Research Unit of Molecular Genetics of Complex Phenotypes, Bambino Gesù Children's Hospital, IRCCS, 4, Piazza Sant'Onofrio, Rome 00165, Italy.
General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pad. Granelli, via F Sforza 35, Milan 20122, Italy.
EBioMedicine. 2021 Mar;65:103249. doi: 10.1016/j.ebiom.2021.103249. Epub 2021 Feb 25.
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.
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).
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.
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.
Ricerca Finalizzata Ministero della Salute GR-2019-12,370,172 (NP), Ricerca Corrente Fondazione IRCCS Cà 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).
rs17618244 G>Aβ-Klotho（KLB）变体通过降低 KLB 表达，与儿科代谢相关脂肪性肝病（MAFLD）患者的气球样变和炎症风险增加相关。在肝细胞中，KLB 下调诱导脂肪堆积和炎症及脂毒性基因的表达。我们旨在首先研究 KLB rs17618244 变异对成年 MAFLD 患者肝损伤的影响，其次研究其对肝星状细胞（HSCs）激活的影响。
对 1111 例 MAFLD 成年患者的回顾性队列进行 KLB rs17618244 变异对组织学肝损伤的影响调查。根据肥胖（BMI>35；n=708）存在情况进行亚组分析。用携带 rs17618244 的野生型（LX-2_KLBwt）或突变型 KLB（LX-2_KLBmut）转染永生化 HSCs（LX-2）。
在序贯回归分析中，KLB rs17618244 变体与肝纤维化（OR 1.23，95%CI 1.004-1.51；p=0.04）相关，但与脂肪变性、炎症和气球样变无关。根据肥胖存在情况对患者进行分层后，KLB A 等位基因与肝小叶炎症（OR 1.32，95%CI 1.02-1.72；p=0.03）和肝硬化（OR 2.51，95%CI 1.23-5.05；p=0.01）进一步相关。此外，肝 KLB 表达与纤维生成基因的表达相关。LX-2_KLBmut 细胞表现出 KLB 蛋白水平降低，同时诱导产生促纤维化基因并增强增殖率。
KLB rs17618244 变体与肥胖 MAFLD 患者的肝纤维化、炎症和肝硬化主要相关，携带该突变的 HSCs 具有高度增殖性，并获得肌成纤维细胞样表型。
意大利卫生部研究专项基金 GR-2019-12370172（NP），意大利米兰 Cà Granda 基金会 IRCCS 研究基金（PD 和 ALF），意大利卫生部研究专项基金 RF-2013-02358319（ALF），意大利米兰 Cà Granda 基金会 IRCCS 研究基金和意大利卫生部 5×1000 研究基金（AA）。
