SIRT3 Overexpression Attenuates Palmitate-Induced Pancreatic β-Cell Dysfunction

Abstract

Abnormally high levels of circulating free fatty acids can lead to pancreatic islet β-cell dysfunction and apoptosis, contributing to β-cell failure in Type 2 diabetes. The NAD+-dependent protein deacetylase Sirtuin-3 (SIRT3) has been implicated in Type 2 diabetes. In this study, we tested whether SIRT3 overexpression affects palmitate-induced β-cell dysfunction in cells of line NIT1, which are derived from mouse pancreatic β-cells. Two different lengths of SIRT3 were overexpressed: full length SIRT3 (SIRT3LF), which was preferentially targeted to mitochondria and partially to the nucleus, and its N-terminal truncated form (SIRT3SF), which was located in the nucleus and cytoplasm. Overexpression of SIRT3LF and SIRT3SF using an adenoviral system alleviated palmitate-induced lipotoxicity such as reduction of cell viability and mitogen-activated protein kinase (MAPK) activation. Chronic exposure to low concentrations of palmitate suppressed glucose-stimulated insulin secretion, but the suppression was effectively reversed by overexpression of SIRT3LF or SIRT3SF. The mRNA levels of the endoplasmic reticulum (ER) stress responsive genes ATF4, GRP94 and FKBP11 were increased by palmitate treatment, but the increases were completely inhibited by SIRT3LF overexpression and less effectively inhibited by SIRT3SF overexpression. This result suggests that overexpression of SIRT3 inhibits induction of ER stress by palmitate. Collectively, we conclude that overexpression of SIRT3 alleviates palmitate-induced β-cell dysfunction.

Sirtuin 3 acts as a negative regulator of autophagy dictating hepatocyte susceptibility to lipotoxicity

“…SIRT3 activation is one of the major mechanisms accounting for many calorie restriction‐derived benefits . Similarly, the beneficial effects of SIRT3 activation have been reported by numerous studies in a variety of experimental and clinical settings . In this study, we demonstrate that SFAs and unsaturated FAs differentially regulate SIRT3 expression in hepatocytes.…”

“…(20,33) Similarly, the beneficial effects of SIRT3 activation have been reported by numerous studies in a variety of experimental and clinical settings. (34,35) In this study, we demonstrate that SFAs and unsaturated FAs differentially regulate SIRT3 expression in hepatocytes. Unexpectedly, our data suggest that SIRT3 activation is associated with increased susceptibility of hepatocytes to PA-induced cell death.…”

1,3,6,7‐Tetrahydroxy‐8‐prenylxanthone ameliorates inflammatory responses resulting from the paracrine interaction of adipocytes and macrophages

“…RAW264.7 macrophages with SIRT3 knockdown expressed higher iNOS protein and transcript levels of inflammatory cytokines, which led to an elevated inflammatory state (Xu et al, ). SIRT3 has been reported to suppress MAPK activation in various models of inflammation (Sundaresan et al, ; Kim et al, ). Overexpression of SIRT3 in H9c2 cells inhibited NF‐κB nuclear translocation, which stimulated SOD2 gene expression and consequently conferred cells with resistance against oxidative insults (Chen et al, ).…”

SIRT3 regulates progression and development of diseases of aging

“…Not surprisingly, transient knockdown of SIRT3 in β-cells in culture results in elevated ROS and impaired insulin secretion [61]. Further, adenoviral overexpression of SIRT3 in primary rat islets rescues lipotoxic impairment glucose-stimulated insulin secretion [62]. Thus, SIRT3 is emerging as a critical player in pancreatic β-cell survival and/or compensation in the presence of a hyperglycemic-hyperlipidemic insult, similar to its role in protecting against hepatic lipotoxicity.…”