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Title: [Overexpression of Numb gene can inhibit the progression of biliary liver fibrosis in adult liver].
Author: Xu YN, Xu W, Chen JM, Liu W, Chen GF, Zhang H, Liu P, Mu YP.
Journal: Zhonghua Gan Zang Bing Za Zhi; 2022 Nov 20; 30(11):1175-1181. PubMed ID: 36891694.
Abstract:
Objective: To investigate whether the overexpression of Numb gene can effectively intervene the progression of cholestatic liver fibrosis (CLF) in adult liver. Methods: Twenty-four SD rats were randomly divided into sham operation (Sham, n=6), common bile duct ligation (BDL, n=6), empty vector plasmid (Numb-EV, n=6) and numb gene overexpression group (Numb-OE, n=6). The CLF model was prepared by common bile duct ligation. Simultaneously, the model was established, and the adeno-associated virus (AAV) carrying the cloned numb gene was injected into the rats' spleens. Samples were collected at the end of four weeks. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (Alb), serum total bilirubin (TBil), serum total bile acid (TBA), liver histopathology, liver tissue hydroxyproline (Hyp) content, and alpha smooth muscle actin (α-SMA), cytokeratin (CK) 7, and CK19 expression conditions were determined in liver tissue. An analysis of variance was used to compare the means of multiple groups. Results: Compared with the Sham group, the Numb mRNA level in the rat liver tissue was significantly decreased in the BDL group (0.872±0.237 vs. 0.452±0.147, P=0.003). Compared with the Numb-EV group, the Numb mRNA level in the liver tissue was significantly increased in the Numb-OE group (0.487±0.122 vs. 1.094±0.345, P＜0.01). Compared with the Sham group, the Hyp content (μg/L) (288.46±49.49 vs. 901.98±271.85, P＜0.01) and the α-SMA mRNA level (0.858±0.234 vs. 8.976±1.398, P＜0.01) were significantly higher in the BDL group. Compared with the Numb-EV group, the Hyp content (864.32±113.54 vs. 580.44±171.77, P=0.039), the α-SMA mRNA level (6.138±1.443 vs. 1.322±0.859, P＜0.01) and the protein levels were significantly reduced in the Numb-OE group. Compared with the Sham group, the serum ALT, AST, TBil, and TBA levels were significantly increased in the BDL group (P＜0.01), and the ALB content was significantly decreased (P＜0.01). Compared with the Numb-EV group, AST and TBil levels were significantly reduced in the Numb-OE group (P＜0.01), as were the ALT and TBA levels (P＜0.05); however, the ALB content was significantly increased (P＜0.01), and the differences were statistically significant. Compared with the Sham group, the mRNA expression levels of CK7 and CK19 were significantly increased in the BDL group (1.40±0.42 vs. 43.78±7.56; 1.11±0.51 vs. 363.81±134.84, P＜0.01). The mRNA expression levels of CK7 and CK19 were significantly reduced in the OE group (343.19±81.22 vs. 3.22±2.34; 40.53±14.02 vs. 15.68±9.36,P＜0.01). Conclusion: Overexpression of the Numb gene can inhibit CLF progression in the adult liver, which may become a new target for CLF therapy. 目的： 探讨成体肝脏Numb基因过表达是否可有效干预胆汁淤积性肝纤维化（CLF）的进展。 方法： SD大鼠24只，随机分为假手术组（Sham，n=6）、胆总管结扎组（BDL，n=6）、空载体质粒组（Numb-EV，n=6）和Numb基因过表达组（Numb-OE，n=6）。胆总管结扎制备CLF模型，并于造模的同时将载有克隆Numb基因的腺相关病毒（AAV）经脾脏注射至大鼠体内，4周末取材。检测血清丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）、白蛋白（Alb）、血清总胆红素（TBil）、血清胆汁酸（TBA）、肝组织羟脯氨酸（Hyp）含量、肝组织中平滑肌肌动蛋白（α-SMA）与细胞角蛋白（CK）7、CK19的表达情况及肝组织病理情况。多组均数比较采用方差分析。 结果： 与Sham组比较，BDL组大鼠肝组织Numb mRNA水平显著降低（0.872±0.237与0.452±0.147，P=0.003）；与Numb-EV组比较，Numb-OE组肝组织Numb mRNA水平显著升高（0.487±0.122与1.094±0.345，P<0.01）。与Sham组比较，BDL组肝组织Hyp含量（μg/L）（288.46±49.49与901.98±271.85，P<0.01）及α-SMA mRNA水平（0.858±0.234与8.976±1.398，P<0.01）均显著升高；与Numb-EV组比较，Numb-OE组Hyp含量（μg/L）（864.32±113.54与580.44±171.77，P=0.039）及α-SMA mRNA水平（6.138±1.443与1.322±0.859，P<0.01）以及蛋白水平显著降低。与Sham组比较，BDL组血清ALT、AST、TBil、TBA水平均显著升高（P值均<0.01），Alb含量显著降低（P<0.01）；与Numb-EV组比较，Numb-OE组AST、TBil水平均显著降低（P值均<0.01），ALT、TBA水平也明显降低（P值均<0.05），Alb含量显著升高（P值均<0.01），差异有统计学意义。与Sham组比较，BDL组CK7、CK19的mRNA表达水平均显著升高（1.40±0.42与43.78±7.56、1.11±0.51与363.81±134.84，P值均<0.01）；与Numb-EV组比较，Numb-OE组CK7、CK19的mRNA表达水平显著降低（343.19±81.22与3.22±2.34、40.53±14.02与15.68±9.36，P值均<0.01）。 结论： 成体肝脏Numb基因过表达可抑制CLF进展，这可能成为CLF治疗的新靶点。.

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