Published online Jul 7, 2015. doi: 10.3748/wjg.v21.i25.7777
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
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.
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.