Int J Biol Sci 2019; 15(7):1533-1545. doi:10.7150/ijbs.32020

Research Paper

Amorphous solid dispersion of Berberine mitigates apoptosis via iPLA2β/Cardiolipin/Opa1 pathway in db/db mice and in Palmitate-treated MIN6 β-cells

Junnan Li1#, Hongwei Du2#, Meishuang Zhang1, Zhi Zhang3, Fei Teng1, Yali Zhao1, Wenyou Zhang1, Yang Yu1, Linjing Feng1, Xinming Cui4, Ming Zhang1, Tzongshi Lu5, Fengying Guan1,5✉, Li Chen1✉

1. Department of Pharmacology, School of Basic Medical Sciences, Jilin University, Changchun 130021, China
2. Department of Pediatric Endocrinology, The First Clinical Hospital Affiliated to Jilin University, Changchun 130021, China
3. School of Life Sciences, Jilin University, Changchun 130012, China.
4. Key Laboratory of Pathobiology, Ministry of Education, School of Basic Medical Sciences, Jilin University, Changchun 130021, China
5. Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, United States
#Equal contribution

Abstract

Aims: Berberine (BBR) improves beta-cell function in Type 2 diabetes (T2D) because of its anti-apoptotic activity, and our laboratory developed a new preparation named Huang-Gui Solid Dispersion (HGSD) to improve the oral bioavailability of BBR. However, the mechanism by which BBR inhibits beta-cell apoptosis is unclear. We hypothesized that the Group VIA Ca2+-Independent Phospholipase A2 (iPLA2β)/Cardiolipin(CL)/Opa1 signaling pathway could exert a protective role in T2D by regulating beta-cell apoptosis and that HGSD could inhibit β-cell apoptosis through iPLA2β/CL/Opa1 upregulation.

Methods: We examined how iPLA2β and BBR regulated apoptosis and insulin secretion through CL/Opa1 in vivo and in vitro. In in vitro studies, we developed Palmitate(PA)-induced apoptotic cell death model in mouse insulinoma cells (MIN6). iPLA2β overexpression and silencing technology were used to examine how the iPLA2β/CL/Opa1 interaction may play an important role in BBR treatment. In in vivo studies, db/db mice were used as a diabetic animal model. The pancreatic islet function and morphology, beta-cell apoptosis and mitochondrial injury were examined to explore the effects of HGSD. The expression of iPLA2β/CL/Opa1 was measured to explore whether the signaling pathway was damaged in T2D and was involved in HGSD treatment.

Results: The overexpression of iPLA2β and BBR treatment significantly attenuated Palmitate- induced mitochondrial injury and apoptotic death compared with Palmitate-treated MIN6 cell. In addition, iPLA2β silencing could simultaneously partly abolish the anti-apoptotic effect of BBR and decrease CL/Opa1 signaling in MIN6 cells. Moreover, HGSD treatment significantly decreased beta-cell apoptosis and resulted in the upregulation of iPLA2β/CL/Opa1 compared to those of the db/db mice.

Conclusion: The results indicated that the regulation of iPLA2β/CL/Opa1 by HGSD may prevent beta-cell apoptosis and may improve islet beta-cell function in Type 2 diabetic mice and in palmitate-treated MIN6 cells.

Keywords: Type 2 diabetes, Beta-cell dysfunction, Apoptosis, Dynamin-related protein(Opa1), Cardiolipin, Group VIA Ca2+-Independent Phospholipase A2 (iPLA2β), Berberine.

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How to cite this article:
Li J, Du H, Zhang M, Zhang Z, Teng F, Zhao Y, Zhang W, Yu Y, Feng L, Cui X, Zhang M, Lu T, Guan F, Chen L. Amorphous solid dispersion of Berberine mitigates apoptosis via iPLA2β/Cardiolipin/Opa1 pathway in db/db mice and in Palmitate-treated MIN6 β-cells. Int J Biol Sci 2019; 15(7):1533-1545. doi:10.7150/ijbs.32020. Available from http://www.ijbs.com/v15p1533.htm