Basic Study
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 7, 2015; 21(25): 7777-7785
Published online Jul 7, 2015. doi: 10.3748/wjg.v21.i25.7777
Berberine inhibits hepatic gluconeogenesis via the LKB1-AMPK-TORC2 signaling pathway in streptozotocin-induced diabetic rats
Shu-Jun Jiang, Hui Dong, Jing-Bin Li, Li-Jun Xu, Xin Zou, Kai-Fu Wang, Fu-Er Lu, Ping Yi
Shu-Jun Jiang, Hui Dong, Li-Jun Xu, Xin Zou, Kai-Fu Wang, Fu-Er Lu, Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
Jing-Bin Li, Ping Yi, Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
Author contributions: Dong H, Lu FE and Yi P designed the research; Jiang SJ, Li JB, Xu LJ, Zou X and Wang KF performed the research; Dong H analyzed the data; Jiang SJ wrote the paper.
Supported by National Natural Science Foundation of China, No. 30973836.
Ethics approval: The various ethics statements related to scientific conduct are detailed below.
Institutional animal care and use committee: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee at Tongji Medical College, Huazhong University of Science and Technology (IACUC number: 372).
Conflict-of-interest statement: The authors declare that there is no conflict of interests regarding the publication of this paper.
Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding author at pyi219@163.com. Participants gave informed consent for data sharing. No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Ping Yi, PhD, Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, Hubei Province, China. pyi219@163.com
Telephone: +86-27-83663217 Fax: +86-27-83663237
Received: January 5, 2015
Peer-review started: January 6, 2015
First decision: January 22, 2015
Revised: February 14, 2015
Accepted: March 31, 2015
Article in press: March 31, 2015
Published online: July 7, 2015
Processing time: 183 Days and 18.3 Hours
Abstract

AIM: To investigate the molecular mechanisms of berberine inhibition of hepatic gluconeogenesis in a diabetic rat model.

METHODS: The 40 rats were randomly divided into five groups. One group was selected as the normal group. In the remaining groups (n = 8 each), the rats were fed on a high-fat diet for 1 mo and received intravenous injection of streptozotocin for induction of the diabetic models. Berberine (156 mg/kg per day) (berberine group) or metformin (184 mg/kg per day) (metformin group) was intragastrically administered to the diabetic rats and 5-aminoimidazole-4-carboxamide1-β-D-ribofuranoside (AICAR) (0.5 mg/kg per day) (AICAR group) was subcutaneously injected to the diabetic rats for 12 wk. The remaining eight diabetic rats served as the model group. Fasting plasma glucose and insulin levels as well as lipid profile were tested. The expressions of proteins were examined by western blotting. The nuclear translocation of CREB-regulated transcription co-activator (TORC)2 was observed by immunohistochemical staining.

RESULTS: Berberine improved impaired glucose tolerance and decreased plasma hyperlipidemia. Moreover, berberine decreased fasting plasma insulin and homeostasis model assessment of insulin resistance (HOMA-IR). Berberine upregulated protein expression of liver kinase (LK)B1, AMP-activated protein kinase (AMPK) and phosphorylated AMPK (p-AMPK). The level of phophorylated TORC2 (p-TORC2) protein in the cytoplasm was higher in the berberine group than in the model group, and no significant difference in total TORC2 protein level was observed. Immunohistochemical staining revealed that more TORC2 was localized in the cytoplasm of the berberine group than in the model group. Moreover, berberine treatment downregulated protein expression of the key gluconeogenic enzymes (phosphoenolpyruvate carboxykinase and glucose-6-phosphatase) in the liver tissues.

CONCLUSION: Our findings revealed that berberine inhibited hepatic gluconeogenesis via the regulation of the LKB1-AMPK-TORC2 signaling pathway.

Keywords: Berberine; Diabetes; AMPK; LKB1; Hepatic gluconeogenesis; TORC2

Core tip: We showed that liver kinase (LK)B1 acts as the upstream regulator of AMP-activated protein kinase (AMPK) and participates in gluconeogenesis. AMPK phosphorylation triggers CREB-regulated transcription co-activator (TORC)2 phosphorylation, which results in the inhibition of the nuclear translocation of TORC2. Thus, gluconeogenesis is restrained. No previous studies have reported the molecular mechanisms of berberine reducing hyperglycemia via the inhibition of hepatic gluconeogenesis. We found that berberine upregulated protein expression of LKB1, AMPK, p-AMPK and p-TORC2. Moreover, we observed that berberine inhibited the translocation of TOCR2 into the cell nucleus.