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2.
Mol Metab ; 85: 101962, 2024 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-38815625

RESUMEN

OBJECTIVE: p63 is a transcription factor involved in multiple biological functions. In the liver, the TAp63 isoform induces lipid accumulation in hepatocytes. However, the role of liver TAp63 in the progression of metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis is unknown. METHODS: We evaluated the hepatic p63 levels in different mouse models of steatohepatitis with fibrosis induced by diet. Next, we used virogenetic approaches to manipulate the expression of TAp63 in adult mice under diet-induced steatohepatitis with fibrosis and characterized the disease condition. Finally, we performed proteomics analysis in mice with overexpression and knockdown of hepatic TAp63. RESULTS: Levels of TAp63, but not of ΔN isoform, are increased in the liver of mice with diet-induced steatohepatitis with fibrosis. Both preventive and interventional strategies for the knockdown of hepatic TAp63 significantly ameliorated diet-induced steatohepatitis with fibrosis in mice fed a methionine- and choline-deficient diet (MCDD) and choline deficient and high fat diet (CDHFD). The overexpression of hepatic TAp63 in mice aggravated the liver condition in mice fed a CDHFD. Proteomic analysis in the liver of these mice revealed alteration in multiple proteins and pathways, such as oxidative phosphorylation, antioxidant activity, peroxisome function and LDL clearance. CONCLUSIONS: These results indicate that liver TAp63 plays a critical role in the progression of diet-induced steatohepatitis with fibrosis, and its inhibition ameliorates the disease.

3.
Cell Rep Med ; 5(2): 101401, 2024 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-38340725

RESUMEN

The p63 protein has pleiotropic functions and, in the liver, participates in the progression of nonalcoholic fatty liver disease (NAFLD). However, its functions in hepatic stellate cells (HSCs) have not yet been explored. TAp63 is induced in HSCs from animal models and patients with liver fibrosis and its levels positively correlate with NAFLD activity score and fibrosis stage. In mice, genetic depletion of TAp63 in HSCs reduces the diet-induced liver fibrosis. In vitro silencing of p63 blunts TGF-ß1-induced HSCs activation by reducing mitochondrial respiration and glycolysis, as well as decreasing acetyl CoA carboxylase 1 (ACC1). Ectopic expression of TAp63 induces the activation of HSCs and increases the expression and activity of ACC1 by promoting the transcriptional activity of HER2. Genetic inhibition of both HER2 and ACC1 blunt TAp63-induced activation of HSCs. Thus, TAp63 induces HSC activation by stimulating the HER2-ACC1 axis and participates in the development of liver fibrosis.


Asunto(s)
Células Estrelladas Hepáticas , Enfermedad del Hígado Graso no Alcohólico , Humanos , Ratones , Animales , Células Estrelladas Hepáticas/metabolismo , Células Estrelladas Hepáticas/patología , Enfermedad del Hígado Graso no Alcohólico/patología , Activación Metabólica , Cirrosis Hepática/genética , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/metabolismo , Fibrosis , Acetil-CoA Carboxilasa/genética , Acetil-CoA Carboxilasa/metabolismo
4.
J Clin Orthop Trauma ; 45: 102277, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-38044955

RESUMEN

Purpose: There is no consensus for management of patellar instability, even in the case of malalignment. The purpose of the review is to evaluate outcomes in the literature of MPFL reconstruction with and without tibial tubercle osteotomy. Methods: Two databases PubMed and Scopus were searched for studies comparing MPFL reconstruction with and without concomitant tibial tuberosity osteotomy. PRISMA guidelines were followed. Data on functional outcomes via Kujala score, redislocation rates and return to sport rates were reported. Results: 9 studies included data from 806 knees: 463 submitted to isolated MPFL reconstruction, and 343 submitted to the combined surgery. Patients submitted to the combined procedure had all TT-TG values superior to 18, while the ones with isolated reconstruction had more heterogeneous values, varying between 13 and 20 mm. 77.78% of the studies reported on postoperative Kujala scores, with a mean value of 83.53 in patients who underwent MPFL reconstruction alone and 83.72 in those who underwent the combined procedure. The mean difference between the two groups was -0.83, with the improvement of the score statistically significant in 22.22% of the studies, regardless of the surgery. Concerning redislocation rate, odds ratio comparing both procedures was 0.84 (p = 0.67). Conclusion: The principal finding is that the MPFL reconstruction with or without TTO resulted in similar functional outcomes, assessed by the Kujala score, and low complications concerning recurrent patellar dislocation. More robust literature is needed in the setting of a high TT-TG distance. Level of evidence: IV.

