Paola Dongiovanni1, Annalisa Crudele2, Nadia Panera2, Ilaria Romito2, Marica Meroni3, Cristiano De Stefanis4, Alessia Palma5, Donatella Comparcola6, Anna Ludovica Fracanzani3, Luca Miele7, Luca Valenti8, Valerio Nobili9, Anna Alisi10. 1. General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy. 2. Research Unit of Molecular Genetics of Complex Phenotypes, Bambino Gesù Children's Hospital - IRCCS, Rome, Italy. 3. General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Italy. 4. Research Laboratories, Bambino Gesù Children's Hospital - IRCCS, Rome, Italy. 5. Genomic Facility Unit, Bambino Gesù Children's Hospital - IRCCS, Rome, Italy. 6. Hepato-Metabolic Disease Unit, Bambino Gesù Children's Hospital - IRCCS, Rome, Italy. 7. Fondazione Policlinico Universitario A. Gemelli - IRCCS, Catholic University of the Sacred Heart, Rome, Italy. 8. Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Italy; Translational Medicine, Department for Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Policlinico, Milano, Italy. 9. Hepatology Gastroenterology and Nutrition Unit, Bambino Gesù Children's Hospital - IRCCS, Rome, Italy; Department of Pediatrics and Infantile Neuropsychiatry, Sapienza University of Rome, Italy. 10. Research Unit of Molecular Genetics of Complex Phenotypes, Bambino Gesù Children's Hospital - IRCCS, Rome, Italy. Electronic address: anna.alisi@opbg.net.
Abstract
BACKGROUND & AIM: Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in adults and children. Along with obesity, diabetes and insulin resistance, genetic factors strongly impact on NAFLD development and progression. Dysregulated bile acid metabolism and the fibroblast growth factor 19 (FGF19) pathway play a pivotal role in NAFLD pathogenesis. However, the mechanism through which the FGF19 receptor system is associated with liver damage in NAFLD remains to be defined. METHODS: We evaluated the impact of the rs17618244 G>A β-Klotho (KLB) variant on liver damage in 249 pediatric patients with biopsy-proven NAFLD and the association of this variant with the expression of hepatic and soluble KLB. In vitro models were established to investigate the role of the KLB mutant. RESULTS: The KLB rs17618244 variant was associated with an increased risk of ballooning and lobular inflammation. KLB plasma levels were lower in carriers of the rs17618244 minor A allele and were associated with lobular inflammation, ballooning and fibrosis. In HepG2 and Huh7 hepatoma cell lines, exposure to free fatty acids caused a severe reduction of intracellular and secreted KLB. Finally, KLB downregulation obtained by the expression of a KLB mutant in HepG2 and Huh7 cells induced intracellular lipid accumulation and upregulation of p62, ACOX1, ACSL1, IL-1β and TNF-α gene expression. CONCLUSION: In conclusion, we showed an association between the rs17618244 KLB variant, which leads to reduced KLB expression, and the severity of NAFLD in pediatric patients. We can speculate that the KLB protein may exert a protective role against lipotoxicity and inflammation in hepatocytes. LAY SUMMARY: Genetic and environmental factors strongly impact on the pathogenesis and progression of non-alcoholic fatty liver disease (NAFLD). The FGF19/FGFR4/KLB pathway plays a pivotal role in the pathogenesis of NAFLD. The aim of the study was to investigate the impact of a genetic variant in the KLB gene on the severity of liver disease. Our data suggest that the KLB protein plays a protective role against lipotoxicity and inflammation in hepatocytes.
BACKGROUND & AIM: Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in adults and children. Along with obesity, diabetes and insulin resistance, genetic factors strongly impact on NAFLD development and progression. Dysregulated bile acid metabolism and the fibroblast growth factor 19 (FGF19) pathway play a pivotal role in NAFLD pathogenesis. However, the mechanism through which the FGF19 receptor system is associated with liver damage in NAFLD remains to be defined. METHODS: We evaluated the impact of the rs17618244 G>A β-Klotho (KLB) variant on liver damage in 249 pediatric patients with biopsy-proven NAFLD and the association of this variant with the expression of hepatic and soluble KLB. In vitro models were established to investigate the role of the KLB mutant. RESULTS: The KLBrs17618244 variant was associated with an increased risk of ballooning and lobular inflammation. KLB plasma levels were lower in carriers of the rs17618244 minor A allele and were associated with lobular inflammation, ballooning and fibrosis. In HepG2 and Huh7hepatoma cell lines, exposure to free fatty acids caused a severe reduction of intracellular and secreted KLB. Finally, KLB downregulation obtained by the expression of a KLB mutant in HepG2 and Huh7 cells induced intracellular lipid accumulation and upregulation of p62, ACOX1, ACSL1, IL-1β and TNF-α gene expression. CONCLUSION: In conclusion, we showed an association between the rs17618244KLB variant, which leads to reduced KLB expression, and the severity of NAFLD in pediatric patients. We can speculate that the KLB protein may exert a protective role against lipotoxicity and inflammation in hepatocytes. LAY SUMMARY: Genetic and environmental factors strongly impact on the pathogenesis and progression of non-alcoholic fatty liver disease (NAFLD). The FGF19/FGFR4/KLB pathway plays a pivotal role in the pathogenesis of NAFLD. The aim of the study was to investigate the impact of a genetic variant in the KLB gene on the severity of liver disease. Our data suggest that the KLB protein plays a protective role against lipotoxicity and inflammation in hepatocytes.
Authors: Mehmet Kanbay; Mustafa C Bulbul; Sidar Copur; Baris Afsar; Alan A Sag; Dimitrie Siriopol; Masanari Kuwabara; Silvia Badarau; Adrian Covic; Alberto Ortiz Journal: J Nephrol Date: 2020-05-21 Impact factor: 3.902
Authors: Jian-Wen Xiong; Jin-Qiong Zhan; Tao Luo; Hai-Bo Chen; Qi-Gen Wan; Yan Wang; Bo Wei; Yuan-Jian Yang Journal: Front Neurosci Date: 2020-06-16 Impact factor: 4.677