid oxidation. Here we identify hypoxia-inducible lipid droplet-associated (Hilpda/Hig2) as a novel PPAR target gene and demonstrate its involvement in hepatic lipid metabolism. Microarray analysis revealed that Hilpda is one of the most highly induced genes by the PPARα agonist Wy14643 in mouse precision cut liver slices. Induction of Hilpda mRNA by Wy14643 was confirmed in mouse and human hepatocytes. Oral dosing with Wy14643 similarly induced Hilpda mRNA levels in livers of wild-type mice but not Ppara(-/-) mice. Transactivation studies and chromatin immunoprecipitation showed that Hilpda is a direct PPARα target gene via a conserved PPAR response element located 1200 base pairs upstream of the transcription start site. Hepatic overexpression of HILPDA in mice via adeno-associated virus led to a 4-fold increase in liver triglyceride storage, without any changes in key genes involved in de novo lipogenesis, ß-oxidation, or lipolysis. Moreover, intracellular lipase activity was not affected by HILPDA overexpression. Strikingly, HILPDA overexpression significantly impaired hepatic triglyceride secretion. Taken together, our data uncover HILPDA as a novel PPAR target that raises hepatic triglyceride storage via regulation of triglyceride secretion.


Asunto(s)
Lipogénesis/fisiología , Hígado/metabolismo , Proteínas de Neoplasias/metabolismo , PPAR alfa/metabolismo , Triglicéridos/metabolismo , Animales , Anticolesterolemiantes/farmacología , Línea Celular , Humanos , Lipogénesis/efectos de los fármacos , Hígado/citología , Ratones , Ratones Noqueados , Proteínas de Neoplasias/genética , PPAR alfa/genética , Pirimidinas/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Elementos de Respuesta/fisiología , Triglicéridos/genética
5.
Biochim Biophys Acta ; 1821(5): 782-9, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22063269

RESUMEN

Plasma triglyceride concentrations are determined by the balance between production of the triglyceride-rich lipoproteins VLDL and chylomicrons in liver and intestine, and their lipoprotein lipase-mediated clearance in peripheral tissues. In the last decade, the group of Angiopoietin-like proteins has emerged as important regulators of circulating triglyceride (TG) levels. Specifically, ANGPTL3 and ANGPTL4 impair TG clearance by inhibiting lipoprotein lipase (LPL). Whereas ANGPTL4 irreversibly inactivates LPL by promoting conversion of active LPL dimers into inactive monomers, ANGPTL3 reversibly inhibits LPL activity. Studies using transgenic or knockout mice have clearly demonstrated the stimulatory effect of Angptl3 and Angptl4 on plasma TG, which is further supported by human genetic data including genome wide association studies. Whereas ANGPTL3 is mainly active in the fed state, ANGPTL4 is elevated by fasting and mediates fasting-induced changes in plasma TG and free fatty acid metabolism. Both proteins undergo oligomerization and are subject to proteolytic cleavage to generate N- and C-terminal fragments with highly divergent biological activities. Expression of ANGPTL3 is exclusive to liver and governed by the liver X receptor (LXR). In contrast, ANGPTL4 is expressed ubiquitously and under sensitive control of the Peroxisome proliferator-activated receptor (PPAR) family and fatty acids. Induction of ANGPTL4 gene expression by fatty acids and via PPARs is part of a feedback mechanism aimed at protecting cells against lipotoxicity. So far there is very little evidence that other ANGPTLs directly impact plasma lipoprotein metabolism. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.


