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1.
Nat Commun ; 8(1): 384, 2017 08 30.
Artículo en Inglés | MEDLINE | ID: mdl-28855500

RESUMEN

The liver integrates multiple metabolic pathways to warrant systemic energy homeostasis. An excessive lipogenic flux due to chronic dietary stimulation contributes to the development of hepatic steatosis, dyslipidemia and hyperglycemia. Here we show that the oxidoreductase retinol saturase (RetSat) is involved in the development of fatty liver. Hepatic RetSat expression correlates with steatosis and serum triglycerides (TGs) in humans. Liver-specific depletion of RetSat in dietary obese mice lowers hepatic and circulating TGs and normalizes hyperglycemia. Mechanistically, RetSat depletion reduces the activity of carbohydrate response element binding protein (ChREBP), a cellular hexose-phosphate sensor and inducer of lipogenesis. Defects upon RetSat depletion are rescued by ectopic expression of ChREBP but not by its putative enzymatic product 13,14-dihydroretinol, suggesting that RetSat affects hepatic glucose sensing independent of retinol conversion. Thus, RetSat is a critical regulator of liver metabolism functioning upstream of ChREBP. Pharmacological inhibition of liver RetSat may represent a therapeutic approach for steatosis.Fatty liver is one of the major features of metabolic syndrome and its development is associated with deregulation of systemic lipid and glucose homeostasis. Here Heidenreich et al. show that retinol saturase is implicated in hepatic lipid metabolism by regulating the activity of the transcription factor ChREBP.


Asunto(s)
Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Hígado Graso/metabolismo , Hígado/metabolismo , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/fisiología , Animales , Glucosa/metabolismo , Hepatocitos/metabolismo , Humanos , Metabolismo de los Lípidos , Masculino , Ratones , Ratones Endogámicos C57BL , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/genética , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/metabolismo , Triglicéridos/sangre
2.
Horm Metab Res ; 49(5): 343-349, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-28351093

RESUMEN

Angiopoietin-like protein 8 (ANGPTL8)/betatrophin expression in visceral adipose tissue and associations with circulating fatty acid profile have not yet been investigated.Forty subjects were included in a cross-sectional study, 57 in a dietary weight reduction intervention. Circulating Angiopoietin-like protein 8/betatrophin was measured in all subjects. Liver and adipose tissue were sampled and plasma fatty acids and tissue Angiopoietin-like protein 8/betatrophin expression were evaluated in the cross-sectional study. In the intervention study oral glucose testing and liver magnetic resonance scanning at baseline and after 6 months were performed. Angiopoietin-like protein 8/betatrophin mRNA was increased in visceral compared to subcutaneous adipose tissue (p<0.001). Circulating ANGPTL8/betatrophin correlated with liver steatosis (r=0.42, p=0.047), triacylglycerols (r=0.34, p=0.046), saturated (r=0.43, p=0.022), monounsaturated (r=0.51, p=0.007), and polyunsaturated fatty acids (r=-0.53, p=0.004). In the intervention study, baseline Angiopoietin-like protein 8/betatrophin correlated with age (r=0.32, p=0.010) and triacylglycerols (r=0.30, p=0.02) and was increased with hepatic steatosis (p=0.033). Weight loss reduced liver fat by 45% and circulating Angiopoietin-like protein 8/betatrophin by 11% (288±17 vs. 258±17 pg/ml; p=0.015). Angiopoietin-like protein 8/betatrophin is related to liver steatosis, while visceral adipose tissue represents an additional site of expression in humans.


Asunto(s)
Proteínas Similares a la Angiopoyetina/genética , Hígado Graso/genética , Grasa Intraabdominal/metabolismo , Hormonas Peptídicas/genética , Proteína 8 Similar a la Angiopoyetina , Proteínas Similares a la Angiopoyetina/metabolismo , Estudios de Cohortes , Dieta , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/genética , Hormonas Peptídicas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo
3.
Hepatol Res ; 47(9): 890-901, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-27689765

RESUMEN

AIMS: Molecular adaptations in human non-alcoholic fatty liver disease (NAFLD) are incompletely understood. This study investigated the main gene categories related to hepatic de novo lipogenesis and lipid oxidation capacity. METHODS: Liver specimens of 48 subjects were histologically classified according to steatosis severity. In-depth analyses were undertaken using real-time polymerase chain reaction, immunoblotting, and immunohistochemistry. Lipid profiles were analyzed by gas chromatography/flame ionization detection, and effects of key fatty acids were studied in primary human hepatocytes. RESULTS: Real-time polymerase chain reaction, immunoblotting, and immunohistochemistry indicated 5'AMP-activated protein kinase (AMPK) to be increased with steatosis score ≥ 2 (all P < 0.05), including various markers of de novo lipogenesis and lipid degradation (all P < 0.05). Regarding endoplasmic reticulum stress, X-Box binding protein-1 (XBP1) was upregulated in steatosis score ≥ 2 (P = 0.029) and correlated with plasma palmitate (r = 0.34; P = 0.035). Palmitate incubation of primary human hepatocytes increased XBP1 and downstream stearoyl CoA desaturase-1 mRNA expression (both P < 0.05). Moreover, plasma and liver tissue exposed a NAFLD-related lipid profile with reduced polyunsaturated/saturated fatty acid ratio, increased palmitate and palmitoleate, and elevated lipogenesis and desaturation indices with steatosis score ≥ 2 (all P < 0.05). CONCLUSION: In humans with advanced fatty liver disease, hepatic AMPK protein is upregulated, potentially in a compensatory manner. Moreover, pathways of lipid synthesis and degradation are co-activated in subjects with advanced steatosis. Palmitate may drive lipogenesis by activating XBP1-mediated endoplasmic reticulum stress and represent a target for future dietary or pharmacological intervention.

