Werge Mikkel Parsberg, Grandt Josephine, Thing Mira, Hetland Liv Eline, Rashu Elias Badal, Jensen Anne-Sofie Houlberg, Junker Anders Ellekær, Richter Michael Martin, Møller Søren, Bendtsen Flemming, Harder Lea Mørch, Mazzoni Gianluca, Viuff Birgitte Martine, Hvid Henning, Prada-Medina Cesar Augusto, Jørgensen Sebastian Beck, Bendtsen Kristian Moss, Kildegaard Jonas, Vyberg Mogens, Serizawa Reza, Galsgaard Elisabeth Douglas, Wewer Albrechtsen Nicolai Jacob, Gluud Lise Lotte
Gastro Unit, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.
NNF Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Hepatol Res. 2025 Apr;55(4):492-504. doi: 10.1111/hepr.14148. Epub 2024 Dec 4.
Increased growth differentiation factor 15 (GDF15) may reflect impaired metabolic health and an inflammatory state in metabolic dysfunction-associated steatotic liver disease (MASLD). We investigated the role of GDF15 in histologically verified MASLD in a meal test (discovery) cohort (n = 20) and a prospective (validation) cohort with 2 years of follow-up (n = 276).
Participants were evaluated clinically and histologically in both cohorts. Fibrosis severity was classified as no/mild (F0/F1) or significant (F2-4). Plasma GDF15 was measured by enzyme-linked immunosorbent assays and the SOMAScan platform. Hepatic GDF15 mRNA expression was analyzed by RNA in situ hybridization and bulk RNA-sequencing. In addition, we used data from public single-nucleus RNA-sequencing datasets.
In both cohorts, plasma GDF15 was increased in MASLD compared with healthy controls (p < 0.0001) with the highest levels in patients with significant fibrosis (area under the curve 0.83; 95% confidence interval [CI], 0.76-0.91). The GDF15 levels were unaffected by a standardized meal and there was no difference in peripheral or hepatic venous concentrations. After 2 years, the increase in GDF15 levels was reduced in patients treated with glucagon-like peptide receptor agonists (GLP-1-RA) compared to patients receiving lifestyle advice (-28%; 95% CI, -44 to -8; p = 0.01). Plasma GDF15 was associated with circulating insulin-like growth factor 1 and related proteins. Hepatic GDF15 mRNA was mainly expressed in hepatocytes and in cholangiocytes in fibrotic areas and was increased in MASLD (p = 0.02) with the highest expression in the group with steatohepatitis (p = 0.009).
Increased hepatic and circulating GDF15 are found in MASLD. Treatment with GLP-1-RA may reduce GDF15, possibly reflecting beneficial metabolic and inflammatory effects.
生长分化因子15（GDF15）水平升高可能反映代谢功能障碍相关脂肪性肝病（MASLD）中代谢健康受损和炎症状态。我们在一个进餐试验（探索性）队列（n = 20）和一个有2年随访的前瞻性（验证性）队列（n = 276）中研究了GDF15在经组织学证实的MASLD中的作用。
在两个队列中对参与者进行临床和组织学评估。纤维化严重程度分为无/轻度（F0/F1）或重度（F2 - 4）。通过酶联免疫吸附测定和SOMAScan平台测量血浆GDF15。通过RNA原位杂交和大量RNA测序分析肝脏GDF15 mRNA表达。此外，我们使用了来自公共单核RNA测序数据集的数据。
在两个队列中，与健康对照相比，MASLD患者的血浆GDF15升高（p < 0.0001），在重度纤维化患者中水平最高（曲线下面积0.83；95%置信区间[CI]，0.76 - 0.91）。GDF15水平不受标准化餐食影响，外周血或肝静脉浓度无差异。2年后，与接受生活方式建议的患者相比，接受胰高血糖素样肽受体激动剂（GLP - 1 - RA）治疗的患者GDF15水平升高幅度降低（-28%；95% CI，-44至-8；p = 0.01）。血浆GDF15与循环胰岛素样生长因子1及相关蛋白相关。肝脏GDF15 mRNA主要在肝细胞和纤维化区域的胆管细胞中表达，在MASLD中升高（p = 0.02），在脂肪性肝炎组中表达最高（p = 0.009）。
在MASLD中发现肝脏和循环中的GDF15升高。GLP - 1 - RA治疗可能降低GDF15，这可能反映了有益的代谢和炎症作用。
