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.
Highlights
The NAD+-dependent protein deacetylase Sirtuin-3 (SIRT3) is a member of the sirtuin family of proteins [1,2]
The processed SIRT3: the long form (SIRT3LF) was abundantly detected in the mitochondria fraction and detected in the nucleus fraction, suggesting that SIRT3LF was mainly localized in the mitochondria and partially localized in the nucleus nuclear localization was not detected in the immunocytochemistry analysis
While the level of SIRT3SF was rapidly reduced, the SIRT3 small form generated from SIRT3LF was quite stable, suggesting that SIRT3 is more stable in the mitochondria than in the nucleus (Fig 1E)
Summary
The NAD+-dependent protein deacetylase Sirtuin-3 (SIRT3) is a member of the sirtuin family of proteins [1,2]. SIRT3 contains mitochondrial localization sequences that direct its import into the mitochondria, where it is cleaved to a shorter form [3,4]. Many proteins of mitochondrial metabolic pathways, such as the tricarboxylic acid pathway, oxidative phosphorylation, and fatty acid β-oxidation, are regulated by acetylation [5]. The importance of the deacetylation activity of SIRT3 in mitochondria is evidenced by the demonstration of hyperacetylation of PLOS ONE | DOI:10.1371/journal.pone.0124744. Roles of SIRT3 in Pancreatic β Cells mitochondrial proteins in SIRT3-/- mice [6]. SIRT3 expression increased in the liver accompanied by altered fatty acid metabolism, whereas mice fed a high-fat diet had lower SIRT3 expression and activity in liver and skeletal muscle [7]. SIRT3-deficient mice were more likely than normal mice to develop insulin resistance and obesity [8,9,10]
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