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1.
Pediatr Res ; 95(4): 912-921, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37990078

RESUMEN

Congenital diaphragmatic hernia (CDH) is a severe birth defect and a major cause of neonatal respiratory distress. Impacting ~2-3 in 10,000 births, CDH is associated with a high mortality rate, and long-term morbidity in survivors. Despite the significant impact of CDH, its etiology remains incompletely understood. In 2003, Greer et al. proposed the Retinoid Hypothesis, stating that the underlying cause of abnormal diaphragm development in CDH was related to altered retinoid signaling. In this review, we provide a comprehensive update to the Retinoid Hypothesis, discussing work published in support of this hypothesis from the past 20 years. This includes reviewing teratogenic and genetic models of CDH, lessons from the human genetics of CDH and epidemiological studies, as well as current gaps in the literature and important areas for future research. The Retinoid Hypothesis is one of the leading hypotheses to explain the etiology of CDH, as we continue to better understand the role of retinoid signaling in diaphragm development, we hope that this information can be used to improve CDH outcomes. IMPACT: This review provides a comprehensive update on the Retinoid Hypothesis, which links abnormal retinoic acid signaling to the etiology of congenital diaphragmatic hernia. The Retinoid Hypothesis was formulated in 2003. Twenty years later, we extensively review the literature in support of this hypothesis from both animal models and humans.


Asunto(s)
Hernias Diafragmáticas Congénitas , Animales , Embarazo , Recién Nacido , Femenino , Humanos , Hernias Diafragmáticas Congénitas/genética , Retinoides/genética , Diafragma , Tretinoina , Parto
2.
Pediatr Res ; 91(1): 83-91, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-33654278

RESUMEN

BACKGROUND: Congenital diaphragmatic hernia (CDH) is a severe birth defect associated with high perinatal mortality and long-term morbidity. The etiology of CDH is poorly understood although abnormal retinoid signaling has been proposed to contribute to abnormal diaphragm development. Existing epidemiological data suggest that inadequate dietary vitamin A intake is a risk factor for developing CDH. METHODS: Using a mouse model of teratogen-induced CDH, the objective of this study was to test the hypothesis that low maternal vitamin A intake contributes to abnormal diaphragm development. To test this hypothesis, we optimized a model of altered maternal dietary vitamin A intake and a teratogenic model of CDH in mice that recapitulates the hallmark features of posterolateral diaphragmatic hernia in humans. RESULTS: Our data uniquely show that low maternal dietary vitamin A intake and marginal vitamin A status increases the incidence of teratogen-induced CDH in mice. CONCLUSION: Low dietary vitamin A intake and marginal vitamin A status lead to an increased incidence of teratogen-induced CDH in mice, highlighting the importance of adequate dietary vitamin A intake and CDH risk. IMPACT: This study describes and validates a mouse model of altered maternal and fetal vitamin A status. This study links existing epidemiological data with a mouse model of teratogen-induced congenital diaphragmatic hernia, highlighting the importance of low maternal vitamin A intake as a risk factor for the development of congenital diaphragmatic hernia. This study supports the Retinoid Hypothesis, which posits that the etiology of congenital diaphragmatic hernia is linked to abnormal retinoid signaling in the developing diaphragm.


Asunto(s)
Hernias Diafragmáticas Congénitas/epidemiología , Teratógenos/toxicidad , Vitamina A/administración & dosificación , Animales , Dieta , Femenino , Hernias Diafragmáticas Congénitas/inducido químicamente , Incidencia , Ratones , Ratones Endogámicos BALB C , Embarazo , Vitamina A/toxicidad
3.
J Neurosci ; 38(25): 5666-5676, 2018 06 20.
Artículo en Inglés | MEDLINE | ID: mdl-29789381