Asunto(s)
Angiopoyetinas/metabolismo , Hígado/metabolismo , Triglicéridos/sangre , Proteína 3 Similar a la Angiopoyetina , Proteína 4 Similar a la Angiopoyetina , Proteínas Similares a la Angiopoyetina , Angiopoyetinas/genética , Animales , Regulación de la Expresión Génica , Humanos , Lipoproteína Lipasa/antagonistas & inhibidores , Lipoproteína Lipasa/genética , Lipoproteína Lipasa/metabolismo , Lipoproteínas VLDL/sangre , Ratones , Ratones Noqueados , Triglicéridos/genética
6.
BMC Physiol ; 12: 13, 2012 Nov 23.
Artículo en Inglés | MEDLINE | ID: mdl-23176178

RESUMEN

BACKGROUND: Lipoprotein lipase (LPL) hydrolyzes triglycerides in lipoproteins and makes fatty acids available for tissue metabolism. The activity of the enzyme is modulated in a tissue specific manner by interaction with other proteins. We have studied how feeding/fasting and some related perturbations affect the expression, in rat adipose tissue, of three such proteins, LMF1, an ER protein necessary for folding of LPL into its active dimeric form, the endogenous LPL inhibitor ANGPTL4, and GPIHBP1, that transfers LPL across the endothelium. RESULTS: The system underwent moderate circadian oscillations, for LPL in phase with food intake, for ANGPTL4 and GPIHBP1 in the opposite direction. Studies with cycloheximide showed that whereas LPL protein turns over rapidly, ANGPTL4 protein turns over more slowly. Studies with the transcription blocker Actinomycin D showed that transcripts for ANGPTL4 and GPIHBP1, but not LMF1 or LPL, turn over rapidly. When food was withdrawn the expression of ANGPTL4 and GPIHBP1 increased rapidly, and LPL activity decreased. On re-feeding and after injection of insulin the expression of ANGPTL4 and GPIHBP1 decreased rapidly, and LPL activity increased. In ANGPTL4(-/-) mice adipose tissue LPL activity did not show these responses. In old, obese rats that showed signs of insulin resistance, the responses of ANGPTL4 and GPIHBP1 mRNA and of LPL activity were severely blunted (at 26 weeks of age) or almost abolished (at 52 weeks of age). CONCLUSIONS: This study demonstrates directly that ANGPTL4 is necessary for rapid modulation of LPL activity in adipose tissue. ANGPTL4 message levels responded very rapidly to changes in the nutritional state. LPL activity always changed in the opposite direction. This did not happen in Angptl4(-/-) mice. GPIHBP1 message levels also changed rapidly and in the same direction as ANGPTL4, i.e. increased on fasting when LPL activity decreased. This was unexpected because GPIHBP1 is known to stabilize LPL. The plasticity of the LPL system is severely blunted or completely lost in insulin resistant rats.


Asunto(s)
Tejido Adiposo/enzimología , Angiopoyetinas/fisiología , Regulación del Apetito/fisiología , Lipoproteína Lipasa/metabolismo , Proteínas de la Membrana/fisiología , Receptores de Lipoproteína/fisiología , Proteína 4 Similar a la Angiopoyetina , Angiopoyetinas/deficiencia , Animales , Ritmo Circadiano/fisiología , Activación Enzimática/fisiología , Resistencia a la Insulina/genética , Resistencia a la Insulina/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratas , Ratas Sprague-Dawley
7.
Adv Sci (Weinh) ; 9(29): e2104291, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-36031387

RESUMEN

Aberrant energy metabolism and cell cycle regulation both critically contribute to malignant cell growth and both processes represent targets for anticancer therapy. It is shown here that depletion of the AAA+-ATPase thyroid hormone receptor interacting protein 13 (Trip13) results in mitotic cell death through a combined mechanism linking lipid metabolism to aberrant mitosis. Diminished Trip13 levels in hepatocellular carcinoma cells result in insulin-receptor-/Akt-pathway-dependent accumulation of lipid droplets, which act as functional acentriolar microtubule organizing centers disturbing mitotic spindle polarity. Specifically, the lipid-droplet-coating protein perilipin 2 (Plin2) is required for multipolar spindle formation, induction of DNA damage, and mitotic cell death. Plin2 expression in different tumor cells confers susceptibility to cell death induced by Trip13 depletion as well as treatment with paclitaxel, a spindle-interfering drug commonly used against different cancers. Thus, assessment of Plin2 levels enables the stratification of tumor responsiveness to mitosis-targeting drugs, including clinically approved paclitaxel and Trip13 inhibitors currently under development.


