Berberine promotes glucose uptake and inhibits gluconeogenesis by inhibiting deacetylase SIRT3
Many studies have confirmed the glucose-lowering effect of berberine in type 2 diabetes patients. Although the mechanism of action of berberine involves the improvement of insulin sensitivity, its hypoglycemic mechanism remains elusive. Here we show a new mechanism by which berberine antagonizes glucagon signaling and find that SIRT3 is involved in the hypoglycemic effect of berberine.
Gene knockout and overexpression were used to assess the inhibitory effect of berberine on SIRT3. Downstream signaling pathways and the hypoglycemic effect of SIRT3 were evaluated by immunoblotting and metabolic monitoring.
We found that berberine led to mitochondrial dysfunction and AMP accumulation by inhibiting deacetylase SIRT3. We confirmed that AMP accumulation activated the AMPK signaling pathway and further promoted glucose uptake. Simultaneously, AMP accumulation reduced cyclic AMP (cAMP) levels and abrogated the phosphorylation of critical protein targets of protein kinase A (PKA). Furthermore, we found that phosphoenolpyruvate carboxykinase 1 (PEPCK1) is a key gluconeogenesis enzyme that can be stabilized by glucagon. Berberine caused significant PEPCK1 ubiquitination and degradation by antagonizing glucagon and was accompanied by high levels of PEPCK1 acetylation. Interestingly, berberine-induced glucagon inhibition is independent of AMPK activation. The in vivo data from sirt3 knockout mice were further confirmed by the in vitro experiments.
Berberine promotes glucose uptake and inhibits gluconeogenesis by inhibiting SIRT3, and regulating mitochondria-related pathways may provide a novel approach to the development of antidiabetic drugs.
KeywordsBerberine PEPCK1 AMP Glucose SIRT3
We thank the Zhao lab for offering their help.
This work was supported by grants from the National Natural Science Foundation of China (No. 81602076, 81672935 and 81472756), Outstanding Youth Project of Nanjing City (No. JQX17002), the Jiangsu Clinical Medical Center of Digestive Disease (BL2012001), the Natural Science Foundation from the Department of Science & Technology of Jiangsu Province (BK20160113), the Fundamental Research Funds for the Central Universities (No. 021414380244), the Foundation of Jiangsu Provincial Commission of Health and Family Planning (Q201611).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
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