RESUMEN

The basic pattern of activity underlying stepping in mammals is generated by a neural network located in the caudal spinal cord. Within this network, the specific circuitry coordinating left-right alternation has been shown to involve several groups of molecularly defined interneurons. Here we characterize a population of spinal neurons that express the Wilms' tumor 1 (WT1) gene and investigate their role during locomotor activity in mice of both sexes. We demonstrate that WT1-expressing cells are located in the ventromedial region of the spinal cord of mice and are also present in the human spinal cord. In the mouse, these cells are inhibitory, project axons to the contralateral spinal cord, terminate in close proximity to other commissural interneuron subtypes, and are essential for appropriate left-right alternation during locomotion. In addition to identifying WT1-expressing interneurons as a key component of the locomotor circuitry, this study provides insight into the manner in which several populations of molecularly defined interneurons are interconnected to generate coordinated motor activity on either side of the body during stepping.SIGNIFICANCE STATEMENT In this study, we characterize WT1-expressing spinal interneurons in mice and demonstrate that they are commissurally projecting and inhibitory. Silencing of this neuronal population during a locomotor task results in a complete breakdown of left-right alternation, whereas flexor-extensor alternation was not significantly affected. Axons of WT1 neurons are shown to terminate nearby commissural interneurons, which coordinate motoneuron activity during locomotion, and presumably regulate their activity. Finally, the WT1 gene is shown to be present in the spinal cord of humans, raising the possibility of functional homology between these species. This study not only identifies a key component of the locomotor circuitry but also begins to unravel the connectivity among the growing number of molecularly defined interneurons that comprise this neural network.


Asunto(s)
Generadores de Patrones Centrales/citología , Interneuronas Comisurales/citología , Locomoción/fisiología , Proteínas Represoras/metabolismo , Médula Espinal/citología , Animales , Generadores de Patrones Centrales/fisiología , Interneuronas Comisurales/fisiología , Femenino , Masculino , Ratones , Vías Nerviosas/citología , Vías Nerviosas/fisiología , Médula Espinal/fisiología , Proteínas WT1
4.
Pediatr Res ; 86(5): 676, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31413356

RESUMEN

A correction to this paper has been published and can be accessed via a link at the top of the paper.

5.
Pediatr Res ; 85(1): 13-19, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30287891

RESUMEN

Congenital diaphragmatic hernia (CDH) is a commonly occurring major congenital anomaly with a profound impact on neonatal mortality. The etiology of CDH is poorly understood and is complicated by multiple clinical presentations, reflecting the location and type of diaphragm defect. With the increased power of genetic screening, more genes are being associated with CDH, creating a knowledge gap between CDH-associated genes and their contribution to diaphragm embryogenesis. Our goal was to investigate CDH-associated genes and identify common pathways that may lead to abnormal diaphragm development. A comprehensive list of CDH-associated genes was identified from the literature and categorized according to multiple factors, including type of CDH. We undertook a large-scale gene function analysis using gene ontology to identify significantly enriched biological pathways and molecular functions associated with our gene set. We identified 218 CDH-associated genes. Our gene ontology analysis showed that genes representing distinct biological pathways are significantly enriched in relation to different clinical presentations of CDH. This includes retinoic acid signaling in Bochdalek CDH, myogenesis in diaphragm eventration, and angiogenesis in central tendon defects. We have identified unique genotype-phenotype relationships highlighting the major genetic drivers of the different types of CDH.


Asunto(s)
Ontología de Genes , Redes Reguladoras de Genes , Hernias Diafragmáticas Congénitas/genética , Regulación de la Expresión Génica , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Hernias Diafragmáticas Congénitas/diagnóstico , Humanos , Fenotipo , Transducción de Señal/genética
6.
Lipids Health Dis ; 18(1): 204, 2019 Nov 22.
Artículo en Inglés | MEDLINE | ID: mdl-31757217

RESUMEN

The ability of mammals to store and draw on fat reserves has been a driving force throughout evolution in an environment with intermittent nutrient availability. The discovery of adipose triglyceride lipase (ATGL) as a triglyceride lipase provided a heightened understanding of the mechanisms governing mobilization of fat reserves from adipose tissue. ATGL catalyses the initial step in adipose triglyceride lipolysis, working in concert with other enzymes to mobilize triglyceride for energy production. In addition to the role of ATGL in adipose tissue triglyceride mobilization, ATGL plays crucial roles in regulating lipid homeostasis in other tissues. These roles have been characterized primarily using transgenic mice with tissue-specific ATGL ablation. For example, the global ATGL knockout induces a severe cardiac defect that results in premature mortality that is mimicked by inducible cardiomyocyte-specific ATGL knockout. Global- and adipose-specific ATGL ablation induces a whole-body shift from lipid metabolism to glucose metabolism to satisfy metabolic demand primarily facilitated by an increase in glucose uptake by skeletal muscle. Generation of liver-specific ATGL knockouts has implicated hepatic lipolysis as a critical component of normal liver function. Analysis of ß-cell ATGL knockouts implicates the necessity of pancreatic ATGL in insulin secretion. The objective of this review is to discuss the contributions of ATGL to systemic lipid- and glucose-homeostasis discovered through the study of transgenic mice.