Asunto(s)
Insulinas , Neoplasias Hepáticas , ATPasas Asociadas con Actividades Celulares Diversas/metabolismo , Proteínas de Ciclo Celular/metabolismo , Muerte Celular , Humanos , Insulinas/metabolismo , Lípidos , Proteínas Mad2/metabolismo , Paclitaxel/farmacología , Perilipina-2 , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores de Hormona Tiroidea/metabolismo
8.
Cell Rep ; 30(6): 1811-1822.e6, 2020 02 11.
Artículo en Inglés | MEDLINE | ID: mdl-32049012

RESUMEN

Obesity leads to a state of chronic, low-grade inflammation that features the accumulation of lipid-laden macrophages in adipose tissue. Here, we determined the role of macrophage lipid-droplet accumulation in the development of obesity-induced adipose-tissue inflammation, using mice with myeloid-specific deficiency of the lipid-inducible HILPDA protein. HILPDA deficiency markedly reduced intracellular lipid levels and accumulation of fluorescently labeled fatty acids. Decreased lipid storage in HILPDA-deficient macrophages can be rescued by inhibition of adipose triglyceride lipase (ATGL) and is associated with increased oxidative metabolism. In diet-induced obese mice, HILPDA deficiency does not alter inflammatory and metabolic parameters, despite markedly reducing lipid accumulation in macrophages. Overall, we find that HILPDA is a lipid-inducible, physiological inhibitor of ATGL-mediated lipolysis in macrophages and uncouples lipid storage in adipose tissue macrophages from inflammation and metabolic dysregulation. Our data question the contribution of lipid droplet accumulation in adipose tissue macrophages in obesity-induced inflammation and metabolic dysregulation.


Asunto(s)
Tejido Adiposo/fisiopatología , Ácidos Grasos/metabolismo , Inflamación/metabolismo , Gotas Lipídicas/metabolismo , Metabolismo de los Lípidos/fisiología , Macrófagos/metabolismo , Proteínas de Neoplasias/metabolismo , Animales , Humanos , Ratones
9.
Endocrinology ; 158(5): 1231-1251, 2017 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-28323980

RESUMEN

Triglycerides are stored in specialized organelles called lipid droplets. Numerous proteins have been shown to be physically associated with lipid droplets and govern their function. Previously, the protein hypoxia-inducible lipid droplet-associated (HILPDA) was localized to lipid droplets and was suggested to inhibit triglyceride lipolysis in hepatocytes. We confirm the partial localization of HILPDA to lipid droplets and show that HILPDA is highly abundant in adipose tissue, where its expression is controlled by the peroxisome proliferator-activated receptor γ and by ß-adrenergic stimulation. Levels of HILPDA markedly increased during 3T3-L1 adipocyte differentiation. Nevertheless, silencing of Hilpda using small interfering RNA or overexpression of Hilpda using adenovirus did not show a clear impact on 3T3-L1 adipogenesis. Following ß-adrenergic stimulation, the silencing of Hilpda in adipocytes did not significantly alter the release of nonesterified fatty acids (NEFA) and glycerol. By contrast, adenoviral-mediated overexpression of Hilpda modestly attenuated the release of NEFA from adipocytes following ß-adrenergic stimulation. In mice, adipocyte-specific inactivation of Hilpda had no effect on plasma levels of NEFA and glycerol after fasting, cold exposure, or pharmacological ß-adrenergic stimulation. In addition, other relevant metabolic parameters were unchanged by adipocyte-specific inactivation of Hilpda. Taken together, we find that HILPDA is highly abundant in adipose tissue, where its levels are induced by peroxisome proliferator-activated receptor γ and ß-adrenergic stimulation. In contrast to the reported inhibition of lipolysis by HILPDA in hepatocytes, our data do not support an important direct role of HILPDA in the regulation of lipolysis in adipocytes in vivo and in vitro.


