First Department of Pharmacology, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.
Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
J Clin Endocrinol Metab. 2020 Mar 1;105(3):e390-400. doi: 10.1210/clinem/dgz172.
To investigate circulating levels and liver gene expression of 3 hormonal pathways associated with obesity, insulin resistance, and inflammation to identify leads towards potential diagnostic markers and therapeutic targets in patients with nonalcoholic fatty liver disease (NAFLD).
We compared circulating levels of (1) proglucagon-derived hormones (glucagon-like peptide [GLP]-1, GLP-2, glicentin, oxyntomodulin, glucagon, major proglucagon fragment [MPGF]), (2) follistatins-activins (follistatin-like [FSTL]3, activin B), (3) IGF axis (insulin-like growth factor [IGF]-1, total and intact IGF binding protein [IGFBP]-3 and IGFBP-4, and pregnancy-associated plasma protein [PAPP]-A) in 2 studies: (1) 18 individuals with early stage NAFLD versus 14 controls (study 1; early NAFLD study) and in (2) 31 individuals with biopsy proven NAFLD (15 with simple steatosis [SS] and 16 with nonalcoholic steatohepatitis [NASH]), vs 50 controls (24 lean and 26 obese) (study 2). Liver gene expression was assessed in 22 subjects (12 controls, 5 NASH, 5 NASH-related cirrhosis).
Patients in early stages of NAFLD demonstrate higher fasting MPGF and lower incremental increase of glicentin during oral glucose tolerance test than controls. In more advanced stages, FSTL3 levels are higher in NASH than simple steatosis and, within NAFLD patients, in those with more severe lobular and portal inflammation. The IGF-1/intact IGFBP-3 ratio is lower in patients with liver fibrosis. Genes encoding follistatin, activin A, activin B, and the IGF-1 receptor are higher in NASH.
MPGF and glicentin may be involved in early stages of NAFLD, whereas FSTL3 and IGF-1/intact IGFBP3 in the progression to NASH and liver fibrosis respectively, suggesting potential as diagnostic markers or therapeutic targets.
研究与肥胖、胰岛素抵抗和炎症相关的 3 种激素途径的循环水平和肝脏基因表达，以确定非酒精性脂肪性肝病 (NAFLD) 患者潜在的诊断标志物和治疗靶点。
我们比较了 2 项研究中（1）前胰高血糖素衍生激素（胰高血糖素样肽[GLP]-1、GLP-2、糖抑胃肽、胰高血糖素、主要前胰高血糖素片段[MPGF]）、（2）卵泡抑素-激活素（卵泡抑素样[FSTL]3、激活素 B）、（3）IGF 轴（胰岛素样生长因子[IGF]-1、总和完整 IGF 结合蛋白[IGFBP]-3 和 IGFBP-4、妊娠相关血浆蛋白[PAPP]-A）的循环水平：（1）18 名早期 NAFLD 患者与 14 名对照者（研究 1；早期 NAFLD 研究），以及（2）31 名经活检证实的 NAFLD 患者（15 名单纯性脂肪变性[SS]和 16 名非酒精性脂肪性肝炎[NASH]）与 50 名对照者（24 名瘦者和 26 名肥胖者）（研究 2）。在 22 名受试者中评估了肝脏基因表达（12 名对照者、5 名 NASH、5 名 NASH 相关肝硬化）。
早期 NAFLD 患者的空腹 MPGF 较高，口服葡萄糖耐量试验时的甘丙肽递增增加较低。在更晚期，NASH 患者的 FSTL3 水平高于单纯性脂肪变性，在 NAFLD 患者中，肝纤维化患者的 FSTL3 水平高于更严重的肝小叶和门脉炎症患者。IGF-1/完整 IGFBP-3 比值在有肝纤维化的患者中较低。编码卵泡抑素、激活素 A、激活素 B 和 IGF-1 受体的基因在 NASH 中更高。
MPGF 和甘丙肽可能参与了 NAFLD 的早期阶段，而 FSTL3 和 IGF-1/完整 IGFBP3 则分别参与了 NASH 和肝纤维化的进展，提示其具有作为诊断标志物或治疗靶点的潜力。