Asunto(s)
Tejido Adiposo/metabolismo , Glucosa/metabolismo , Glucólisis/genética , Lipasa/genética , Lipólisis/genética , Triglicéridos/metabolismo , Animales , Expresión Génica , Homeostasis/genética , Insulina/metabolismo , Lipasa/deficiencia , Lipasa/metabolismo , Hígado/metabolismo , Ratones , Ratones Transgénicos , Músculo Esquelético/metabolismo , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Páncreas/metabolismo
7.
Alcohol Clin Exp Res ; 42(12): 2298-2312, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30192394

RESUMEN

BACKGROUND: The first stage of alcoholic liver disease is hepatic steatosis. While alcohol is known to profoundly impact hepatic lipid metabolism, gaps in our knowledge remain regarding the mechanisms leading to alcohol-induced hepatic triglyceride (TG) accumulation. As the sole enzymes catalyzing the final step in TG synthesis, diacylglycerol O-acyltransferase (DGAT) 1 and 2 are potentially important contributors to alcoholic steatosis. Our goal was to study the effects of dietary fat content on alcohol-induced hepatic TG accumulation, and the relative contribution of DGAT1 and DGAT2 to alcoholic steatosis. METHODS: These studies were carried out in wild-type (WT) mice fed alcohol-containing high-fat or low-fat formulations of Lieber-DeCarli liquid diets, as well as follow-up studies in Dgat1-/- mice. RESULTS: A direct comparison of the low-fat and high-fat liquid diet in WT mice revealed surprisingly similar levels of alcoholic steatosis, although there were underlying differences in the pattern of hepatic lipid accumulation and expression of genes involved in hepatic lipid metabolism. Follow-up studies in Dgat1-/- mice revealed that these animals are protected from alcoholic steatosis when consumed as part of a high-fat diet, but not a low-fat diet. CONCLUSIONS: Dietary macronutrient composition influences the relative contribution of DGAT1 and DGAT2 to alcoholic steatosis, such that in the context of alcohol and a high-fat diet, DGAT1 predominates.


Asunto(s)
Diacilglicerol O-Acetiltransferasa/genética , Dieta , Hígado Graso Alcohólico/genética , Nutrientes , Animales , Dieta con Restricción de Grasas , Grasas de la Dieta , Hígado Graso Alcohólico/patología , Regulación Enzimológica de la Expresión Génica , Metabolismo de los Lípidos/efectos de los fármacos , Metabolismo de los Lípidos/genética , Hígado/metabolismo , Hígado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Triglicéridos/metabolismo
8.
J Lipid Res ; 58(8): 1692-1701, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-28634191

RESUMEN

The scavenger receptor and multiligand transporter CD36 functions to promote cellular free fatty acid uptake and regulates aspects of both hepatic and intestinal cholesterol metabolism. However, the role of CD36 in regulating canalicular and biliary cholesterol transport and secretion is unknown. Here, we show that germline Cd36 knockout (KO) mice are protected against lithogenic diet (LD)-induced gallstones compared with congenic (C57BL6/J) controls. Cd36 KO mice crossed into congenic L-Fabp KO mice (DKO mice) demonstrated protection against LD-induced gallstones, reversing the susceptibility phenotype observed in L-Fabp KO mice. DKO mice demonstrated reduced biliary cholesterol secretion and a shift into more hydrophophilic bile acid species, without changes in either BA pool size or fecal excretion. In addition, we found that the mean and maximum force of gallbladder contraction was increased in germline Cd36 KO mice, and gallbladder lipid content was reduced compared with wild-type controls. Finally, whereas germline Cd36 KO mice were protected against LD-induced gallstones, neither liver- nor intestine-specific Cd36 KO mice were protected. Taken together, our findings show that CD36 plays an important role in modifying gallstone susceptibility in mice, at least in part by altering biliary lipid composition, but also by promoting gallbladder contractility.


