The KLB rs17618244 gene variant is associated with fibrosing MAFLD by promoting hepatic stellate cell activation
| Autor: | Luca Miele, Erika Paolini, Miriam Longo, Valentina D'Oria, Annalisa Crudele, Marco Maggioni, Luca Valenti, Marica Meroni, Paola Dongiovanni, Emanuele Bellacchio, Anna Alisi, Nadia Panera, Anna Ludovica Fracanzani |
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| Rok vydání: | 2021 |
| Předmět: |
Male
HSCS activation 0301 basic medicine Cirrhosis FGFR Fibroblast Growth Factor Receptor BMI body mass index lcsh:Medicine GAPDH Glyceraldehyde3-Phosphate Dehydrogenase PDGF platelet-derived growth factor 0302 clinical medicine IR insulin resistance IGT impaired glucose tolerance LDL low-density lipoprotein Nonalcoholic fatty liver disease Odds Ratio CYP7A1 cholesterol 7a-hydroxylase FGF19 Fibroblast Growth Factor 19 lcsh:R5-920 MTTP microsomal triglyceride transfer protein Fatty liver General Medicine Middle Aged COL1A1 collagen type I alpha 1 chain Liver protein stability αSMA Alpha-smooth muscle actin 030220 oncology & carcinogenesis PM plasma membrane MAFLD nonalcoholic fatty liver disease wt wild type PNPLA3 Patatin-like Phospholipase domain-containing 3 lcsh:Medicine (General) MBOAT7 Membrane Bound O-Acyltransferase Domain Containing 7 NASH nonalcoholic steatohepatitis HSCs hepatic stellate cells Research Paper Liver damage medicine.medical_specialty Genotype Settore MED/12 - GASTROENTEROLOGIA HDL high-density lipoprotein KLB β-Klotho MAFLD BA Bile acids Polymorphism Single Nucleotide General Biochemistry Genetics and Molecular Biology Cell Line ER endoplasmic reticulum 03 medical and health sciences CHX cycloheximide FBS fetal bovine serum PPARα peroxisome proliferator-activated receptor Internal medicine T2D type 2 diabetes mellitus Hepatic Stellate Cells medicine Humans TGFβ Transforming Growth Factor-beta Obesity Klotho Proteins Alleles Cell Proliferation Retrospective Studies Inflammation business.industry lcsh:R Mut mutant TM6SF2 Transmembrane 6 Superfamily member gene 2 Membrane Proteins SHP-1 short heterodimer partner medicine.disease Fibrosis Hepatic stellate cell activation Fatty Liver 030104 developmental biology Endocrinology COL3A1 collagen type III alpha 1 chain FGF21 Fibroblast Growth Factor 21 Mutagenesis Site-Directed Hepatic stellate cell Steatosis HCC hepatocellular carcinoma Hepatic fibrosis business TM6SF2 |
| Zdroj: | EBioMedicine EBioMedicine, Vol 65, Iss, Pp 103249-(2021) |
| ISSN: | 2352-3964 |
| DOI: | 10.1016/j.ebiom.2021.103249 |
| Popis: | Background The rs17618244 G>A β-Klotho (KLB) variant has been associated with increased risk of ballooning and inflammation in pediatric patients with metabolic associated fatty liver disease (MAFLD), by reducing KLB expression. In hepatocytes, KLB downregulation induced fat accumulation and the expression of inflammatory and lipotoxic genes. We aimed to examine firstly the impact of the KLB rs17618244 variation on liver damage in adult patients with MAFLD and secondly its effect on hepatic stellate cells (HSCs) activation. Methods The impact of the KLB rs17618244 variant on histological liver damage was surveyed in a retrospective cohort of 1111 adult patients with MAFLD. Subgroup analysis was performed according to the presence of obesity (BMI>35; n = 708). Immortalized HSCs (LX-2) were transfected with the KLB wild type (LX-2_KLBwt), or with the mutant one carrying the rs17618244 (LX-2_KLBmut). Findings At ordinal regression analysis the KLB rs17618244 variant was associated with hepatic fibrosis (OR 1.23, 95% C.I.1.004–1.51; p = 0.04), but not with steatosis, inflammation and ballooning. By stratifying patients according to the presence of obesity, the KLB A allele was further associated with lobular inflammation (OR 1.32, 95% C.I.1.02–1.72; p = 0.03) and cirrhosis (OR 2.51, 95% C.I.1.23–5.05; p = 0.01) Moreover, hepatic KLB expression correlated with that of fibrogenic genes. LX-2_KLBmut cells showed reduced KLB protein levels paralleled by an induction of pro-fibrogenic genes and enhanced proliferative rate. Interpretation The KLB rs17618244 variant is associated with hepatic fibrosis, inflammation and cirrhosis mainly in obese patients with MAFLD and HSCs which carry this mutation are highly proliferative and acquire a myofibroblast-like phenotype. Funding Ricerca Finalizzata Ministero della Salute GR-2019–12,370,172 (NP), Ricerca Corrente Fondazione IRCCS Ca Granda (PD and ALF), Ricerca Finalizzata Ministero della Salute RF-2013–02,358,319 (ALF), and Ricerca Corrente and 5 × 1000 Ministero della Salute (AA). |
| Databáze: | OpenAIRE |
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