Asunto(s)
Tejido Adiposo/metabolismo , Lipólisis/genética , Proteínas de Neoplasias/fisiología , Células 3T3-L1 , Adipocitos/fisiología , Adipogénesis/genética , Animales , Femenino , Gotas Lipídicas/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados
10.
Cell Metab ; 26(6): 842-855.e5, 2017 Dec 05.
Artículo en Inglés | MEDLINE | ID: mdl-29056512

RESUMEN

Breast tumor recurrence and metastasis represent the main causes of cancer-related death in women, and treatments are still lacking. Here, we define the lipogenic enzyme acetyl-CoA carboxylase (ACC) 1 as a key player in breast cancer metastasis. ACC1 phosphorylation was increased in invading cells both in murine and human breast cancer, serving as a point of convergence for leptin and transforming growth factor (TGF) ß signaling. ACC1 phosphorylation was mediated by TGFß-activated kinase (TAK) 1, and ACC1 inhibition was indispensable for the elevation of cellular acetyl-CoA, the subsequent increase in Smad2 transcription factor acetylation and activation, and ultimately epithelial-mesenchymal transition and metastasis induction. ACC1 deficiency worsened tumor recurrence upon primary tumor resection in mice, and ACC1 phosphorylation levels correlated with metastatic potential in breast and lung cancer patients. Given the demonstrated effectiveness of anti-leptin receptor antibody treatment in halting ACC1-dependent tumor invasiveness, our work defines a "metabolocentric" approach in metastatic breast cancer therapy.


Asunto(s)
Acetil-CoA Carboxilasa/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias Pulmonares/secundario , Recurrencia Local de Neoplasia/patología , Acetil-CoA Carboxilasa/genética , Acetilación , Animales , Modelos Animales de Enfermedad , Femenino , Células HEK293 , Humanos , Leptina/metabolismo , Células MCF-7 , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/metabolismo , Análisis de Matrices Tisulares
11.
Cell Rep ; 20(6): 1422-1434, 2017 08 08.
Artículo en Inglés | MEDLINE | ID: mdl-28793265

RESUMEN

Increased pro-inflammatory signaling is a hallmark of metabolic dysfunction in obesity and diabetes. Although both inflammatory and energy substrate handling processes represent critical layers of metabolic control, their molecular integration sites remain largely unknown. Here, we identify the heterodimerization interface between the α and ß subunits of transcription factor GA-binding protein (GAbp) as a negative target of tumor necrosis factor alpha (TNF-α) signaling. TNF-α prevented GAbpα and ß complex formation via reactive oxygen species (ROS), leading to the non-energy-dependent transcriptional inactivation of AMP-activated kinase (AMPK) ß1, which was identified as a direct hepatic GAbp target. Impairment of AMPKß1, in turn, elevated downstream cellular cholesterol biosynthesis, and hepatocyte-specific ablation of GAbpα induced systemic hypercholesterolemia and early macro-vascular lesion formation in mice. As GAbpα and AMPKß1 levels were also found to correlate in obese human patients, the ROS-GAbp-AMPK pathway may represent a key component of a hepato-vascular axis in diabetic long-term complications.


Asunto(s)
Aterosclerosis/metabolismo , Factor de Transcripción de la Proteína de Unión a GA/metabolismo , Hepatocitos/metabolismo , Hipercolesterolemia/metabolismo , Proteínas Quinasas/metabolismo , Transducción de Señal , Quinasas de la Proteína-Quinasa Activada por el AMP , Animales , Aterosclerosis/etiología , Aterosclerosis/patología , Línea Celular , Células Cultivadas , Colesterol/metabolismo , Factor de Transcripción de la Proteína de Unión a GA/química , Hipercolesterolemia/complicaciones , Masculino , Ratones , Ratones Endogámicos C57BL , Multimerización de Proteína , Subunidades de Proteína/química , Subunidades de Proteína/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo
12.
Mol Metab ; 3(2): 135-44, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24634819