Asunto(s)
Antígenos CD36/deficiencia , Antígenos CD36/genética , Dieta/efectos adversos , Cálculos Biliares/genética , Animales , Ácidos y Sales Biliares/química , Ácidos y Sales Biliares/metabolismo , Colesterol/metabolismo , Vesícula Biliar/metabolismo , Vesícula Biliar/fisiopatología , Cálculos Biliares/etiología , Cálculos Biliares/metabolismo , Cálculos Biliares/fisiopatología , Técnicas de Inactivación de Genes , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Contracción Muscular/genética
9.
Subcell Biochem ; 81: 95-125, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27830502

RESUMEN

It is well established that chylomicron remnant (dietary) vitamin A is taken up from the circulation by hepatocytes, but more than 80 % of the vitamin A in the liver is stored in hepatic stellate cells (HSC). It presently is not known how vitamin A is transferred from hepatocytes to HSCs for storage. Since retinol-binding protein 4 (RBP4), a protein that is required for mobilizing stored vitamin A, is synthesized solely by hepatocytes and not HSCs, it similarly is not known how vitamin A is transferred from HSCs to hepatocytes. Although it has long been thought that RBP4 is absolutely essential for delivering vitamin A to tissues, recent research has proven that this notion is incorrect since total RBP4-deficiency is not lethal. In addition to RBP4, vitamin A is also found in the circulation bound to lipoproteins and as retinoic acid bound to albumin. It is not known how these different circulating pools of vitamin A contribute to the vitamin A needs of different tissues. In our view, better insight into these three issues is required to better understand vitamin A absorption, storage and mobilization. Here, we provide an up to date synthesis of current knowledge regarding the intestinal uptake of dietary vitamin A, the storage of vitamin A within the liver, and the mobilization of hepatic vitamin A stores, and summarize areas where our understanding of these processes is incomplete.


Asunto(s)
Hígado/metabolismo , Vitamina A/metabolismo , Tejido Adiposo/metabolismo , Animales , Transporte Biológico , Carotenoides/metabolismo , Quilomicrones/metabolismo , Predicción , Células Estrelladas Hepáticas/metabolismo , Hepatocitos/metabolismo , Humanos , Absorción Intestinal , Lipoproteínas/metabolismo , Modelos Biológicos , Proteínas Plasmáticas de Unión al Retinol/metabolismo , Albúmina Sérica/metabolismo , Deficiencia de Vitamina A/metabolismo
10.
FASEB J ; 29(9): 3654-67, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25985802

RESUMEN

The alcohol-induced depletion of hepatic retinoid stores correlates with the progression of liver injury; however, the mechanisms underlying alcohol's effects have not been fully elucidated. Our goal was to gain a mechanistic understanding of alcohol-induced hepatic retinoid depletion. Wild-type and mutant mice were continuously fed alcohol through Lieber-DeCarli liquid diets, with matched control animals pair fed an isocaloric alcohol-free diet to ensure equal nutrient and calorie intake between groups. A systematic analysis of tissue retinol and retinyl ester levels was performed with HPLC, complemented by gene and protein expression analyses. Our results delineated 2 phases of alcohol-induced depletion of hepatic retinoid. Initially, ∼15% of hepatic retinoid content was mobilized from the liver, causing extrahepatic tissue retinoid levels to increase. Subsequently, there was a precipitous drop in hepatic retinoid content (>60%), without further retinoid accumulation in the periphery. Follow-up studies in mutant mice revealed roles for RBP, CRBP1, and CD36 in retinoid mobilization and extrahepatic retinoid uptake, as well as a role for CYP2E1 in the catabolism of hepatic retinoid. In summary, alcohol has a biphasic effect on hepatic retinoid stores, characterized by an initial phase of rapid mobilization to extrahepatic tissues followed by extensive catabolism within the liver.


Asunto(s)
Consumo de Bebidas Alcohólicas/metabolismo , Hígado/metabolismo , Retinoides/metabolismo , Consumo de Bebidas Alcohólicas/genética , Consumo de Bebidas Alcohólicas/patología , Animales , Antígenos CD36/genética , Antígenos CD36/metabolismo , Enfermedad Crónica , Hígado/patología , Ratones , Ratones Noqueados , Retinoides/genética , Proteínas Celulares de Unión al Retinol/genética , Proteínas Celulares de Unión al Retinol/metabolismo
11.
J Lipid Res ; 55(2): 239-46, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24280415