4.
Cell Cycle ; 14(14): 2293-300, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25945652

RESUMEN

Diabetes mellitus type 2 (T2DM), insulin therapy, and hyperinsulinemia are independent risk factors of liver cancer. Recently, the use of a novel inhibitor of insulin degrading enzyme (IDE) was proposed as a new therapeutic strategy in T2DM. However, IDE inhibition might stimulate liver cell proliferation via increased intracellular insulin concentration. The aim of this study was to characterize effects of inhibition of IDE activity in HepG2 hepatoma cells and to analyze liver specific expression of IDE in subjects with T2DM. HepG2 cells were treated with 10 nM insulin for 24 h with or without inhibition of IDE activity using IDE RNAi, and cell transcriptome and proliferation rate were analyzed. Human liver samples (n = 22) were used for the gene expression profiling by microarrays. In HepG2 cells, IDE knockdown changed expression of genes involved in cell cycle and apoptosis pathways. Proliferation rate was lower in IDE knockdown cells than in controls. Microarray analysis revealed the decrease of hepatic IDE expression in subjects with T2DM accompanied by the downregulation of the p53-dependent genes FAS and CCNG2, but not by the upregulation of proliferation markers MKI67, MCM2 and PCNA. Similar results were found in the liver microarray dataset from GEO Profiles database. In conclusion, IDE expression is decreased in liver of subjects with T2DM which is accompanied by the dysregulation of p53 pathway. Prolonged use of IDE inhibitors for T2DM treatment should be carefully tested in animal studies regarding its potential effect on hepatic tumorigenesis.


Asunto(s)
Proliferación Celular/efectos de los fármacos , Insulina/farmacología , Insulisina/metabolismo , Hígado/metabolismo , Adulto , Anciano , Apoptosis/efectos de los fármacos , Estudios de Cohortes , Ciclina G2/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Femenino , Perfilación de la Expresión Génica , Células Hep G2 , Humanos , Insulisina/antagonistas & inhibidores , Insulisina/genética , Antígeno Ki-67/metabolismo , Masculino , Persona de Mediana Edad , Componente 2 del Complejo de Mantenimiento de Minicromosoma/metabolismo , Antígeno Nuclear de Célula en Proliferación/metabolismo , Interferencia de ARN , Transcriptoma/efectos de los fármacos , Receptor fas/metabolismo
5.
Diabetes ; 64(3): 856-66, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25281430

RESUMEN

WISP1 (Wnt1-inducible signaling pathway protein-1, also known as CCN4) is a member of the secreted extracellular matrix-associated proteins of the CCN family and a target gene of the Wingless-type (WNT) signaling pathway. Growing evidence links the WNT signaling pathway to the regulation of adipogenesis and low-grade inflammation in obesity. We aimed to validate WISP1 as a novel adipokine. Human adipocyte differentiation was associated with increased WISP1 expression and secretion. Stimulation of human macrophages with WISP1 led to a proinflammatory response. Circulating WISP1 and WISP1 subcutaneous adipose tissue expression were regulated by weight changes in humans and mice. WISP1 expression in visceral and subcutaneous fat tissue was associated with markers of insulin resistance and inflammation in glucose-tolerant subjects. In patients with nonalcoholic fatty liver disease, we found no correlation among disease activity score, liver fat content, and WISP1 expression. Insulin regulated WISP1 expression in adipocytes in vitro but had no acute effect on WISP1 gene expression in subcutaneous fat tissue in overweight subjects who had undergone hyperinsulinemic clamp experiments. The data suggest that WISP1 may play a role in linking obesity to inflammation and insulin resistance and could be a novel therapeutic target for obesity.


Asunto(s)
Adipoquinas/metabolismo , Proteínas CCN de Señalización Intercelular/metabolismo , Inflamación/metabolismo , Obesidad/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Tejido Adiposo/metabolismo , Animales , Western Blotting , Proteínas CCN de Señalización Intercelular/genética , Células Cultivadas , Humanos , Grasa Intraabdominal/metabolismo , Macrófagos/metabolismo , Imagen por Resonancia Magnética , Masculino , Células Madre Mesenquimatosas , Ratones , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Proteínas Proto-Oncogénicas/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Grasa Subcutánea/metabolismo
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