Yongjun Liang1, Bo Yu2, Yueqian Wang1, Zhengdong Qiao1, Ting Cao1, Peng Zhang3. 1. Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China. 2. Center for Metabolic and Bariatric Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China. 3. Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China; Center for Metabolic and Bariatric Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China. Electronic address: zhangpg@yahoo.com.
Abstract
BACKGROUND: The duodenum plays a role in the mechanism of type 2 diabetes remission after bariatric surgery. Roux-en-Y gastric bypass (RYGB) may change gene expression in the duodenum and metabolism. Long noncoding RNAs (lncRNAs) constitute a novel class of RNAs that regulate gene expression. Little is known about how duodenal lncRNAs respond to RYGB. Logically, studies on the changes of duodenal lncRNAs potentially can lead to an understanding of the mechanisms of bariatric surgery, as well as discovery of antidiabetic drug targets and biomarkers predicting postoperative outcome. OBJECTIVES: To investigate the expression signature of duodenal lncRNAs associated with glycemic improvement by duodenal-jejunal bypass (DJB), a component of RYGB, on a genome-wide scale in high-fat diet-induced diabetic mice. SETTING: University medical center. METHODS: High fat diet-induced diabetic mice were randomized into 2 groups receiving either the DJB or a sham procedure. Microarray was applied to screen the differentially expressed lncRNAs and messenger RNAs (mRNAs) in the duodenum between the DJB and sham groups, and the result was validated by quantitative real-time polymerase chain reaction in another cohort of animals. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to predict the potential lncRNA functions. Based on Pearson correlation analysis, the lncRNA-mRNA and lncRNA-transcription factor (TF) interaction networks were constructed to identify and rank core regulatory lncRNAs and transcription factors. RESULTS: A total of 301 lncRNAs, including 232 that were upregulated and 69 downregulated (fold change≥2.0), were differentially expressed in the duodenum between the DJB and sham groups. GO enrichment indicated that these lncRNA-coexpressed mRNAs were correlated with biological processes including cell proliferation, digestion, and catabolic and biosynthetic processes. KEGG pathway analysis revealed that in addition to the digestion and absorption signaling pathways, pancreatic secretion- and inflammatory process-related signaling pathways were mostly enriched in the DJB group. In addition, the lncRNA-mRNA interaction network combined with GO and KEGG pathway analysis suggested that as a top-ranked gene, NONMMUG021726 may play an important role in the mechanism of type 2 diabetes remission after DJB. CONCLUSION: DJB leads to drastic changes in lncRNA and mRNA expressions in the duodenum. The majority of top-ranked lncRNAs and mRNAs have roles in pancreatic secretion and inflammatory processes, implying that bypass of the duodenum may initiate insulin secretion and attenuate inflammation. In addition, modulators of such lncRNAs, most likely NONMMUG021726, have potential to become therapeutic targets or biomarkers for prediction of the outcomes of bariatric surgery.
BACKGROUND: The duodenum plays a role in the mechanism of type 2 diabetes remission after bariatric surgery. Roux-en-Y gastric bypass (RYGB) may change gene expression in the duodenum and metabolism. Long noncoding RNAs (lncRNAs) constitute a novel class of RNAs that regulate gene expression. Little is known about how duodenal lncRNAs respond to RYGB. Logically, studies on the changes of duodenal lncRNAs potentially can lead to an understanding of the mechanisms of bariatric surgery, as well as discovery of antidiabetic drug targets and biomarkers predicting postoperative outcome. OBJECTIVES: To investigate the expression signature of duodenal lncRNAs associated with glycemic improvement by duodenal-jejunal bypass (DJB), a component of RYGB, on a genome-wide scale in high-fat diet-induced diabeticmice. SETTING: University medical center. METHODS: High fat diet-induced diabeticmice were randomized into 2 groups receiving either the DJB or a sham procedure. Microarray was applied to screen the differentially expressed lncRNAs and messenger RNAs (mRNAs) in the duodenum between the DJB and sham groups, and the result was validated by quantitative real-time polymerase chain reaction in another cohort of animals. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to predict the potential lncRNA functions. Based on Pearson correlation analysis, the lncRNA-mRNA and lncRNA-transcription factor (TF) interaction networks were constructed to identify and rank core regulatory lncRNAs and transcription factors. RESULTS: A total of 301 lncRNAs, including 232 that were upregulated and 69 downregulated (fold change≥2.0), were differentially expressed in the duodenum between the DJB and sham groups. GO enrichment indicated that these lncRNA-coexpressed mRNAs were correlated with biological processes including cell proliferation, digestion, and catabolic and biosynthetic processes. KEGG pathway analysis revealed that in addition to the digestion and absorption signaling pathways, pancreatic secretion- and inflammatory process-related signaling pathways were mostly enriched in the DJB group. In addition, the lncRNA-mRNA interaction network combined with GO and KEGG pathway analysis suggested that as a top-ranked gene, NONMMUG021726 may play an important role in the mechanism of type 2 diabetes remission after DJB. CONCLUSION: DJB leads to drastic changes in lncRNA and mRNA expressions in the duodenum. The majority of top-ranked lncRNAs and mRNAs have roles in pancreatic secretion and inflammatory processes, implying that bypass of the duodenum may initiate insulin secretion and attenuate inflammation. In addition, modulators of such lncRNAs, most likely NONMMUG021726, have potential to become therapeutic targets or biomarkers for prediction of the outcomes of bariatric surgery.
Authors: Andriy Myronovych; Bailey C E Peck; Mingrui An; Jianhui Zhu; Anna Warm; Aleksander Kupe; David M Lubman; Randy J Seeley Journal: Am J Physiol Gastrointest Liver Physiol Date: 2020-11-11 Impact factor: 4.052