5.
Neurobiol Dis ; 187: 106300, 2023 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-37717662

RESUMEN

Celia's encephalopathy or progressive encephalopathy with/without lipodystrophy is a neurodegenerative disease with a fatal prognosis in childhood. It is generally caused by the c.985C > T variant in the BSCL2 gene, leading to the skipping of exon 7 and resulting in an aberrant seipin protein (Celia-seipin). To precisely define the temporal evolution and the mechanisms involved in neurodegeneration, lipodystrophy and fatty liver in Celia's encephalopathy, our group has generated the first global knock-in murine model for the aberrant human transcript of BSCL2 (Bscl2Celia/Celia) using a strategy based on the Cre/loxP recombination system. In order to carry out a characterization at the neurological, adipose tissue and hepatic level, behavioral studies, brain PET, metabolic, histological and molecular studies were performed. Around 12% of homozygous and 5.4% of heterozygous knock-in mice showed severe neurological symptoms early in life, and their life expectancy was dramatically reduced. Severe generalized lipodystrophy and mild hepatic steatosis were present in these affected animals, while serum triglycerides and glucose metabolism were normal, with no insulin resistance. Furthermore, the study revealed a reduction in brain glucose uptake, along with patchy loss of Purkinje cells and the presence of intranuclear inclusions in cerebellar cortex cells. Homozygous, non-severely-affected knock-in mice showed a decrease in locomotor activity and greater anxiety compared with their wild type littermates. Bscl2Celia/Celia is the first murine model of Celia's encephalopathy which partially recapitulates the phenotype and severe neurodegenerative picture suffered by these patients. This model will provide a helpful tool to investigate both the progressive encephalopathy with/without lipodystrophy and congenital generalized lipodystrophy.

6.
Cell Metab ; 35(8): 1373-1389.e8, 2023 08 08.
Artículo en Inglés | MEDLINE | ID: mdl-37527658

RESUMEN

There has been an intense focus to uncover the molecular mechanisms by which fasting triggers the adaptive cellular responses in the major organs of the body. Here, we show that in mice, hepatic S-adenosylmethionine (SAMe)-the principal methyl donor-acts as a metabolic sensor of nutrition to fine-tune the catabolic-fasting response by modulating phosphatidylethanolamine N-methyltransferase (PEMT) activity, endoplasmic reticulum-mitochondria contacts, ß-oxidation, and ATP production in the liver, together with FGF21-mediated lipolysis and thermogenesis in adipose tissues. Notably, we show that glucagon induces the expression of the hepatic SAMe-synthesizing enzyme methionine adenosyltransferase α1 (MAT1A), which translocates to mitochondria-associated membranes. This leads to the production of this metabolite at these sites, which acts as a brake to prevent excessive ß-oxidation and mitochondrial ATP synthesis and thereby endoplasmic reticulum stress and liver injury. This work provides important insights into the previously undescribed function of SAMe as a new arm of the metabolic adaptation to fasting.


Asunto(s)
Neoplasias Hepáticas , S-Adenosilmetionina , Ratones , Animales , S-Adenosilmetionina/metabolismo , Hígado/metabolismo , Neoplasias Hepáticas/metabolismo , Ayuno , Adenosina Trifosfato/metabolismo , Metionina Adenosiltransferasa/metabolismo , Fosfatidiletanolamina N-Metiltransferasa/metabolismo
7.
Mol Metab ; 75: 101776, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37453647