RESUMEN

CD36 is a scavenger receptor with multiple ligands and cellular functions, including facilitating cellular uptake of free fatty acids (FFAs). Chronic alcohol consumption increases hepatic CD36 expression, leading to the hypothesis that this promotes uptake of circulating FFAs, which then serve as a substrate for triglyceride (TG) synthesis and the development of alcoholic steatosis. We investigated this hypothesis in alcohol-fed wild-type and Cd36-deficient (Cd36(-/-)) mice using low-fat/high-carbohydrate Lieber-DeCarli liquid diets, positing that Cd36(-/-) mice would be resistant to alcoholic steatosis. Our data show that the livers of Cd36(-/-) mice are resistant to the lipogenic effect of consuming high-carbohydrate liquid diets. These mice also do not further develop alcoholic steatosis when chronically fed alcohol. Surprisingly, we did not detect an effect of alcohol or CD36 deficiency on hepatic FFA uptake; however, the lower baseline levels of hepatic TG in Cd36(-/-) mice fed a liquid diet were associated with decreased expression of genes in the de novo lipogenesis pathway and a lower rate of hepatic de novo lipogenesis. In conclusion, Cd36(-/-) mice are resistant to hepatic steatosis when fed a high-carbohydrate liquid diet, and they are also resistant to alcoholic steatosis. These studies highlight an important role for CD36 in hepatic lipid homeostasis that is not associated with hepatic fatty acid uptake.


Asunto(s)
Antígenos CD36/deficiencia , Carbohidratos de la Dieta/efectos adversos , Resistencia a la Enfermedad , Hígado Graso Alcohólico/etiología , Hígado Graso Alcohólico/metabolismo , Animales , Grasas de la Dieta/análisis , Resistencia a la Enfermedad/efectos de los fármacos , Glucosa/metabolismo , Lipogénesis/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Triglicéridos/metabolismo
12.
Biochim Biophys Acta ; 1831(7): 1276-86, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24046868

RESUMEN

Retinoids (vitamin A and its metabolites) are essential micronutrients that regulate many cellular processes. Greater than 70% of the body's retinoid reserves are stored in the liver as retinyl ester (RE). Chronic alcohol consumption induces depletion of hepatic retinoid stores, and the extent of this has been correlated with advancing stages of alcoholic liver disease. The goal of this study was to analyze the mechanisms responsible for depletion of hepatic RE stores by alcohol consumption A change in the fatty-acyl composition of RE in alcohol-fed mice was observed within two weeks after the start of alcohol consumption. Specifically, alcohol-feeding was associated with a significant decline in hepatic retinyl palmitate levels; however, total RE levels were maintained by a compensatory increase in levels of usually minor RE species, particularly retinyl oleate. Our data suggests that alcohol feeding initially stimulates a futile cycle of RE hydrolysis and synthesis, and that the change in RE acyl composition is associated with a change in the acyl composition of hepatic phosphatidylcholine. The alcohol-induced change in RE acyl composition was specific to the liver, and was not seen in lung or white adipose tissue. This shift in hepatic RE fatty acyl composition is a sensitive indicator of alcohol consumption and may be an early biomarker for events associated with the development of alcoholic liver disease.


Asunto(s)
Consumo de Bebidas Alcohólicas/metabolismo , Hepatopatías Alcohólicas/metabolismo , Hígado/metabolismo , Vitamina A/análogos & derivados , Aciltransferasas/metabolismo , Tejido Adiposo Blanco/metabolismo , Consumo de Bebidas Alcohólicas/sangre , Animales , Diacilglicerol O-Acetiltransferasa/metabolismo , Diterpenos , Esterificación , Ésteres/metabolismo , Glicerol-3-Fosfato O-Aciltransferasa/metabolismo , Hidrólisis , Hepatopatías Alcohólicas/sangre , Pulmón/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Fosfatidilcolinas/metabolismo , Ésteres de Retinilo , Vitamina A/sangre , Vitamina A/metabolismo
13.
Zoo Biol ; 33(6): 527-35, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24958673

RESUMEN

Vitamin A status is an important consideration in the health of both wild and captive amphibians. Data concerning whole body vitamin A homeostasis in amphibians are scarce, although these animals have been used as experimental models to study the actions of vitamin A in vision, limb regeneration and embryogenesis. The available data suggest that many aspects of vitamin A biology in amphibians are similar to the canonical characteristics of vitamin A metabolism and actions established in mammals. This is consistent with the evolutionary conservation of these important biological processes. Amphibians must obtain vitamin A in their diet, with captive animals being prone to vitamin A deficiency. There is still much to be learned about vitamin A biology in amphibians that can only be achieved through rigorous scientific research. Improved understanding of amphibian vitamin A biology will aid the conservation of endangered amphibians in the wild, as well as the successful maintenance of ex situ populations.