RESUMEN

Dietary triglycerides are hydrolyzed in the small intestine principally by pancreatic lipase. Following uptake by enterocytes and secretion as chylomicrons, dietary lipids are cleared from the bloodstream via lipoprotein lipase. Whereas lipoprotein lipase is inhibited by several proteins including Angiopoietin-like 4 (Angptl4), no endogenous regulator of pancreatic lipase has yet been identified. Here we present evidence that Angptl4 is an endogenous inhibitor of dietary lipid digestion. Angptl4-/- mice were heavier compared to their wild-type counterparts without any difference in food intake, energy expenditure or locomotor activity. However, Angptl4-/- mice showed decreased lipid content in the stools and increased accumulation of dietary triglycerides in the small intestine, which coincided with elevated luminal lipase activity in Angptl4-/- mice. Furthermore, recombinant Angptl4 reduced the activity of pancreatic lipase as well as the lipase activity in human ileostomy output. In conclusion, our data suggest that Angptl4 is an endogenous inhibitor of intestinal lipase activity.

13.
Cell Metab ; 20(3): 458-70, 2014 Sep 02.
Artículo en Inglés | MEDLINE | ID: mdl-25066055

RESUMEN

Sel1L is an essential adaptor protein for the E3 ligase Hrd1 in the endoplasmic reticulum (ER)-associated degradation (ERAD), a universal quality-control system in the cell; but its physiological role remains unclear. Here we show that mice with adipocyte-specific Sel1L deficiency are resistant to diet-induced obesity and exhibit postprandial hypertriglyceridemia. Further analyses reveal that Sel1L is indispensable for the secretion of lipoprotein lipase (LPL), independent of its role in Hrd1-mediated ERAD and ER homeostasis. Sel1L physically interacts with and stabilizes the LPL maturation complex consisting of LPL and lipase maturation factor 1 (LMF1). In the absence of Sel1L, LPL is retained in the ER and forms protein aggregates, which are degraded primarily by autophagy. The Sel1L-mediated control of LPL secretion is also seen in other LPL-expressing cell types including cardiac myocytes and macrophages. Thus, our study reports a role of Sel1L in LPL secretion and systemic lipid metabolism.


Asunto(s)
Metabolismo de los Lípidos , Lipoproteína Lipasa/metabolismo , Proteínas/metabolismo , Adipocitos/metabolismo , Animales , Células Cultivadas , Dieta Alta en Grasa/efectos adversos , Degradación Asociada con el Retículo Endoplásmico , Femenino , Eliminación de Gen , Hiperglucemia/genética , Hiperglucemia/metabolismo , Péptidos y Proteínas de Señalización Intracelular , Lipoproteína Lipasa/química , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Obesidad/etiología , Obesidad/genética , Obesidad/metabolismo , Agregado de Proteínas , Multimerización de Proteína , Proteínas/genética
14.
Am J Clin Nutr ; 97(2): 255-60, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23283507

