Rocío Gallego-Durán, Javier Ampuero, Douglas Maya-Miles, Helena Pastor-Ramírez, Rocío Montero-Vallejo, Jesús Rivera-Esteban, Leticia Álvarez-Amor, María Jesús Pareja, María Carmen Rico, Raquel Millán, María José Robles-Frías, Rocío Aller, Ángela Rojas, Rocío Muñoz-Hernández, Antonio Gil-Gómez, Sheila Gato, María García-Lozano, María Teresa Arias-Loste, Javier Abad, José Luis Calleja, Raúl J Andrade, Javier Crespo, Águeda González-Rodríguez, Carmelo García-Monzón, Fausto Andreola, Juan Manuel Pericás, Rajiv Jalan, Francisco Martín-Bermudo, Manuel Romero-Gómez
{"title":"成纤维细胞生长因子 21 是一种参与 MASLD 进展的肝脏因子。","authors":"Rocío Gallego-Durán, Javier Ampuero, Douglas Maya-Miles, Helena Pastor-Ramírez, Rocío Montero-Vallejo, Jesús Rivera-Esteban, Leticia Álvarez-Amor, María Jesús Pareja, María Carmen Rico, Raquel Millán, María José Robles-Frías, Rocío Aller, Ángela Rojas, Rocío Muñoz-Hernández, Antonio Gil-Gómez, Sheila Gato, María García-Lozano, María Teresa Arias-Loste, Javier Abad, José Luis Calleja, Raúl J Andrade, Javier Crespo, Águeda González-Rodríguez, Carmelo García-Monzón, Fausto Andreola, Juan Manuel Pericás, Rajiv Jalan, Francisco Martín-Bermudo, Manuel Romero-Gómez","doi":"10.1002/ueg2.12534","DOIUrl":null,"url":null,"abstract":"<p><strong>Aim: </strong>We aimed to assess the role of FGF21 in metabolic dysfunction-associated steatotic liver disease (MASLD) at a multi-scale level.</p><p><strong>Methods: </strong>We used human MASLD pathology samples for FGF21 gene expression analyses (qPCR and RNAseq), serum to measure circulating FGF21 levels and DNA for genotyping the FGF21 rs838133 variant in both estimation and validation cohorts. A hepatocyte-derived cell line was exposed to free fatty acids at different timepoints. Finally, C57BL/6J mice were fed a high-fat and choline-deficient diet (CDA-HFD) for 16 weeks to assess hepatic FGF21 protein expression and FGF21 levels by ELISA.</p><p><strong>Results: </strong>A significant upregulation in FGF21 mRNA expression was observed in the liver analysed by both qPCR (fold change 5.32 ± 5.25 vs. 0.59 ± 0.66; p = 0.017) and RNA-Seq (3.5 fold; FDR: 0.006; p < 0.0001) in MASLD patients vs. controls. Circulating levels of FGF21 were increased in patients with steatohepatitis vs. bland steatosis (386.6 ± 328.9 vs. 297.9 ± 231.5 pg/mL; p = 0.009). Besides, sex, age, A-allele from FGF21, GG genotype from PNPLA3, ALT, type 2 diabetes mellitus and BMI were independently associated with MASH and significant fibrosis in both estimation and validation cohorts. In vitro exposure of Huh7.5 cells to high concentrations of free fatty acids (FFAs) resulted in overexpression of FGF21 (p < 0.001). Finally, Circulating FGF21 levels and hepatic FGF21 expression were found to be significantly increased (p < 0.001) in animals under CDA-HFD.</p><p><strong>Conclusions: </strong>Hepatic and circulating FGF21 expression was increased in MASH patients, in Huh7.5 cells under FFAs and in CDA-HFD animals. The A-allele from the rs838133 variant was also associated with an increased risk of steatohepatitis and significant and advanced fibrosis in MASLD patients.</p>","PeriodicalId":23444,"journal":{"name":"United European Gastroenterology Journal","volume":null,"pages":null},"PeriodicalIF":5.8000,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11485537/pdf/","citationCount":"0","resultStr":"{\"title\":\"Fibroblast growth factor 21 is a hepatokine involved in MASLD progression.\",\"authors\":\"Rocío Gallego-Durán, Javier Ampuero, Douglas Maya-Miles, Helena Pastor-Ramírez, Rocío Montero-Vallejo, Jesús Rivera-Esteban, Leticia Álvarez-Amor, María Jesús Pareja, María Carmen Rico, Raquel Millán, María José Robles-Frías, Rocío Aller, Ángela Rojas, Rocío Muñoz-Hernández, Antonio Gil-Gómez, Sheila Gato, María García-Lozano, María Teresa Arias-Loste, Javier Abad, José Luis Calleja, Raúl J Andrade, Javier Crespo, Águeda González-Rodríguez, Carmelo García-Monzón, Fausto Andreola, Juan Manuel Pericás, Rajiv Jalan, Francisco Martín-Bermudo, Manuel Romero-Gómez\",\"doi\":\"10.1002/ueg2.12534\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Aim: </strong>We aimed to assess the role of FGF21 in metabolic dysfunction-associated steatotic liver disease (MASLD) at a multi-scale level.</p><p><strong>Methods: </strong>We used human MASLD pathology samples for FGF21 gene expression analyses (qPCR and RNAseq), serum to measure circulating FGF21 levels and DNA for genotyping the FGF21 rs838133 variant in both estimation and validation cohorts. A hepatocyte-derived cell line was exposed to free fatty acids at different timepoints. Finally, C57BL/6J mice were fed a high-fat and choline-deficient diet (CDA-HFD) for 16 weeks to assess hepatic FGF21 protein expression and FGF21 levels by ELISA.