Original Article
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World J Gastroenterol. Jan 7, 2014; 20(1): 175-182
Published online Jan 7, 2014. doi: 10.3748/wjg.v20.i1.175
Bile acid increases expression of the histamine-producing enzyme, histidine decarboxylase, in gastric cells
Hye Jin Ku, Hye Young Kim, Hyeong Hoe Kim, Hee Ju Park, Jae Hun Cheong
Hye Jin Ku, Hee Ju Park, Department of Pediatrics, College of Medicine, Pusan National University, Busan 601-721, South Korea
Hye Young Kim, Jae Hun Cheong, Department of Molecular Biology, College of Natural Sciences, Pusan National University, Busan 609-735, South Korea
Hyeong Hoe Kim, Department of Experimental Medicine, College of Medicine, Pusan National University, Busan 601-721, South Korea
Author contributions: All the authors contributed to this manuscript.
Supported by National Research Foundation of Korea grant funded by the Korea government, No. 2009-0093193
Correspondence to: Jae Hun Cheong, PhD, Department of Molecular Biology, College of Natural Sciences, Pusan National University, Busan 609-735, South Korea. molecule85@pusan.ac.kr
Telephone: + 82-51-5102277 Fax: +82-51-5139258
Received: July 14, 2013
Revised: September 16, 2013
Accepted: October 17, 2013
Published online: January 7, 2014
Processing time: 190 Days and 10.7 Hours
Abstract

AIM: To investigate the effect of bile acid on the expression of histidine decarboxylase (HDC), which is a major enzyme involved in histamine production, and gene expression of gastric transcription factors upon cooperative activation.

METHODS: HDC expression was examined by immunohistochemistry, reverse transcriptase polymerase chain reaction, and promoter assay in human gastric precancerous tissues, normal stomach tissue, and gastric cancer cell lines. The relationship between gastric precancerous state and HDC expression induced by bile acid was determined. The association between the expression of HDC and various specific transcription factors in gastric cells was also evaluated. MKN45 and AGS human gastric carcinoma cell lines were transfected with farnesoid X receptor (FXR), small heterodimer partner (SHP), and caudal-type homeodomain transcription factor (CDX)1 expression plasmids. The effects of various transcription factors on HDC expression were monitored by luciferase-reporter promoter assay.

RESULTS: Histamine production and secretion in the stomach play critical roles in gastric acid secretion and in the pathogenesis of gastric diseases. Here, we show that bile acid increased the expression of HDC, which is a rate-limiting enzyme of the histamine production pathway. FXR was found to be a primary regulatory transcription factor for bile acid-induced HDC expression. In addition, the transcription factors CDX1 and SHP synergistically enhanced bile acid-induced elevation of HDC gene expression. We confirmed similar expression patterns for HDC, CDX1, and SHP in patient tissues.

CONCLUSION: HDC production in the stomach is associated with bile acid exposure and its related transcriptional regulation network of FXR, SHP, and CDX1.

Keywords: Histamine; Histidine decarboxylase; Bile acid; Farnesoid X receptor

Core tip: Histamine production and secretion in the stomach play critical roles in gastric acid secretion and in the pathogenesis of gastric diseases. Bile acids are tumor promoters, and higher levels of bile acids are found in patients with atrophic chronic gastritis and intestinal metaplasia. Increased histidine decarboxylase (HDC), which is a histamine producing enzyme, has been detected in intestinal-type gastric carcinoma. In this study, we provide new evidence that bile acids induce HDC expression in gastric cells and a series of specific transcription factors (farnesoid X receptor, small heterodimer partner, and caudal-type homeodomain transcription factor 1) play critical roles in bile acid-mediated HDC induction.