Asunto(s)
Anfibios/metabolismo , Crianza de Animales Domésticos/métodos , Fenómenos Fisiológicos Nutricionales de los Animales , Conservación de los Recursos Naturales/métodos , Vitamina A/metabolismo , Animales , Especificidad de la Especie
14.
Alcohol Clin Exp Res (Hoboken) ; 48(6): 1036-1049, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38649284

RESUMEN

BACKGROUND: Chronic alcohol consumption is a major public health issue. The primary organ damaged by alcohol abuse is the liver, leading to alcohol-associated liver disease (ALD). ALD begins with hepatic steatosis and can progress to fibrosis and cirrhosis; however, we have an incomplete understanding of ALD pathogenesis. Interestingly, the liver is also the major organ for vitamin A metabolism and storage, and ALD has previously been linked with altered hepatic vitamin A homeostasis. We hypothesize that alcohol-induced vitamin A depletion disrupts its normal function in the liver, contributing to the pathogenesis of ALD. To test this hypothesis, we postulated that adding copious vitamin A to the diet might alleviate ALD, and conversely, that a vitamin A deficient diet would worsen ALD. METHODS: We conducted two dietary intervention studies in mice comparing deficient (0 IU/g diet) and copious (25 IU/g diet) dietary vitamin A intake versus control (4 IU/g diet), using the NIAAA chronic-binge model of ALD. Hepatic steatosis was assessed using histopathological and biochemical approaches. Tissue Vitamin A levels were measured using high-performance liquid chromatography. Markers of ALD, hepatic inflammation and lipid metabolism were analyzed by the quantitative polymerase chain reaction and western blotting. RESULTS: As expected, a 0 IU/g Vitamin A diet decreased, and a 25 IU/g Vitamin A diet increased hepatic Vitamin A stores. However, alcohol induced changes in hepatic triglyceride levels, markers of hepatic lipid metabolism, inflammation and fibrosis were not significantly different in mice consuming a copious or deficient vitamin A diet compared to control. CONCLUSIONS: Altered vitamin A intake and hepatic vitamin A storage have a minor effect on the pathogenesis of ALD. Thus, given the known link between altered retinoic acid signaling and ALD, future studies that further explore this linkage are warranted.

15.
J Mol Cell Cardiol ; 59: 30-40, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23422163

RESUMEN

Alcohol, a major cause of human cardiomyopathy, decreases cardiac contractility in both animals and man. However, key features of alcohol-related human heart disease are not consistently reproduced in animal models. Accordingly, we studied cardiac histology, contractile function, cardiomyocyte long chain fatty acid (LCFA) uptake, and gene expression in male C57BL/6J mice consuming 0, 10, 14, or 18% ethanol in drinking water for 3months. At sacrifice, all EtOH groups had mildly decreased body and increased heart weights, dose-dependent increases in cardiac triglycerides and a marked increase in cardiac fatty acid ethyl esters. [(3)H]-oleic acid uptake kinetics demonstrated increased facilitated cardiomyocyte LCFA uptake, associated with increased expression of genes encoding the LCFA transporters CD36 and Slc27a1 (FATP1) in EtOH-fed animals. Although SCD-1 expression was increased, lipidomic analysis did not indicate significantly increased de novo LCFA synthesis. By echocardiography, ejection fraction (EF) and the related fractional shortening (FS) of left ventricular diameter during systole were reduced and negatively correlated with cardiac triglycerides. Expression of myocardial PGC-1α and multiple downstream target genes in the oxidative phosphorylation pathway, including several in the electron transport and ATP synthase complexes of the inner mitochondrial membrane, were down-regulated. Cardiac ATP was correspondingly reduced. The data suggest that decreased expression of PGC-1α and its target genes result in decreased cardiac ATP levels, which may explain the decrease in myocardial contractile function caused by chronic EtOH intake. This model recapitulates important features of human alcoholic cardiomyopathy and illustrates a potentially important pathophysiologic link between cardiac lipid metabolism and function.