RESUMEN

OBJECTIVE: O-GlcNAcylation is a post-translational modification that directly couples the processes of nutrient sensing, metabolism, and signal transduction, affecting protein function and localization, since the O-linked N-acetylglucosamine moiety comes directly from the metabolism of glucose, lipids, and amino acids. The addition and removal of O-GlcNAc of target proteins are mediated by two highly conserved enzymes: O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) and O-GlcNAcase (OGA), respectively. Deregulation of O-GlcNAcylation has been reported to be associated with various human diseases such as cancer, diabetes, and cardiovascular diseases. The contribution of deregulated O-GlcNAcylation to the progression and pathogenesis of NAFLD remains intriguing, and a better understanding of its roles in this pathophysiological context is required to uncover novel avenues for therapeutic intervention. By using a translational approach, our aim is to describe the role of OGT and O-GlcNAcylation in the pathogenesis of NAFLD. METHODS: We used primary mouse hepatocytes, human hepatic cell lines and in vivo mouse models of steatohepatitis to manipulate O-GlcNAc transferase (OGT). We also studied OGT and O-GlcNAcylation in liver samples from different cohorts of people with NAFLD. RESULTS: O-GlcNAcylation was upregulated in the liver of people and animal models with steatohepatitis. Downregulation of OGT in NAFLD-hepatocytes improved diet-induced liver injury in both in vivo and in vitro models. Proteomics studies revealed that mitochondrial proteins were hyper-O-GlcNAcylated in the liver of mice with steatohepatitis. Inhibition of OGT is able to restore mitochondrial oxidation and decrease hepatic lipid content in in vitro and in vivo models of NAFLD. CONCLUSIONS: These results demonstrate that deregulated hyper-O-GlcNAcylation favors NAFLD progression by reducing mitochondrial oxidation and promoting hepatic lipid accumulation.


Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Humanos , Ratones , Animales , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Regulación hacia Abajo , Acetilglucosamina/metabolismo , Mitocondrias/metabolismo , Hepatocitos/metabolismo , Lípidos
8.
Gut ; 72(3): 472-483, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-35580962

RESUMEN

OBJECTIVE: p63 is a transcription factor within the p53 protein family that has key roles in development, differentiation and prevention of senescence, but its metabolic actions remain largely unknown. Herein, we investigated the physiological role of p63 in glucose metabolism. DESIGN: We used cell lines and mouse models to genetically manipulate p63 in hepatocytes. We also measured p63 in the liver of patients with obesity with or without type 2 diabetes (T2D). RESULTS: We show that hepatic p63 expression is reduced on fasting. Mice lacking the specific isoform TAp63 in the liver (p63LKO) display higher postprandial and pyruvate-induced glucose excursions. These mice have elevated SIRT1 levels, while SIRT1 knockdown in p63LKO mice normalises glycaemia. Overexpression of TAp63 in wild-type mice reduces postprandial, pyruvate-induced blood glucose and SIRT1 levels. Studies carried out in hepatocyte cell lines show that TAp63 regulates SIRT1 promoter by repressing its transcriptional activation. TAp63 also mediates the inhibitory effect of insulin on hepatic glucose production, as silencing TAp63 impairs insulin sensitivity. Finally, protein levels of TAp63 are reduced in obese persons with T2D and are negatively correlated with fasting glucose and homeostasis model assessment index. CONCLUSIONS: These results demonstrate that p63 physiologically regulates glucose homeostasis.


Asunto(s)
Diabetes Mellitus Tipo 2 , Sirtuina 1 , Transactivadores , Animales , Ratones , Glucosa/metabolismo , Hígado/metabolismo , Piruvatos/metabolismo , Sirtuina 1/metabolismo , Transactivadores/metabolismo
9.
Hip Int ; 33(6): 1100-1106, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-36253960

