Identification of miR-26a as a target gene of bile acid receptor GPBAR-1/TGR5

Xiaosong Chen; Haixia Xu; Lili Ding; Guiyu Lou; Yan Liu; Yalan Yao; Liangwan Chen; Wendong Huang; Xianghui Fu

doi:10.1371/journal.pone.0131294

Identification of miR-26a as a target gene of bile acid receptor GPBAR-1/TGR5

PLoS One. 2015 Jun 24;10(6):e0131294. doi: 10.1371/journal.pone.0131294. eCollection 2015.

Authors

Xiaosong Chen¹, Haixia Xu², Lili Ding³, Guiyu Lou⁴, Yan Liu¹, Yalan Yao², Liangwan Chen¹, Wendong Huang³, Xianghui Fu²

Affiliations

¹ Department of Plastic Surgery, The Union Hospital of Fujian Medical University, 29 Xinquan Road, Fuzhou, Fujian, 350001, China.
² Division of Endocrinology and Metabolism, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, 610041, China.
³ Department of Diabetes Complications and Metabolism, Diabetes & Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, 1500 Duarte Road, Duarte, CA, 91010, United States of America.
⁴ Department of Diabetes Complications and Metabolism, Diabetes & Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, 1500 Duarte Road, Duarte, CA, 91010, United States of America; Central Laboratory, Henan People's Hospital and Zhengzhou University People's Hospital, No.7 Wei Wu Road, Zhengzhou, Henan, 450003, China.

Abstract

GPBAR1/TGR5 is a G protein-coupled receptor of bile acids. TGR5 is known to regulate the BA homeostasis and energy metabolism. Recent studies highlight an important role of TGR5 in alleviating obesity and improving glucose regulation, however, the mechanism of which is still unclear. Here we report that TGR5 is involved in mediating the anti-obesity and anti-hyperglycemia effect of a natural compound, oleanolic acid. By comparing the miRNA profiles between wild type and TGR5-/- livers after OA treatment, we identified miR-26a as a novel downstream target gene of TGR5 activation. The expression of miR-26a in the liver was induced in a TGR5-dependent manner after feeding the mice with a bile acid diet. TGR5 activation strongly increased the expression of miR-26a in macrophages, including the Kupffer cells in the liver. We further demonstrated that JNK pathway was required for miR-26a induction by TGR5 activation. Interestingly, we located the TGR5-responsive DNA element to a proximal region of miR-26's promoter, which was independent of the transcription of its host genes. These results unravel a new mechanism by which bile acid receptor TGR5 activates a miRNA gene expression.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adipose Tissue / metabolism
Animals
Anti-Obesity Agents / chemistry
Bile Acids and Salts / metabolism
Cell Line, Tumor
DNA / analysis
Gene Expression Profiling
Gene Expression Regulation*
Glucose Tolerance Test
Humans
Hypoglycemic Agents / chemistry
Isoxazoles / chemistry
Kupffer Cells / cytology
Liver / metabolism
MAP Kinase Kinase 4 / metabolism
Macrophages / metabolism
Macrophages, Peritoneal / metabolism
Mice
Mice, Inbred C57BL
Mice, Transgenic
MicroRNAs / physiology*
Oleanolic Acid / chemistry
Receptors, G-Protein-Coupled / metabolism*

Substances

Anti-Obesity Agents
Bile Acids and Salts
GPBAR1 protein, human
Gpbar1 protein, mouse
Hypoglycemic Agents
Isoxazoles
MIRN26A microRNA, human
MicroRNAs
Mirn26 microRNA, mouse
Receptors, G-Protein-Coupled
Oleanolic Acid
DNA
MAP Kinase Kinase 4
GW 4064

Grants and funding

This work is supported partially by the National Natural Science Foundation of China-Grant No. 81372092, Fujian Natural Science Foundation-Grant No. 2011J01173, Fujian Municipal Natural Science Foundation-Grant No. 2011Y0029, Foundation of Fujian Educational Committee National-Grant No. JA11122 to X.C., National Natural Science Foundation of China-Grant No. 81441121 to X.F., and National Cancer Institute-Grant No. R01-139158 to W.H. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.