Intestinal BMP-9 locally upregulates FGF19 and is down-regulated in obese patients with diabetes

被引：5

作者：

Drexler, Stephan ^{[1
]}

Cai, Chen ^{[1
]}

Hartmann, Anna-Lena ^{[2
]}

Moch, Denise ^{[2
]}

Gaitantzi, Haristi ^{[2
]}

Ney, Theresa ^{[2
]}

Kraemer, Malin ^{[2
]}

Chu, Yuan ^{[2
]}

Zheng, Yuwei ^{[2
]}

Rahbari, Mohammad ^{[3
]}

Treffs, Annalena ^{[2
]}

Reiser, Alena ^{[2
]}

Lenoir, Benedicte ^{[4
]}

Valous, Nektarios A. ^{[4
]}

Jaeger, Dirk ^{[4
,5
,6
]}

Birgin, Emrullah ^{[2
]}

Sawant, Tejas A. ^{[1
]}

Li, Qi ^{[7
]}

Xu, Keshu ^{[8
]}

Dong, Lingyue ^{[9
]}

Otto, Mirko ^{[2
]}

Itzel, Timo ^{[10
,11
]}

Teufel, Andreas ^{[10
,11
]}

Gretz, Norbert ^{[12
]}

Hawinkels, Lukas J. A. C. ^{[13
]}

Sanchez, Aranzazu ^{[14
]}

Herrera, Blanca ^{[14
]}

Schubert, Rudolf ^{[15
]}

Moshage, Han ^{[16
]}

Reissfelder, Christoph ^{[2
,11
]}

Ebert, Matthias P. A. ^{[1
,11
]}

Rahbari, Nuh N. ^{[2
]}

Breitkopf-Heinlein, Katja ^{[2
]}

机构：

[1] Heidelberg Univ, Univ Med Ctr Mannheim, Med Fac Mannheim, Dept Med 2, D-68167 Mannheim, Germany

[2] Heidelberg Univ, Univ Med Ctr Mannheim, Med Fac Mannheim, Dept Surg, D-68167 Mannheim, Germany

[3] German Canc Res Ctr, Div Chron Inflammat & Canc, D-69120 Heidelberg, Germany

[4] German Canc Res Ctr, Clin Cooperat Unit Appl Tumor Immun, D-69120 Heidelberg, Germany

[5] Natl Ctr Tumor Dis, Dept Med Oncol, D-69120 Heidelberg, Germany

[6] Heidelberg Univ Hosp, D-69120 Heidelberg, Germany

[7] Capital Med Univ, Dept Gastroenterol & Hepatol, Beijing Youan Hosp, Beijing, Peoples R China

[8] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Div Gastroenterol, 1277 Jiefang Ave, Wuhan, Hubei, Peoples R China

[9] Capital Med Univ, Dept Cell Biol, Beijing 100054, Fengtai, Peoples R China

[10] Heidelberg Univ, Med Fac Mannheim, Dept Med 2, Div Hepatol,Div Clin Bioinformat, D-68167 Mannheim, Germany

[11] Heidelberg Univ, Med Fac Mannheim, Ctr Prevent Med & Digital Hlth, Clin Cooperat Unit Hlth Metab, D-68167 Mannheim, Germany

[12] Heidelberg Univ, Med Fac Mannheim, Med Res Ctr, D-68167 Mannheim, Germany

[13] Leiden Univ, Med Ctr, Dept Gastroenterol & Hepatol, Albinusdreef 2, NL-2333 ZA Leiden, Netherlands

[14] Complutense Univ Madrid UCM, Hlth Res Inst, Hosp Clin San Carlos IdISSC, Dept Biochem & Mol Biol, E-28040 Madrid, Spain

[15] Univ Augsburg, Inst Theoret Med, Fac Med, Physiol, D-86159 Augsburg, Germany

[16] Univ Groningen, Univ Med Ctr Groningen, Dept Gastroenterol & Hepatol, NL-9712 CP Groningen, Netherlands

来源：

MOLECULAR AND CELLULAR ENDOCRINOLOGY | 2023年 / 570卷

关键词：

Diabetes; BMP-9; GDF2; Obesity; Liver steatosis; LPS; FATTY LIVER-DISEASE; GROWTH-FACTOR; 21; METABOLIC-ACTIVITY; HUMAN HEPATOCYTES; BETA-KLOTHO; EXPRESSION; FGF21; PROTEIN-9;

D O I：

10.1016/j.mce.2023.111934

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Bone morphogenetic protein (BMP)-9, a member of the TGF beta-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 supplemen-tation of BMP-9 an interesting new approach for future therapies aiming at prevention of the development of a metabolic syndrome and liver steatosis.

引用

页数：12