RESUMEN

INTRODUCTION: Proximal femur geometry (PFG) represents an important risk factor for the occurrence of hip fractures. There are currently few studies regarding the correlation between PFG and the occurrence of a specific fracture subtype, and those that exist have small cohorts and present with different methodologies and contradictory results. Therefore, there is no consensus in the literature regarding this topic. The present study aimed to establish the contribution of the PFG in the occurrence of different subtypes of proximal femur fractures (PFF): intertrochanteric, neck and subtrochanteric. METHODS: Analysis of 1022 plain anteroposterior pelvic radiographs of patients consecutively admitted to the emergency room of a Level 1 Trauma Centre between 2013 and 2019 after low energy trauma who presented with PFF and underwent surgical treatment. Patients were analysed considering age, gender and subtype of PFF (intertrochanteric, neck or subtrochanteric). Radiological parameters including cervicodiaphyseal angle (CDA), horizontal offset (HO), femoral neck width (FNW), femoral neck length (FNL), great trochanter-pubic symphysis distance (GTPSD), acetabular teardrop distance (ATD) and width of the intertrochanteric region (WIR) were measured and compared between the different subtypes of fractures (7154 measurements). Statistical analysis was conducted recurring to absolute measurements and measurements ratios. The correlation was assessed using t-test. RESULTS: There were statistically significant differences in proximal femur geometry between the different subtypes of fractures. Patients presenting with femoral neck fractures had greater CDA (132.5 ± 6.9 vs. 130.0 ± 7.3; p < 0.001) and lower HO (45.8 ± 7.4 vs. 49.0 ± 8.0; p < 0.001), HO/ATD (0.34 ± 0.068 vs. 0.37 ± 0.072; p < 0.001) and HO/GTPSD (0.26 ± 0.049 vs. 0.28 ± 0.039; p < 0.001) than patients with intertrochanteric/subtrochanteric fractures. CONCLUSIONS: PFG represents an important contributor to the occurrence of different fracture subtypes. Femoral neck fractures are associated with greater CDA and lower HO, HO/ATD and HO/GTPSD when compared to intertrochanteric or subtrochanteric fractures.


Asunto(s)
Artroplastia de Reemplazo de Cadera , Fracturas del Cuello Femoral , Fracturas de Cadera , Fracturas Femorales Proximales , Humanos , Fémur/patología , Fracturas de Cadera/diagnóstico por imagen , Fracturas de Cadera/cirugía , Fracturas de Cadera/epidemiología , Fracturas del Cuello Femoral/diagnóstico por imagen , Fracturas del Cuello Femoral/cirugía , Fracturas del Cuello Femoral/epidemiología , Cuello Femoral/diagnóstico por imagen , Cuello Femoral/patología
10.
Nat Metab ; 4(7): 901-917, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35879461

RESUMEN

Early-life determinants are thought to be a major factor in the rapid increase of obesity. However, while maternal nutrition has been extensively studied, the effects of breastfeeding by the infant on the reprogramming of energy balance in childhood and throughout adulthood remain largely unknown. Here we show that delayed weaning in rat pups protects them against diet-induced obesity in adulthood, through enhanced brown adipose tissue thermogenesis and energy expenditure. In-depth metabolic phenotyping in this rat model as well as in transgenic mice reveals that the effects of prolonged suckling are mediated by increased hepatic fibroblast growth factor 21 (FGF21) production and tanycyte-controlled access to the hypothalamus in adulthood. Specifically, FGF21 activates GABA-containing neurons expressing dopamine receptor 2 in the lateral hypothalamic area and zona incerta. Prolonged breastfeeding thus constitutes a protective mechanism against obesity by affecting long-lasting physiological changes in liver-to-hypothalamus communication and hypothalamic metabolic regulation.


Asunto(s)
Lactancia Materna , Obesidad , Animales , Femenino , Factores de Crecimiento de Fibroblastos , Humanos , Hipotálamo/metabolismo , Hígado/metabolismo , Ratones , Obesidad/metabolismo , Obesidad/prevención & control , Ratas
11.
Int J Mol Sci ; 23(6)2022 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-35328539

