PAHSAs reduce cellular senescence and protect pancreatic beta cells from metabolic stress through regulation of Mdm2/p53

Author:

Rubin de Celis Maria F.1,Garcia-Martin Ruben2,Syed Ismail1,Lee Jennifer1,Aguayo-Mazzucato Cristina2ORCID,Bonner-Weir Susan2ORCID,Kahn Barbara B.1ORCID

Affiliation:

1. Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215

2. Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215

Abstract

Senescence in pancreatic beta cells plays a major role in beta cell dysfunction, which leads to impaired glucose homeostasis and diabetes. Therefore, prevention of beta cell senescence could reduce the risk of diabetes. Treatment of nonobese diabetic (NOD) mice, a model of type 1 autoimmune diabetes (T1D), with palmitic acid hydroxy stearic acids (PAHSAs), a novel class of endogenous lipids with antidiabetic and antiinflammatory effects, delays the onset and reduces the incidence of T1D from 82% with vehicle treatment to 35% with PAHSAs. Here, we show that a major mechanism by which PAHSAs protect islets of the NOD mice is by directly preventing and reversing the initial steps of metabolic stress–induced senescence. In vitro PAHSAs increased Mdm2 expression, which decreases the stability of p53, a key inducer of senescence-related genes. In addition, PAHSAs enhanced expression of protective genes, such as those regulating DNA repair and glutathione metabolism and promoting autophagy. We demonstrate the translational relevance by showing that PAHSAs prevent and reverse early stages of senescence in metabolically stressed human islets by the same Mdm2 mechanism. Thus, a major mechanism for the dramatic effect of PAHSAs in reducing the incidence of type 1 diabetes in NOD mice is decreasing cellular senescence; PAHSAs may have a similar benefit in humans.

Funder

HHS | National Institutes of Health

JPB Foundation

Deutsche Forschungsgemeinschaft

Joslin Diabetes Center

Diabetes and Wellness Foundation

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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