Activation of SIRT1 protects pancreatic β-cells against palmitate-induced dysfunction

Abstract

Sirtuin 1 (SIRT1), a nicotinamide adenosine dinucleotide-dependent histone deacetylase, is an important regulator of energy homeostasis in response to nutrient availability. In pancreatic β-cells, SIRT1 has been shown to up-regulate insulin secretion in response to glucose stimulation. However, the potential roles of SIRT1 in islet β-cells against lipotoxicity remain poorly understood. Here, we demonstrated that SIRT1 mRNA and protein expressions were markedly reduced in the islets isolated from rats infused with 20% Intralipid for 24h. Long-term exposure to 0.4mmol/L palmitate also decreased SIRT1 expression in cultured INS-1 cells and isolated rat islets, which was prevented by 10μmol/L resveratrol, a SIRT1 agonist. In addition, resveratrol improved glucose-stimulated insulin secretion decreased by palmitate, which was abrogated by EX527, a specific SIRT1 inhibitor. Furthermore, inhibition of SIRT1 activity by EX527 or a knockdown of SIRT1 suppressed insulin promoter activity, along with decreased insulin, v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA), and NK6 homeodomain 1 (NKX6.1) mRNA expressions. Activation of SIRT1 by resveratrol or overexpression of SIRT1 antagonized palmitate-inhibited insulin transcriptional activity. SIRT1 overexpression exerted an additive effect on pancreatic and duodenal homeobox 1 (PDX1)-stimulated insulin promoter activity and abolished forkhead box O1 protein (FOXO1)-decreased insulin transcriptional activity. Resveratrol reversed FOXO1 nuclear translocation induced by palmitate. Our findings indicate that SIRT1 protects against palmitate-induced β-cell dysfunction.

Palmitate Inhibits SIRT1-Dependent BMAL1/CLOCK Interaction and Disrupts Circadian Gene Oscillations in Hepatocytes

“…SIRT1 expression or activity has been shown to be reduced or inhibited in obesity or after palmitate exposure [59–61]. To test whether SIRT1 might be involved in palmitate-induced repression of BMAL1-CLOCK interaction, we overexpressed Sirt1 in 293T cells in which we detected a very low level of the endogenous SIRT1.…”

“…However, significant amount of CLOCK-FLAG is present in immuno-precipitated CBP-SBP-Bmal1 in the presence of Sirt1 overexpression. We next used SIRT1-specific inhibitor EX527 [61–63] to test how inhibition of SIRT1 activity affects BMAL1-CLOCK interaction in PMH hepatocytes transduced with Ad-Bmal1-Flag. While elevated levels of acetylated p53 after SIRT1 suppression by EX527 is consistent with the literature [63], a lower amount of the endogenous CLOCK is shown to interact with FLAG-tagged BMAL1 after immuno-precipitation with anti-FLAG ( Fig 5B ).…”

Methyl-deficient diet promotes colitis and SIRT1-mediated endoplasmic reticulum stress

“…We used a well-known SIRT1 activator, namely SRT172027 and EX527, a SIRT1 inhibitor 34. In TO cells, expression levels of BIP, HSP27 and HSP90 were increased following SRT1720 stimulation (p<0.01), whereas in OT cells inhibiting SIRT1 activity with EX527 reduced the expression level of these molecular chaperones (p<0.01) (figure 6A).…”

“…Resveratrol, a natural agonist of SIRT1, protects cell form apoptosis by inhibiting ER stress in hepatocytes and pancreatic β cells 34 39. In HepG2 cells, SIRT1 also improved palmitate-induced insulin resistance via regulation of ER stress 40.…”

SIRT1 metabolic actions: Integrating recent advances from mouse models

“…Supporting this hypothesis, increasing NAD + by nicotinamide mononucleotide (NMN) supplementation rescues the benefits of β-cell SIRT1 overexpression in aged mice [77]. In line with the beneficial effects of SIRT1 on pancreatic function, SIRT1 activation could also be a promising strategy to prevent the deleterious effects of lipotoxicity on insulin secretion and β-cell function [78]. The requirement of SIRT1 for proper adult pancreatic β-cell function was finally consolidated by a recent report using floxed SIRT1 mice crossed with the Pdx1-CreER deleter strain [79].…”