RESUMEN

BACKGROUND: Angiopoietin-like protein 4 (ANGPTL4) has been identified as an inhibitor of lipoprotein lipase. Preliminary data suggest that plasma nonesterified fatty acids (NEFAs) raise plasma ANGPTL4 concentrations in humans. OBJECTIVE: The objective was to assess plasma ANGPTL4 concentrations after various nutritional interventions that increase NEFA concentrations in healthy subjects and in patients with type 2 diabetes mellitus. DESIGN: We studied 4 groups, both at baseline and after 3 d of either fasting (n = 22 healthy men), a very-low-calorie diet (VLCD; n = 10 healthy men and n = 10 patients with diabetes), or a high-fat, high-energy diet (HFED; n = 15 healthy men). Plasma ANGPTL4, NEFA, and triglyceride concentrations were measured. RESULTS: In healthy men, a VLCD increased ANGPTL4 from 13.2 (IQR: 8.1-24.2) at baseline to 18.2 (16.7-33.4) ng/mL (P < 0.05), fasting increased ANGPTL4 from 10.6 (7.6-17.6) to 28.0 (23.1-35.0) ng/mL (P < 0.05), and an HFED increased ANGPTL4 from 13.9 (8.2-22.0) to 17.2 (11.2-23.6) ng/mL (P < 0.05). In men with diabetes, a VLCD also increased ANGPTL4, from 10.9 ± 2.4 to 19.2 ± 3.2 ng/mL (P < 0.05). All interventions significantly increased plasma NEFAs in both healthy men and patients with diabetes. The change in ANGPTL4 positively correlated with the change in NEFA concentrations (ß = 0.048, P < 0.001) and negatively correlated with the change in plasma triglycerides (ß = -0.051, P = 0.01). CONCLUSIONS: Three days of either fasting, a VLCD, or an HFED increased plasma ANGPTL4 concentrations in healthy men, concomitantly with increased plasma NEFA concentrations. Similarly, a VLCD in patients with diabetes increased ANGPTL4 concentrations, concomitantly with increased NEFA concentrations.


Asunto(s)
Angiopoyetinas/sangre , Restricción Calórica , Diabetes Mellitus Tipo 2/dietoterapia , Ingestión de Energía , Ácidos Grasos no Esterificados/sangre , Regulación hacia Arriba , Adulto , Proteína 4 Similar a la Angiopoyetina , Diabetes Mellitus Tipo 2/sangre , Dieta Alta en Grasa/efectos adversos , Ensayo de Inmunoadsorción Enzimática , Ayuno/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Triglicéridos/sangre , Adulto Joven
15.
Diabetes ; 61(11): 2679-90, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22807032

RESUMEN

Type 2 diabetes is characterized by excessive lipid storage in skeletal muscle. Excessive intramyocellular lipid (IMCL) storage exceeds intracellular needs and induces lipotoxic events, ultimately contributing to the development of insulin resistance. Lipid droplet (LD)-coating proteins may control proper lipid storage in skeletal muscle. Perilipin 2 (PLIN2/adipose differentiation-related protein [ADRP]) is one of the most abundantly expressed LD-coating proteins in skeletal muscle. Here we examined the role of PLIN2 in myocellular lipid handling and insulin sensitivity by investigating the effects of in vitro PLIN2 knockdown and in vitro and in vivo overexpression. PLIN2 knockdown decreased LD formation and triacylglycerol (TAG) storage, marginally increased fatty-acid (FA) oxidation, and increased incorporation of palmitate into diacylglycerols and phospholipids. PLIN2 overexpression in vitro increased intramyocellular TAG storage paralleled with improved insulin sensitivity. In vivo muscle-specific PLIN2 overexpression resulted in increased LD accumulation and blunted the high-fat diet-induced increase in protein content of the subunits of the oxidative phosphorylation (OXPHOS) chain. Diacylglycerol levels were unchanged, whereas ceramide levels were increased. Despite the increased IMCL accumulation, PLIN2 overexpression improved skeletal muscle insulin sensitivity. We conclude that PLIN2 is essential for lipid storage in skeletal muscle by enhancing the partitioning of excess FAs toward TAG storage in LDs, thereby blunting lipotoxicity-associated insulin resistance.


Asunto(s)
Gránulos Citoplasmáticos/metabolismo , Resistencia a la Insulina , Metabolismo de los Lípidos , Proteínas de la Membrana/metabolismo , Músculo Esquelético/metabolismo , Animales , Línea Celular , Gránulos Citoplasmáticos/ultraestructura , Dieta Alta en Grasa/efectos adversos , Electroporación , Femenino , Perfilación de la Expresión Génica , Técnicas de Transferencia de Gen , Masculino , Proteínas de la Membrana/antagonistas & inhibidores , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Músculo Esquelético/ultraestructura , Fosforilación Oxidativa , Perilipina-2 , Interferencia de ARN , ARN Interferente Pequeño , Ratas , Ratas Wistar , Proteínas Recombinantes/metabolismo
16.
Cell Metab ; 14(1): 1-2, 2011 Jul 06.
Artículo en Inglés | MEDLINE | ID: mdl-21723496

RESUMEN

Lipotoxicity describes the process of cellular dysfunction in response to lipid overload. In this issue of Cell Metabolism, Michel and colleagues (2011) provide evidence for a role of snoRNAs in palmitate-induced oxidative stress.