Asunto(s)
Etanol/efectos adversos , Ácidos Grasos/metabolismo , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/metabolismo , Contracción Miocárdica/efectos de los fármacos , Animales , Células Cultivadas , Ecocardiografía , Ratones , Ratones Endogámicos C57BL , Microscopía Electrónica de Transmisión , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa
16.
Biochim Biophys Acta ; 1821(1): 124-36, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21763780

RESUMEN

The liver is the most important tissue site in the body for uptake of postprandial retinoid, as well as for retinoid storage. Within the liver, both hepatocytes and hepatic stellate cells (HSCs) are importantly involved in retinoid metabolism. Hepatocytes play an indispensable role in uptake and processing of dietary retinoid into the liver, and in synthesis and secretion of retinol-binding protein (RBP), which is required for mobilizing hepatic retinoid stores. HSCs are the central cellular site for retinoid storage in the healthy animal, accounting for as much as 50-60% of the total retinoid present in the entire body. The liver is also an important target organ for retinoid actions. Retinoic acid is synthesized in the liver and can interact with retinoid receptors which control expression of a large number of genes involved in hepatic processes. Altered retinoid metabolism and the accompanying dysregulation of retinoid signaling in the liver contribute to hepatic disease. This is related to HSCs, which contribute significantly to the development of hepatic disease when they undergo a process of cellular activation. HSC activation results in the loss of HSC retinoid stores and changes in extracellular matrix deposition leading to the onset of liver fibrosis. An association between hepatic disease progression and decreased hepatic retinoid storage has been demonstrated. In this review article, we summarize the essential role of the liver in retinoid metabolism and consider briefly associations between hepatic retinoid metabolism and disease. This article is part of a Special Issue entitled Retinoid and Lipid Metabolism.


Asunto(s)
Hepatopatías/metabolismo , Hígado/metabolismo , Retinoides/metabolismo , Animales , Transporte Biológico , Células Estrelladas Hepáticas/metabolismo , Humanos , Metabolismo de los Lípidos , Hígado/patología , Hepatopatías/patología , Ratones , Ratas , Proteínas de Unión al Retinol/metabolismo , Transducción de Señal
17.
Biochim Biophys Acta ; 1831(7): 1276-86, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23583843

RESUMEN

Retinoids (vitamin A and its metabolites) are essential micronutrients that regulate many cellular processes. Greater than 70% of the body's retinoid reserves are stored in the liver as retinyl ester (RE). Chronic alcohol consumption induces depletion of hepatic retinoid stores, and the extent of this has been correlated with advancing stages of alcoholic liver disease. The goal of this study was to analyze the mechanisms responsible for depletion of hepatic RE stores by alcohol consumption. A change in the fatty-acyl composition of RE in alcohol-fed mice was observed within two weeks after the start of alcohol consumption. Specifically, alcohol-feeding was associated with a significant decline in hepatic retinyl palmitate levels; however, total RE levels were maintained by a compensatory increase in levels of usually minor RE species, particularly retinyl oleate. Our data suggests that alcohol feeding initially stimulates a futile cycle of RE hydrolysis and synthesis, and that the change in RE acyl composition is associated with a change in the acyl composition of hepatic phosphatidylcholine. The alcohol-induced change in RE acyl composition was specific to the liver, and was not seen in lung or white adipose tissue. This shift in hepatic RE fatty acyl composition is a sensitive indicator of alcohol consumption and may be an early biomarker for events associated with the development of alcoholic liver disease.