RESUMEN

Weight gain is a hallmark of decreased estradiol (E2) levels because of menopause or following surgical ovariectomy (OVX) at younger ages. Of note, this weight gain tends to be around the abdomen, which is frequently associated with impaired metabolic homeostasis and greater cardiovascular risk in both rodents and humans. However, the molecular underpinnings and the neuronal basis for these effects remain to be elucidated. The aim of this study is to elucidate whether the kappa-opioid receptor (k-OR) system is involved in mediating body weight changes associated with E2 withdrawal. Here, we document that body weight gain induced by OVX occurs, at least partially, in a k-OR dependent manner, by modulation of energy expenditure independently of food intake as assessed in Oprk1-/-global KO mice. These effects were also observed following central pharmacological blockade of the k-OR system using the k-OR-selective antagonist PF-04455242 in wild type mice, in which we also observed a decrease in OVX-induced weight gain associated with increased UCP1 positive immunostaining in brown adipose tissue (BAT) and browning of white adipose tissue (WAT). Remarkably, the hypothalamic mTOR pathway plays an important role in regulating weight gain and adiposity in OVX mice. These findings will help to define new therapies to manage metabolic disorders associated with low/null E2 levels based on the modulation of central k-OR signaling.


Asunto(s)
Ingestión de Alimentos , Receptores Opioides kappa , Tejido Adiposo Pardo/metabolismo , Animales , Peso Corporal , Metabolismo Energético , Estrógenos/metabolismo , Femenino , Humanos , Ratones , Obesidad/tratamiento farmacológico , Obesidad/etiología , Obesidad/metabolismo , Ovariectomía/efectos adversos , Receptores Opioides kappa/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Aumento de Peso
12.
J Hepatol ; 77(1): 15-28, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35167910

RESUMEN

BACKGROUND & AIMS: The pathogenesis of liver fibrosis requires activation of hepatic stellate cells (HSCs); once activated, HSCs lose intracellular fatty acids but the role of fatty acid oxidation and carnitine palmitoyltransferase 1A (CPT1A) in this process remains largely unexplored. METHODS: CPT1A was found in HSCs of patients with fibrosis. Pharmacological and genetic manipulation of CPT1A were performed in human HSC cell lines and primary HCSs. Finally, we induced fibrosis in mice lacking CPT1A specifically in HSCs. RESULTS: Herein, we show that CPT1A expression is elevated in HSCs of patients with non-alcoholic steatohepatitis, showing a positive correlation with the fibrosis score. This was corroborated in rodents with fibrosis, as well as in primary human HSCs and LX-2 cells activated by transforming growth factor ß1 (TGFß1) and fetal bovine serum (FBS). Furthermore, both pharmacological and genetic silencing of CPT1A prevent TGFß1- and FBS-induced HSC activation by reducing mitochondrial activity. The overexpression of CPT1A, induced by saturated fatty acids and reactive oxygen species, triggers mitochondrial activity and the expression of fibrogenic markers. Finally, mice lacking CPT1A specifically in HSCs are protected against fibrosis induced by a choline-deficient high-fat diet, a methionine- and choline-deficient diet, or treatment with carbon tetrachloride. CONCLUSIONS: These results indicate that CPT1A plays a critical role in the activation of HSCs and is implicated in the development of liver fibrosis, making it a potentially actionable target for fibrosis treatment. LAY SUMMARY: We show that the enzyme carnitine palmitoyltransferase 1A (CPT1A) is elevated in hepatic stellate cells (HSCs) in patients with fibrosis and mouse models of fibrosis, and that CPT1A induces the activation of these cells. Inhibition of CPT1A ameliorates fibrosis by preventing the activation of HSCs.


Asunto(s)
Carnitina O-Palmitoiltransferasa , Células Estrelladas Hepáticas , Animales , Carnitina O-Palmitoiltransferasa/genética , Carnitina O-Palmitoiltransferasa/metabolismo , Colina , Ácidos Grasos/metabolismo , Fibrosis , Células Estrelladas Hepáticas/metabolismo , Humanos , Hígado/patología , Cirrosis Hepática/metabolismo , Cirrosis Hepática/prevención & control , Ratones
13.
J Hepatol ; 76(1): 11-24, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34555423

