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1.
Hepatology ; 78(3): 709-726, 2023 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-36999529

RESUMEN

BACKGROUND AND AIMS: Cholestasis is characterized by intrahepatic accumulation of bile constituents, including bile acids (BAs), which promote liver damage. The apical sodium-dependent BA transporter (ASBT) plays an important role in BA reabsorption and signaling in ileum, bile ducts, and kidneys. Our aim was to investigate the pharmacokinetics and pharmacological activity of A3907, an oral and systemically available ASBT inhibitor in experimental mouse models of cholestasis. In addition, the tolerability, pharmacokinetics, and pharmacodynamics of A3907 were examined in healthy humans. APPROACH AND RESULTS: A3907 was a potent and selective ASBT inhibitor in vitro. In rodents, orally administered A3907 distributed to the ASBT-expressing organs, that is, ileum, liver, and kidneys, and dose dependently increased fecal BA excretion. A3907 improved biochemical, histological, and molecular markers of liver and bile duct injury in Mdr2-/- mice and also had direct protective effects on rat cholangiocytes exposed to cytotoxic BA concentrations in vitro . In bile duct ligated mice, A3907 increased urinary BA elimination, reduced serum BA levels, and prevented body weight loss, while improving markers of liver injury. A3907 was well tolerated and demonstrated target engagement in healthy volunteers. Plasma exposure of A3907 in humans was within the range of systemic concentrations that achieved therapeutic efficacy in mouse. CONCLUSIONS: The systemic ASBT inhibitor A3907 improved experimental cholestatic disease by targeting ASBT function at the intestinal, liver, and kidney levels, resulting in marked clearance of circulating BAs and liver protection. A3907 is well tolerated in humans, supporting further clinical development for the treatment of cholestatic liver diseases.


Asunto(s)
Colestasis , Simportadores , Humanos , Ratones , Animales , Ratas , Colestasis/tratamiento farmacológico , Hígado , Conductos Biliares , Bilis , Ácidos y Sales Biliares/uso terapéutico , Proteínas de Transporte de Membrana , Transportadores de Anión Orgánico Sodio-Dependiente
2.
PLoS One ; 17(10): e0275901, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36260611

RESUMEN

Non-invasive biomarkers of non-alcoholic fatty liver disease (NAFLD) supporting diagnosis and monitoring disease progression are urgently needed. The present study aimed to establish a bioinformatics pipeline capable of defining and validating NAFLD biomarker candidates based on paired hepatic global gene expression and plasma bioanalysis from individuals representing different stages of histologically confirmed NAFLD (no/mild, moderate, more advanced NAFLD). Liver secretome gene signatures were generated in a patient cohort of 26 severely obese individuals with the majority having no or mild fibrosis. To this end, global gene expression changes were compared between individuals with no/mild NAFLD and moderate/advanced NAFLD with subsequent filtering for candidate gene products with liver-selective expression and secretion. Four candidate genes, including LPA (lipoprotein A), IGFBP-1 (insulin-like growth factor-binding protein 1), SERPINF2 (serpin family F member 2) and MAT1A (methionine adenosyltransferase 1A), were differentially expressed in moderate/advanced NAFLD, which was confirmed in three independent RNA sequencing datasets from large, publicly available NAFLD studies. The corresponding gene products were quantified in plasma samples but could not discriminate among different grades of NAFLD based on NAFLD activity score. Conclusion: We demonstrate a novel approach based on the liver transcriptome allowing for identification of secreted hepatic gene products as potential circulating diagnostic biomarkers of NAFLD. Using this approach in larger NAFLD patient cohorts may yield potential circulating biomarkers for NAFLD severity.


Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Serpinas , Somatomedinas , Humanos , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/genética , Proteína 1 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Metionina Adenosiltransferasa/genética , Secretoma , Serpinas/metabolismo , Biomarcadores , Somatomedinas/metabolismo , Lipoproteína(a)/metabolismo
3.
J Clin Endocrinol Metab ; 106(2): e966-e981, 2021 01 23.
Artículo en Inglés | MEDLINE | ID: mdl-33135737

RESUMEN

CONTEXT: The mechanisms underlying Roux-en-Y gastric bypass (RYGB) surgery-induced weight loss and the immediate postoperative beneficial metabolic effects associated with the operation remain uncertain. Enteroendocrine cell (EEC) secretory function has been proposed as a key factor in the marked metabolic benefits from RYGB surgery. OBJECTIVE: To identify novel gut-derived peptides with therapeutic potential in obesity and/or diabetes by profiling EEC-specific molecular changes in obese patients following RYGB-induced weight loss. SUBJECTS AND METHODS: Genome-wide expression analysis was performed in isolated human small intestinal EECs obtained from 20 gut-biopsied obese subjects before and after RYGB. Targets of interest were profiled for preclinical and clinical metabolic effects. RESULTS: Roux-en-Y gastric bypass consistently increased expression levels of the inverse ghrelin receptor agonist, liver-expressed antimicrobial peptide 2 (LEAP2). A secreted endogenous LEAP2 fragment (LEAP238-47) demonstrated robust insulinotropic properties, stimulating insulin release in human pancreatic islets comparable to the gut hormone glucagon-like peptide-1. LEAP238-47 showed reciprocal effects on growth hormone secretagogue receptor (GHSR) activity, suggesting that the insulinotropic action of the peptide may be directly linked to attenuation of tonic GHSR activity. The fragment was infused in healthy human individuals (n = 10), but no glucoregulatory effect was observed in the chosen dose as compared to placebo. CONCLUSIONS: Small intestinal LEAP2 expression was upregulated after RYGB. The corresponding circulating LEAP238-47 fragment demonstrated strong insulinotropic action in vitro but failed to elicit glucoregulatory effects in healthy human subjects.


Asunto(s)
Péptidos Catiónicos Antimicrobianos/metabolismo , Proteínas Sanguíneas/metabolismo , Derivación Gástrica/métodos , Tracto Gastrointestinal/metabolismo , Islotes Pancreáticos/metabolismo , Obesidad/cirugía , Fragmentos de Péptidos/metabolismo , Transcriptoma , Adolescente , Adulto , Péptidos Catiónicos Antimicrobianos/genética , Biomarcadores/análisis , Proteínas Sanguíneas/genética , Estudios de Casos y Controles , Estudios Cruzados , Método Doble Ciego , Células Enteroendocrinas/metabolismo , Células Enteroendocrinas/patología , Femenino , Estudios de Seguimiento , Humanos , Islotes Pancreáticos/patología , Masculino , Obesidad/patología , Fragmentos de Péptidos/genética , Pronóstico , Estudios Prospectivos , Adulto Joven
4.
Nat Genet ; 51(4): 716-727, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30833796

RESUMEN

Mesenchymal (stromal) stem cells (MSCs) constitute populations of mesodermal multipotent cells involved in tissue regeneration and homeostasis in many different organs. Here we performed comprehensive characterization of the transcriptional and epigenomic changes associated with osteoblast and adipocyte differentiation of human MSCs. We demonstrate that adipogenesis is driven by considerable remodeling of the chromatin landscape and de novo activation of enhancers, whereas osteogenesis involves activation of preestablished enhancers. Using machine learning algorithms for in silico modeling of transcriptional regulation, we identify a large and diverse transcriptional network of pro-osteogenic and antiadipogenic transcription factors. Intriguingly, binding motifs for these factors overlap with SNPs related to bone and fat formation in humans, and knockdown of single members of this network is sufficient to modulate differentiation in both directions, thus indicating that lineage determination is a delicate balance between the activities of many different transcription factors.


Asunto(s)
Adipogénesis/genética , Osteogénesis/genética , Factor de Células Madre/genética , Factores de Transcripción/genética , Células A549 , Adipocitos/fisiología , Diferenciación Celular/genética , Línea Celular Tumoral , Células Cultivadas , Células HEK293 , Humanos , Células Madre Mesenquimatosas/fisiología , Osteoblastos/fisiología , Polimorfismo de Nucleótido Simple/genética
5.
Nat Genet ; 51(4): 766, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30911162

RESUMEN

In the version of this article initially published, in the graph keys in Fig. 1i, the colors indicating 'Ob' and 'Ad' were red and blue, respectively, but should have been blue and red, respectively; the shapes indicating 'MUS' and 'BM' were a triangle and a square, respectively, but should have been a square and a triangle, respectively. The errors have been corrected in the HTML and PDF versions of the article.

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