</p><p><strong>Results: </strong>A significant upregulation in FGF21 mRNA expression was observed in the liver analysed by both qPCR (fold change 5.32 ± 5.25 vs. 0.59 ± 0.66; p = 0.017) and RNA-Seq (3.5 fold; FDR: 0.006; p < 0.0001) in MASLD patients vs. controls. Circulating levels of FGF21 were increased in patients with steatohepatitis vs. bland steatosis (386.6 ± 328.9 vs. 297.9 ± 231.5 pg/mL; p = 0.009). Besides, sex, age, A-allele from FGF21, GG genotype from PNPLA3, ALT, type 2 diabetes mellitus and BMI were independently associated with MASH and significant fibrosis in both estimation and validation cohorts. In vitro exposure of Huh7.5 cells to high concentrations of free fatty acids (FFAs) resulted in overexpression of FGF21 (p < 0.001). Finally, Circulating FGF21 levels and hepatic FGF21 expression were found to be significantly increased (p < 0.001) in animals under CDA-HFD.</p><p><strong>Conclusions: </strong>Hepatic and circulating FGF21 expression was increased in MASH patients, in Huh7.5 cells under FFAs and in CDA-HFD animals. The A-allele from the rs838133 variant was also associated with an increased risk of steatohepatitis and significant and advanced fibrosis in MASLD patients.</p>\",\"PeriodicalId\":23444,\"journal\":{\"name\":\"United European Gastroenterology Journal\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":5.8000,\"publicationDate\":\"2024-10-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11485537/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"United European Gastroenterology Journal\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1002/ueg2.12534\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/6/18 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"GASTROENTEROLOGY & HEPATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"United European Gastroenterology Journal","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/ueg2.12534","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/6/18 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"GASTROENTEROLOGY & HEPATOLOGY","Score":null,"Total":0}
Fibroblast growth factor 21 is a hepatokine involved in MASLD progression.
Aim: We aimed to assess the role of FGF21 in metabolic dysfunction-associated steatotic liver disease (MASLD) at a multi-scale level.
Methods: We used human MASLD pathology samples for FGF21 gene expression analyses (qPCR and RNAseq), serum to measure circulating FGF21 levels and DNA for genotyping the FGF21 rs838133 variant in both estimation and validation cohorts. A hepatocyte-derived cell line was exposed to free fatty acids at different timepoints. Finally, C57BL/6J mice were fed a high-fat and choline-deficient diet (CDA-HFD) for 16 weeks to assess hepatic FGF21 protein expression and FGF21 levels by ELISA.
Results: A significant upregulation in FGF21 mRNA expression was observed in the liver analysed by both qPCR (fold change 5.32 ± 5.25 vs. 0.59 ± 0.66; p = 0.017) and RNA-Seq (3.5 fold; FDR: 0.006; p < 0.0001) in MASLD patients vs. controls. Circulating levels of FGF21 were increased in patients with steatohepatitis vs. bland steatosis (386.6 ± 328.9 vs. 297.9 ± 231.5 pg/mL; p = 0.009). Besides, sex, age, A-allele from FGF21, GG genotype from PNPLA3, ALT, type 2 diabetes mellitus and BMI were independently associated with MASH and significant fibrosis in both estimation and validation cohorts. In vitro exposure of Huh7.5 cells to high concentrations of free fatty acids (FFAs) resulted in overexpression of FGF21 (p < 0.001). Finally, Circulating FGF21 levels and hepatic FGF21 expression were found to be significantly increased (p < 0.001) in animals under CDA-HFD.
Conclusions: Hepatic and circulating FGF21 expression was increased in MASH patients, in Huh7.5 cells under FFAs and in CDA-HFD animals. The A-allele from the rs838133 variant was also associated with an increased risk of steatohepatitis and significant and advanced fibrosis in MASLD patients.
期刊介绍:
United European Gastroenterology Journal (UEG Journal) is the official Journal of the United European Gastroenterology (UEG), a professional non-profit organisation combining all the leading European societies concerned with digestive disease. UEG’s member societies represent over 22,000 specialists working across medicine, surgery, paediatrics, GI oncology and endoscopy, which makes UEG a unique platform for collaboration and the exchange of knowledge.