RESUMEN

BACKGROUND & AIMS: Autophagy-related gene 3 (ATG3) is an enzyme mainly known for its actions in the LC3 lipidation process, which is essential for autophagy. Whether ATG3 plays a role in lipid metabolism or contributes to non-alcoholic fatty liver disease (NAFLD) remains unknown. METHODS: By performing proteomic analysis on livers from mice with genetic manipulation of hepatic p63, a regulator of fatty acid metabolism, we identified ATG3 as a new target downstream of p63. ATG3 was evaluated in liver samples from patients with NAFLD. Further, genetic manipulation of ATG3 was performed in human hepatocyte cell lines, primary hepatocytes and in the livers of mice. RESULTS: ATG3 expression is induced in the liver of animal models and patients with NAFLD (both steatosis and non-alcoholic steatohepatitis) compared with those without liver disease. Moreover, genetic knockdown of ATG3 in mice and human hepatocytes ameliorates p63- and diet-induced steatosis, while its overexpression increases the lipid load in hepatocytes. The inhibition of hepatic ATG3 improves fatty acid metabolism by reducing c-Jun N-terminal protein kinase 1 (JNK1), which increases sirtuin 1 (SIRT1), carnitine palmitoyltransferase 1a (CPT1a), and mitochondrial function. Hepatic knockdown of SIRT1 and CPT1a blunts the effects of ATG3 on mitochondrial activity. Unexpectedly, these effects are independent of an autophagic action. CONCLUSIONS: Collectively, these findings indicate that ATG3 is a novel protein implicated in the development of steatosis. LAY SUMMARY: We show that autophagy-related gene 3 (ATG3) contributes to the progression of non-alcoholic fatty liver disease in humans and mice. Hepatic knockdown of ATG3 ameliorates the development of NAFLD by stimulating mitochondrial function. Thus, ATG3 is an important factor implicated in steatosis.


Asunto(s)
Proteínas Relacionadas con la Autofagia/antagonistas & inhibidores , Hígado Graso/prevención & control , Mitocondrias Hepáticas/metabolismo , Enzimas Ubiquitina-Conjugadoras/antagonistas & inhibidores , Animales , Proteínas Relacionadas con la Autofagia/farmacología , Modelos Animales de Enfermedad , Hígado Graso/fisiopatología , Metabolismo de los Lípidos/genética , Ratones , Mitocondrias Hepáticas/fisiología , Proteómica/métodos , Enzimas Ubiquitina-Conjugadoras/farmacología
14.
Nat Commun ; 12(1): 5068, 2021 08 20.
Artículo en Inglés | MEDLINE | ID: mdl-34417460

RESUMEN

p53 regulates several signaling pathways to maintain the metabolic homeostasis of cells and modulates the cellular response to stress. Deficiency or excess of nutrients causes cellular metabolic stress, and we hypothesized that p53 could be linked to glucose maintenance. We show here that upon starvation hepatic p53 is stabilized by O-GlcNAcylation and plays an essential role in the physiological regulation of glucose homeostasis. More specifically, p53 binds to PCK1 promoter and regulates its transcriptional activation, thereby controlling hepatic glucose production. Mice lacking p53 in the liver show a reduced gluconeogenic response during calorie restriction. Glucagon, adrenaline and glucocorticoids augment protein levels of p53, and administration of these hormones to p53 deficient human hepatocytes and to liver-specific p53 deficient mice fails to increase glucose levels. Moreover, insulin decreases p53 levels, and over-expression of p53 impairs insulin sensitivity. Finally, protein levels of p53, as well as genes responsible of O-GlcNAcylation are elevated in the liver of type 2 diabetic patients and positively correlate with glucose and HOMA-IR. Overall these results indicate that the O-GlcNAcylation of p53 plays an unsuspected key role regulating in vivo glucose homeostasis.


Asunto(s)
Acetilglucosamina/metabolismo , Glucosa/metabolismo , Hígado/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Animales , Secuencia de Bases , Restricción Calórica , Línea Celular , Colforsina/farmacología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Epinefrina/metabolismo , Glucagón/metabolismo , Glucocorticoides/metabolismo , Gluconeogénesis/efectos de los fármacos , Glicosilación , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Hidrocortisona/metabolismo , Hiperglucemia/complicaciones , Hiperglucemia/metabolismo , Resistencia a la Insulina , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Hígado/efectos de los fármacos , Ratones Endogámicos C57BL , Ratones Noqueados , Obesidad/complicaciones , Obesidad/metabolismo , Fosfoenolpiruvato Carboxiquinasa (GTP)/metabolismo , Regiones Promotoras Genéticas/genética , Unión Proteica/efectos de los fármacos , Estabilidad Proteica/efectos de los fármacos , Ácido Pirúvico/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transcripción Genética/efectos de los fármacos , Proteína p53 Supresora de Tumor/genética
15.
Redox Biol ; 41: 101945, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33744652

