PMID- 35609386 OWN - NLM STAT- MEDLINE DCOM- 20220614 LR - 20220615 IS - 1618-095X (Electronic) IS - 0944-7113 (Linking) VI - 102 DP - 2022 Jul 20 TI - Cyclocarya paliurus triterpenoids suppress hepatic gluconeogenesis via AMPK-mediated cAMP/PKA/CREB pathway. PG - 154175 LID - S0944-7113(22)00253-7 [pii] LID - 10.1016/j.phymed.2022.154175 [doi] AB - BACKGROUND: Abnormal enhancement of hepatic gluconeogenesis is a vital mechanism of the pathogenesis of Type 2 diabetes mellitus (T2DM); thus, its suppression may present an efficient therapeutic strategy for T2DM. Cyclocarya paliurus (CP), a plant species native to China, has been reported to have anti-hyperglycemia activity. Our previous studies have revealed that Cyclocarya paliurus triterpenic acids (CPT) exert the favorable glucose-lowering activity, but the regulatory effect of CPT on hepatic gluconeogenesis is still unclarified. PURPOSE: This study aimed to investigate the potential role and mechanism of CPT in gluconeogenesis. STUDY DESIGN: In this study, the ameliorative effect and underlying mechanism of CPT on gluconeogenesis were investigated: high-fat diet and streptozotocin-induced T2DM mice and glucagon-challenged mouse primary hepatocytes. METHODS: T2DM model mice with or without oral administration of CPT for 4 weeks were monitored for body weight, glucose and lipid metabolism. Hematoxylin and eosin staining was used to observe liver lipid deposition. Real-time PCR assays were performed to examine the mRNA expression of glucose-6-phosphate (G6Pase), and phosphoenolpyruvate carboxykinase (PEPCK), two key enzymes involved in liver gluconeogenesis. Western blotting was used to determine AMP-dependent protein kinase (AMPK) expression and induction of the glucagon signaling pathway. The possible mechanism of CPT on liver gluconeogenesis was further explored in glucagon-induced mouse primary hepatocytes. RESULTS: In vivo and in vitro experiments revealed that CPT treatment significantly reduced fasting blood glucose, total cholesterol and triglyceride levels, and improved insulin resistance. Furthermore, CPT could obviously decreased the mRNA and protein expression of G6Pase and PEPCK, the cyclic AMP content, the phosphorylation level of protein kinase A and cyclic AMP response element-binding protein. But CPT promoted the phosphorylation of AMP-dependent protein kinase (AMPK) and activation of phosphodiesterase 4B. Mechanistically, intervention with Compound C (an AMPK inhibitor) partially blocked the suppressive effect of CPT on hepatic gluconeogenesis. CONCLUSION: These findings suggested that CPT may inhibit hepatic gluconeogenesis against T2DM by activating AMPK. CI - Copyright (c) 2022. Published by Elsevier GmbH. FAU - Cao, Jingjing AU - Cao J AD - Department of Endocrinology, Nanjing Lishui District Hospital of Traditional Chinese Medicine, Nanjing, 211200, China; Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, China. FAU - Zheng, Rendong AU - Zheng R AD - Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, China. FAU - Chang, Xiaoyan AU - Chang X AD - Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, China. FAU - Zhao, Yuanyuan AU - Zhao Y AD - Department of Endocrinology, Nanjing Lishui District Hospital of Traditional Chinese Medicine, Nanjing, 211200, China. FAU - Zhang, Dongjian AU - Zhang D AD - Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, China; Laboratory of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, China. FAU - Gao, Meng AU - Gao M AD - Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, China; Laboratory of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, China. FAU - Yin, Zhiqi AU - Yin Z AD - Department of TCMs Pharmaceuticals, School of TCM & State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China. FAU - Jiang, Cuihua AU - Jiang C AD - Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, China; Laboratory of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, China. Electronic address: jiangshan806@163.com. FAU - Zhang, Jian AU - Zhang J AD - Department of Endocrinology, Nanjing Lishui District Hospital of Traditional Chinese Medicine, Nanjing, 211200, China; Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, China. Electronic address: zhangjian@jsatcm.com. LA - eng PT - Journal Article DEP - 20220516 PL - Germany TA - Phytomedicine JT - Phytomedicine : international journal of phytotherapy and phytopharmacology JID - 9438794 RN - 0 (RNA, Messenger) RN - 0 (Triterpenes) RN - 415SHH325A (Adenosine Monophosphate) RN - 9007-92-5 (Glucagon) RN - E0399OZS9N (Cyclic AMP) RN - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) RN - IY9XDZ35W2 (Glucose) SB - IM MH - AMP-Activated Protein Kinases/metabolism MH - Adenosine Monophosphate MH - Animals MH - Cyclic AMP/metabolism MH - Cyclic AMP-Dependent Protein Kinases/metabolism MH - *Diabetes Mellitus, Type 2/drug therapy/metabolism MH - Glucagon/metabolism/pharmacology/therapeutic use MH - Gluconeogenesis MH - Glucose/metabolism MH - *Juglandaceae/chemistry MH - Liver MH - Mice MH - RNA, Messenger/metabolism MH - *Triterpenes/metabolism OTO - NOTNLM OT - AMPK OT - Cyclocarya paliurus OT - Gluconeogenesis OT - Triterpenic acids OT - Type 2 diabetes mellitus EDAT- 2022/05/25 06:00 MHDA- 2022/06/15 06:00 CRDT- 2022/05/24 18:17 PHST- 2021/07/11 00:00 [received] PHST- 2022/05/06 00:00 [revised] PHST- 2022/05/14 00:00 [accepted] PHST- 2022/05/25 06:00 [pubmed] PHST- 2022/06/15 06:00 [medline] PHST- 2022/05/24 18:17 [entrez] AID - S0944-7113(22)00253-7 [pii] AID - 10.1016/j.phymed.2022.154175 [doi] PST - ppublish SO - Phytomedicine. 2022 Jul 20;102:154175. doi: 10.1016/j.phymed.2022.154175. Epub 2022 May 16.