18.
J Nutr Biochem ; 112: 109227, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36435294

RESUMEN

Long-term alterations in kidney structure and function have been observed in offspring exposed to perinatal stressors such as iron deficiency (ID), albeit the mechanisms underlying these changes remain unclear. Here, we assessed how perinatal ID alters renal vitamin A metabolism, an important contributor to nephrogenesis, in the developing kidney. Pregnant Sprague Dawley rats were fed either an iron-restricted or -replete diet throughout gestation, and offspring were studied on postnatal day (PD)1 and 28. Maternal iron restriction results in reduced renal retinoid concentrations in male and female offspring on PD1 (P=.005). Nephron endowment was reduced by 21% in male perinatal ID offspring (P<.001), whereas it was unaffected in perinatal ID females. Perinatal ID resulted in sex-dependent changes in kidney retinoid synthesis and metabolism, whereby male offspring exhibited increased expression of Raldh2 and Rar/Rxr isoforms, while females exhibited unchanged or decreased expression (all interaction P<.05). Male perinatal ID offspring exhibit sex-specific enhancements of retinoic acid pathway signaling components on PD1, including Gdnf (P<.01) and Ctnnb1 (P<.01), albeit robust upregulation of RA transcriptional target Stra6 was observed in both sexes (P=.006). On PD28, perinatal ID resulted in elevated renal retinoid concentrations (P=.02) coinciding with enhanced expression of Raldh2 (P=.04), but not any Rar isoform or Rxr. Further, perinatal ID resulted in robust upregulation of Gdnf, Ret, Ctnnb1, associated with further increases in both Cxcr4 and Stra6 (all P<.01) at PD28. Together, these data suggest perinatal ID results in sustained sex-dependent perturbations in vitamin A metabolism, which likely underlie sex-specific reductions in nephron endowment.


Asunto(s)
Deficiencias de Hierro , Tretinoina , Embarazo , Ratas , Animales , Masculino , Femenino , Factor Neurotrófico Derivado de la Línea Celular Glial , Ratas Sprague-Dawley , Vitamina A , Riñón/metabolismo , Hierro/metabolismo
19.
Metabolites ; 13(2)2023 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-36837793

RESUMEN

Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, is a global health problem. Currently, no pharmacological treatment is approved for NAFLD. Natural health products, including bioactive peptides, are potential candidates to aid in the management of metabolic syndrome-related conditions, including insulin resistance and obesity. In this study, we hypothesized that an egg-white-derived bioactive peptide QAMPFRVTEQE (Peptide 2) would improve systemic and local white adipose tissue insulin sensitivity, thereby preventing high-fat diet-induced exacerbation of pathological features associated with NAFLD, such as lipid droplet size and number, inflammation, and hepatocyte hypertrophy in high-fat diet-fed mice. Similar to rosiglitazone, Peptide 2 supplementation improved systemic insulin resistance during the hyperinsulinemic-euglycemic clamp and enhanced insulin signalling in white adipose tissue, modulating ex vivo lipolysis. In the liver, compared with high-fat diet fed animals, Peptide 2 supplemented animals presented decreased hepatic cholesterol accumulation (p < 0.05) and area of individual hepatic lipid droplet by around 50% (p = 0.09) and reduced hepatic inflammatory infiltration (p < 0.05) whereas rosiglitazone exacerbated steatosis. In conclusion, Peptide 2 supplementation improved insulin sensitivity and decreased hepatic steatosis, unlike the insulin-sensitizing drug rosiglitazone.

20.
Front Physiol ; 13: 940974, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35864895

RESUMEN

Alcohol-associated liver disease (ALD) is a major public health issue that significantly contributes to human morbidity and mortality, with no FDA-approved therapeutic intervention available. The health burden of ALD has worsened during the COVID-19 pandemic, which has been associated with a spike in alcohol abuse, and a subsequent increase in hospitalization rates for ALD. A key knowledge gap that underlies the lack of novel therapies for ALD is a need to better understand the pathogenic mechanisms that contribute to ALD initiation, particularly with respect to hepatic lipid accumulation and the development of fatty liver, which is the first step in the ALD spectrum. The goal of this review is to evaluate the existing literature to gain insight into the pathogenesis of alcohol-associated fatty liver, and to synthesize alcohol's known effects on hepatic lipid metabolism. To achieve this goal, we specifically focus on studies from transgenic mouse models of ALD, allowing for a genetic dissection of alcohol's effects, and integrate these findings with our current understanding of ALD pathogenesis. Existing studies using transgenic mouse models of ALD have revealed roles for specific genes involved in hepatic lipid metabolic pathways including fatty acid uptake, mitochondrial ß-oxidation, de novo lipogenesis, triglyceride metabolism, and lipid droplet formation. In addition to reviewing this literature, we conclude by identifying current gaps in our understanding of how alcohol abuse impairs hepatic lipid metabolism and identify future directions to address these gaps. In summary, transgenic mice provide a powerful tool to understand alcohol's effect on hepatic lipid metabolism and highlight that alcohol abuse has diverse effects that contribute to the development of alcohol-associated fatty liver disease.

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