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TGR5-HNF4α axis contributes to bile acid-induced gastric intestinal metaplasia markers expression.

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机构： [1]State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032 China. [2]Department of Gastroenterology, General Hospital of Western Theater Command, Chengdu, Sichuan 610083 China. [3]Department of Gastroenterology, Second Affiliated Hospital of Xi'an Medical College, Xi'an, Shaanxi 710038 China. [4]Department of Endocrinology, General Hospital of Western Theater Command, Chengdu, Sichuan 610083 China. [5]Department of Gastroenterology, 989 Hospital of the People's Liberation Army, Luoyang, Henan 471003 China. [6]Department of Gastroenterology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052 China. [7]Department of Medicine and Cancer Center, Howard University, Washington, DC 20060 USA. [8]Department of Internal Medicine, Meharry Medical College, Nashville, TN 37208 USA.

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Intestinal metaplasia (IM) increases the risk of gastric cancer. Our previous results indicated that bile acids (BAs) reflux promotes gastric IM development through kruppel-like factor 4 (KLF4) and caudal-type homeobox 2 (CDX2) activation. However, the underlying mechanisms remain largely elusive. Herein, we verified that secondary BAs responsive G-protein-coupled bile acid receptor 1 (GPBAR1, also known as TGR5) was increased significantly in IM specimens. Moreover, TGR5 contributed to deoxycholic acid (DCA)-induced metaplastic phenotype through positively regulating KLF4 and CDX2 at transcriptional level. Then we employed PCR array and identified hepatocyte nuclear factor 4α (HNF4α) as a candidate mediator. Mechanically, DCA treatment could induce HNF4α expression through TGR5 and following ERK1/2 pathway activation. Furthermore, HNF4α mediated the effects of DCA treatment through directly regulating KLF4 and CDX2. Finally, high TGR5 levels were correlated with high HNF4α, KLF4, and CDX2 levels in IM tissues. These findings highlight the TGR5-ERK1/2-HNF4α axis during IM development in patients with BAs reflux, which may help to understand the mechanism underlying IM development and provide prospective strategies for IM treatment. © The Author(s) 2020.

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出版当年[2020]版：

大类 | 2 区医学

小类 | 3 区细胞生物学

最新[2023]版：

大类 | 2 区生物学

小类 | 2 区细胞生物学

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第一作者机构： [1]State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032 China. [2]Department of Gastroenterology, General Hospital of Western Theater Command, Chengdu, Sichuan 610083 China.

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