RESUMEN

Sirtuin 3 (SIRT3) is one of the seven mammalian sirtuin homologs of the yeast Sir2 gene that has emerged as an important player in the regulation of energy metabolism in peripheral tissues. However, its role in the hypothalamus has not been explored. Herein, we show that the genetic inhibition of SIRT3 in the hypothalamic arcuate nucleus (ARC) induced a negative energy balance and improvement of several metabolic parameters. These effects are specific for POMC neurons, because ablation of SIRT3 in POMC, but not in AgRP neurons, decreased body weight and adiposity, increased energy expenditure and brown adipose tissue (BAT) activity, and induced browning in white adipose tissue (WAT). Notably, the depletion of SIRT3 in POMC neurons caused these effects in male mice fed a chow diet but failed to affect energy balance in males fed a high fat diet and females under both type of diets. Overall, we provide the first evidence pointing for a key role of SIRT3 in POMC neurons in the regulation of energy balance.


Asunto(s)
Proopiomelanocortina , Sirtuina 3 , Tejido Adiposo Pardo/metabolismo , Animales , Dieta Alta en Grasa , Metabolismo Energético , Femenino , Masculino , Ratones , Neuronas/metabolismo , Proopiomelanocortina/metabolismo , Sirtuina 3/metabolismo
16.
Hepatology ; 73(2): 606-624, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-32329085

RESUMEN

BACKGROUND AND AIMS: G protein-coupled receptor (GPR) 55 is a putative cannabinoid receptor, and l-α-lysophosphatidylinositol (LPI) is its only known endogenous ligand. Although GPR55 has been linked to energy homeostasis in different organs, its specific role in lipid metabolism in the liver and its contribution to the pathophysiology of nonalcoholic fatty liver disease (NAFLD) remains unknown. APPROACH AND RESULTS: We measured (1) GPR55 expression in the liver of patients with NAFLD compared with individuals without obesity and without liver disease, as well as animal models with steatosis and nonalcoholic steatohepatitis (NASH), and (2) the effects of LPI and genetic disruption of GPR55 in mice, human hepatocytes, and human hepatic stellate cells. Notably, we found that circulating LPI and liver expression of GPR55 were up-regulated in patients with NASH. LPI induced adenosine monophosphate-activated protein kinase activation of acetyl-coenzyme A carboxylase (ACC) and increased lipid content in human hepatocytes and in the liver of treated mice by inducing de novo lipogenesis and decreasing ß-oxidation. The inhibition of GPR55 and ACCα blocked the effects of LPI, and the in vivo knockdown of GPR55 was sufficient to improve liver damage in mice fed a high-fat diet and in mice fed a methionine-choline-deficient diet. Finally, LPI promoted the initiation of hepatic stellate cell activation by stimulating GPR55 and activation of ACC. CONCLUSIONS: The LPI/GPR55 system plays a role in the development of NAFLD and NASH by activating ACC.


Asunto(s)
Lisofosfolípidos/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Obesidad/complicaciones , Receptores de Cannabinoides/metabolismo , Acetil-CoA Carboxilasa/antagonistas & inhibidores , Acetil-CoA Carboxilasa/metabolismo , Adulto , Anciano , Animales , Biopsia , Agonistas de Receptores de Cannabinoides/farmacología , Línea Celular , Estudios de Cohortes , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Femenino , Técnicas de Silenciamiento del Gen , Células Estrelladas Hepáticas , Hepatocitos , Humanos , Lipogénesis/efectos de los fármacos , Hígado/patología , Lisofosfolípidos/sangre , Masculino , Ratones , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/patología , Obesidad/sangre , Obesidad/metabolismo , Receptores de Cannabinoides/genética , Regulación hacia Arriba
18.
Biomaterials ; 247: 120016, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32272302

