骨形成蛋白（BMP）-9是TGFβ细胞因子家族的成员，据信主要在肝脏中产生。报道称新诊断的糖尿病患者血清中BMP-9水平降低，BMP-9过表达改善高脂饮食诱导的肥胖小鼠模型中的脂肪肝。此外，小鼠注射BMP-9可以增强成纤维细胞生长因子（FGF）21的表达。然而，BMP-9是否也调节相关的FGF19的表达并不清楚。因为FGF21和19均被认为保护肝脏免受脂肪肝的影响，所以我们进一步研究了BMP-9在这方面的作用。我们首先分析了STZ诱导的糖尿病大鼠（1型糖尿病模型）的血清BMP-9水平，并确认了糖尿病期间BMP-9血清水平的下降。我们对BMP-9 KO和野生型小鼠（C57/Bl6背景）的肝脏和肠道组织的RNA样品进行了微阵列分析，发现两个组织中均有BMP-9的基础表达，并且KO小鼠的肝脏Fgf21和肠道Fgf19表达下调。接下来，我们分析了带或不带糖尿病的肥胖患者的BMP-9水平。血清中BMP-9水平与糖尿病无关，但肝脏BMP-9 mRNA表达与尚未发展成糖尿病的患者中肝脏脂肪变性呈负相关。同样，肝脏BMP-9表达还与血清内毒素水平呈负相关。原位杂交分析证实了肠道BMP-9表达，糖尿病会降低肠道（但不是肝脏）BMP-9 mRNA水平，并与肠道E-Cadherin表达呈正相关。使用器官样品进行的体外研究表明，BMP-9可以直接诱导肠道而不是肝细胞器官样品的FGF19表达，而没有发现BMP-9直接诱导肝脏FGF21的证据。与体外数据一致，患者样本中肠道BMP-9 mRNA表达和FGF19表达之间存在相关性。总之，我们的数据证实了BMP-9参与人类糖尿病的发展和FGF轴的调控。更重要的是，我们的数据意味着不仅肝脏而且肠道BMP-9与糖尿病和脂肪肝的发展有关，并且可以控制FGF19表达。这些数据支持结论，即在早期肝脂肪变性的情况下，增加BMP-9水平可能是有益的，使BMP-9补充成为未来预防代谢综合症和肝脏脂肪肝发展的有趣新方法。版权所有©2023。Elsevier B.V.发表。

Bone morphogenetic protein (BMP)-9, a member of the TGFβ-family of cytokines, is believed to be mainly produced in the liver. The serum levels of BMP-9 were reported to be reduced in newly diagnosed diabetic patients and BMP-9 overexpression ameliorated steatosis in the high fat diet-induced obesity mouse model. Furthermore, injection of BMP-9 in mice enhanced expression of fibroblast growth factor (FGF)21. However, whether BMP-9 also regulates the expression of the related FGF19 is not clear. Because both FGF21 and 19 were described to protect the liver from steatosis, we have further investigated the role of BMP-9 in this context. We first analyzed BMP-9 levels in the serum of streptozotocin (STZ)-induced diabetic rats (a model of type I diabetes) and confirmed that BMP-9 serum levels decrease during diabetes. Microarray analyses of RNA samples from hepatic and intestinal tissue from BMP-9 KO- and wild-type mice (C57/Bl6 background) pointed to basal expression of BMP-9 in both organs and revealed a down-regulation of hepatic Fgf21 and intestinal Fgf19 in the KO mice. Next, we analyzed BMP-9 levels in a cohort of obese patients with or without diabetes. Serum BMP-9 levels did not correlate with diabetes, but hepatic BMP-9 mRNA expression negatively correlated with steatosis in those patients that did not yet develop diabetes. Likewise, hepatic BMP-9 expression also negatively correlated with serum LPS levels. In situ hybridization analyses confirmed intestinal BMP-9 expression. Intestinal (but not hepatic) BMP-9 mRNA levels were decreased with diabetes and positively correlated with intestinal E-Cadherin expression. In vitro studies using organoids demonstrated that BMP-9 directly induces FGF19 in gut but not hepatocyte organoids, whereas no evidence of a direct induction of hepatic FGF21 by BMP-9 was found. Consistent with the in vitro data, a correlation between intestinal BMP-9 and FGF19 mRNA expression was seen in the patients' samples. In summary, our data confirm that BMP-9 is involved in diabetes development in humans and in the control of the FGF-axis. More importantly, our data imply that not only hepatic but also intestinal BMP-9 associates with diabetes and steatosis development and controls FGF19 expression. The data support the conclusion that increased levels of BMP-9 would most likely be beneficial under pre-steatotic conditions, making supplementation of BMP-9 an interesting new approach for future therapies aiming at prevention of the development of a metabolic syndrome and liver steatosis.Copyright © 2023. Published by Elsevier B.V.