Division of Endocrinology, Department of Internal Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea.
Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Gyeonggi-do, Korea.
Liver Int. 2018 Apr;38(4):695-705. doi: 10.1111/liv.13587. Epub 2017 Sep 30.
BACKGROUND & AIMS: We explored whether growth differentiation factor 15 (GDF15) affects the histological severity of non-alcoholic fatty liver disease (NAFLD) independent of insulin resistance.
In a biopsy-proven NAFLD cohort, we measured serum GDF15 levels using enzyme-linked immunosorbent assays.
Among 190 subjects (mean age, 53 ± 14 years; men, 52.1%), 72 (men, 65.3%) and 78 (men, 44.9%) were diagnosed with biopsy-proven non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH) respectively. GDF15 levels were significantly higher in NASH patients than in controls (P = .010) or NAFL patients (P = .001). Subjects with advanced fibrosis (≥F3) also showed higher GDF15 levels compared to the others (F0-2; P < .001). Among NAFLD patients, the highest quartile of GDF15 levels was significantly associated with a risk of advanced fibrosis even after adjustment for age, gender, body mass index, smoking status, hypertension, diabetes, aspartate aminotransferase, platelet, albumin, insulin resistance and low skeletal muscle mass (odds ratio, 4.27; 95% confidence interval, 1.04-17.63), but not with NASH risk. GDF15 levels showed a significant positive correlation with liver stiffness (Spearman's ρ, .525; P < .001). Palmitate treatment increased the GDF15 mRNA expression level significantly in Kupffer cells, but not in hepatocytes. In LX-2 cells, GDF15 treatment resulted in enhanced expression of α-smooth muscle actin and collagen I, as well as phosphorylation of SMAD2 and SMAD3.
Our findings suggest that GDF15 may serve as a novel biomarker of advanced fibrosis in NAFLD, thereby indicating the need for urgent anti-fibrotic pharmacotherapy.
我们探索了生长分化因子 15（GDF15）是否在不依赖胰岛素抵抗的情况下影响非酒精性脂肪性肝病（NAFLD）的组织学严重程度。
在经肝活检证实的 NAFLD 队列中，我们使用酶联免疫吸附测定法测量血清 GDF15 水平。
在 190 名受试者中（平均年龄 53±14 岁；男性 52.1%），72 名（男性，65.3%）和 78 名（男性，44.9%）分别被诊断为经肝活检证实的非酒精性脂肪肝（NAFL）和非酒精性脂肪性肝炎（NASH）。NASH 患者的 GDF15 水平明显高于对照组（P=.010）或 NAFL 患者（P=.001）。纤维化程度较高（≥F3）的患者与其他患者相比，GDF15 水平也更高（F0-2；P<.001）。在 NAFLD 患者中，即使在调整年龄、性别、体重指数、吸烟状况、高血压、糖尿病、天门冬氨酸转氨酶、血小板、白蛋白、胰岛素抵抗和低骨骼肌量后，GDF15 水平最高四分位数与进展性纤维化的风险显著相关（比值比，4.27；95%置信区间，1.04-17.63），但与 NASH 风险无关。GDF15 水平与肝硬度呈显著正相关（Spearman's ρ，.525；P<.001）。棕榈酸处理可显著增加库普弗细胞中 GDF15mRNA 的表达水平，但对肝细胞无影响。在 LX-2 细胞中，GDF15 处理可导致α-平滑肌肌动蛋白和胶原 I 的表达增强，以及 SMAD2 和 SMAD3 的磷酸化。
我们的研究结果表明，GDF15 可能是 NAFLD 进展性纤维化的一种新型生物标志物，表明迫切需要进行抗纤维化药物治疗。