17.
Cell Metab ; 13(4): 389-400, 2011 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-21459324

RESUMEN

The aberrant accumulation of lipids in the liver ("fatty liver") is tightly associated with several components of the metabolic syndrome, including type 2 diabetes, coronary heart disease, and atherosclerosis. Here we show that the impaired hepatic expression of transcriptional cofactor transducin beta-like (TBL) 1 represents a common feature of mono- and multigenic fatty liver mouse models. Indeed, the liver-specific ablation of TBL1 gene expression in healthy mice promoted hypertriglyceridemia and hepatic steatosis under both normal and high-fat dietary conditions. TBL1 deficiency resulted in inhibition of fatty acid oxidation due to impaired functional cooperation with its heterodimerization partner TBL-related (TBLR) 1 and the nuclear receptor peroxisome proliferator-activated receptor (PPAR) α. As TBL1 expression levels were found to also inversely correlate with liver fat content in human patients, the lack of hepatic TBL1/TBLR1 cofactor activity may represent a molecular rationale for hepatic steatosis in subjects with obesity and the metabolic syndrome.


Asunto(s)
Hígado Graso/etiología , Hipertrigliceridemia/etiología , Hígado/metabolismo , Transducina/metabolismo , Animales , Grasas de la Dieta/farmacología , Dimerización , Modelos Animales de Enfermedad , Humanos , Metabolismo de los Lípidos/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Ratones Transgénicos , Proteínas Nucleares/metabolismo , PPAR alfa/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Proteínas Represoras/metabolismo , Transducina/antagonistas & inhibidores , Transducina/genética
18.
Cell Metab ; 12(6): 580-92, 2010 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-21109191

RESUMEN

Dietary saturated fat is linked to numerous chronic diseases, including cardiovascular disease. Here we study the role of the lipoprotein lipase inhibitor Angptl4 in the response to dietary saturated fat. Strikingly, in mice lacking Angptl4, saturated fat induces a severe and lethal phenotype characterized by fibrinopurulent peritonitis, ascites, intestinal fibrosis, and cachexia. These abnormalities are preceded by a massive acute phase response induced by saturated but not unsaturated fat or medium-chain fat, originating in mesenteric lymph nodes (MLNs). MLNs undergo dramatic expansion and contain numerous lipid-laden macrophages. In peritoneal macrophages incubated with chyle, Angptl4 dramatically reduced foam cell formation, inflammatory gene expression, and chyle-induced activation of ER stress. Induction of macrophage Angptl4 by fatty acids is part of a mechanism that serves to reduce postprandial lipid uptake from chyle into MLN-resident macrophages by inhibiting triglyceride hydrolysis, thereby preventing macrophage activation and foam cell formation and protecting against progressive, uncontrolled saturated fat-induced inflammation.


Asunto(s)
Angiopoyetinas/metabolismo , Grasas de la Dieta/efectos adversos , Ácidos Grasos/farmacocinética , Inflamación/prevención & control , Ganglios Linfáticos/citología , Macrófagos/metabolismo , Reacción de Fase Aguda/metabolismo , Proteína 4 Similar a la Angiopoyetina , Angiopoyetinas/genética , Animales , Ascitis/genética , Ascitis/patología , Línea Celular , Ácidos Grasos/metabolismo , Técnicas Histológicas , Humanos , Inmunohistoquímica , Inflamación/etiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratas , Ratas Wistar
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