RESUMEN

Gene-activated matrices (GAMs) encoding pivotal transcription factors (TFs) represent a powerful tool to direct stem cell specification for tissue engineering applications. However, current TF-based GAMs activated with pDNA, are challenged by their low transfection efficiency and delayed transgene expression. Here, we report a GAM technology activated with mRNAs encoding TFs SOX9 (cartilage) and MYOD (muscle). We find that these mRNA-GAMs induce a higher and faster TF expression compared to pDNA-GAMs, especially in the case of RNase resistant mRNA sequences. This potent TF expression was translated into a high synthesis of cartilage- and muscle-specific markers, and ultimately, into successful tissue specification in vitro. Additionally, we show that the expression of tissue-specific markers can be further modulated by altering the properties of the mRNA-GAM environment. These results highlight the value of this GAM technology for priming cell lineage specification, a key centerpiece for future tissue engineering devices.


Asunto(s)
Ingeniería de Tejidos , Factores de Transcripción , Diferenciación Celular , ARN Mensajero/genética , Transfección
19.
Neuroendocrinology ; 110(11-12): 1042-1054, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31945763

RESUMEN

Linaclotide is a synthetic peptide approved by the FDA for the treatment of constipation-predominant irritable bowel syndrome and chronic constipation. Linaclotide binds and activates the transmembrane receptor guanylate cyclase 2C (Gucy2c). Uroguanylin (UGN) is a 16 amino acid peptide that is mainly secreted by enterochromaffin cells in the duodenum and proximal small intestine. UGN is the endogenous ligand of Gucy2c and decreases body weight in diet-induced obese (DIO) mice via the activation of the thermogenic program in brown adipose tissue. Therefore, we wanted to evaluate whether oral linaclotide could also improve DIO mice metabolic phenotype. In this study, we have demonstrated that DIO mice orally treated with linaclotide exhibited a significant reduction of body weight without modifying food intake. Linaclotide exerts its actions through the central nervous system, and more specifically, via Gucy2c receptors located in the mediobasal hypothalamus, leading to the activation of the sympathetic nervous system to trigger the thermogenic activity of brown fat stimulating energy expenditure. These findings indicate for first time that, in addition to its effects at intestinal level to treat irritable bowel syndrome with constipation and chronic constipation, linaclotide also exerts a beneficial effect in whole body metabolism.


Asunto(s)
Tejido Adiposo Pardo/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Agonistas de la Guanilato Ciclasa C/farmacología , Hipotálamo/efectos de los fármacos , Obesidad/tratamiento farmacológico , Péptidos/farmacología , Receptores de Enterotoxina/efectos de los fármacos , Termogénesis/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Dieta Alta en Grasa , Masculino , Ratones , Ratones Endogámicos C57BL
20.
Nat Metab ; 1(8): 811-829, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31579887

RESUMEN

Dopamine signaling is a crucial part of the brain reward system and can affect feeding behavior. Dopamine receptors are also expressed in the hypothalamus, which is known to control energy metabolism in peripheral tissues. Here we show that pharmacological or chemogenetic stimulation of dopamine receptor 2 (D2R) expressing cells in the lateral hypothalamic area (LHA) and the zona incerta (ZI) decreases body weight and stimulates brown fat activity in rodents in a feeding-independent manner. LHA/ZI D2R stimulation requires an intact sympathetic nervous system and orexin system to exert its action and involves inhibition of PI3K in the LHA/ZI. We further demonstrate that, as early as 3 months after onset of treatment, patients treated with the D2R agonist cabergoline experience an increase in energy expenditure that persists for one year, leading to total body weight and fat loss through a prolactin-independent mechanism. Our results may provide a mechanistic explanation for how clinically used D2R agonists act in the CNS to regulate energy balance.


Asunto(s)
Tejido Adiposo Pardo/metabolismo , Dopamina/metabolismo , Hipotálamo/metabolismo , Transducción de Señal , Termogénesis/fisiología , Animales , Bromocriptina/administración & dosificación , Bromocriptina/farmacología , Femenino , Humanos , Hipotálamo/efectos de los fármacos , Inyecciones Intraventriculares , Masculino , Ratas
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