Downregulation of the longevity-associated protein sirtuin 1 in insulin resistance and metabolic syndrome: potential biochemical mechanisms.
OBJECTIVE
Sirtuins (SIRTs) are NAD(+)-dependent deacetylases that regulate metabolism and life span. We used peripheral blood mononuclear cells (PBMCs) to determine ex vivo whether insulin resistance/metabolic syndrome influences SIRTs. We also assessed the potential mechanisms linking metabolic alterations to SIRTs in human monocytes (THP-1) in vitro.


METHODS
SIRT1-SIRT7 gene and protein expression was determined in PBMCs of 54 subjects (41 with normal glucose tolerance and 13 with metabolic syndrome). Insulin sensitivity was assessed by the minimal model analysis. Subclinical atherosclerosis was assessed by carotid intima-media thickness (IMT). In THP-1 cells exposed to high glucose or fatty acids in vitro, we explored SIRT1 expression, p53 acetylation, Jun NH(2)-terminal kinase (JNK) activation, NAD(+) levels, and nicotinamide phosphoribosyltransferase (NAMPT) expression. The effects of SIRT1 induction by resveratrol and of SIRT1 gene silencing were also assessed.


RESULTS
In vivo, insulin resistance and metabolic syndrome were associated with low PBMC SIRT1 gene and protein expression. SIRT1 gene expression was negatively correlated with carotid IMT. In THP-1 cells, high glucose and palmitate reduced SIRT1 and NAMPT expression and reduced the levels of intracellular NAD(+) through oxidative stress. No effect was observed in cells exposed to linoleate or insulin. High glucose and palmitate increased p53 acetylation and JNK phosphorylation; these effects were abolished in siRNA SIRT1-treated cells. Glucose- and palmitate-mediated effects on NAMPT and SIRT1 were prevented by resveratrol in vitro.


CONCLUSIONS
Insulin resistance and subclinical atherosclerosis are associated with SIRT1 downregulation in monocytes. Glucotoxicity and lypotoxicity play a relevant role in quenching SIRT1 expression.
de Kreutzenberg
Saula Vigili
SV
Department of Clinical and Experimental Medicine, Metabolic Diseases, University of Padova, Padova, Italy. saula.dekreutzenberg@unipd.it
Ceolotto
Giulio
G
Papparella
Italia
I
Bortoluzzi
Alessia
A
Semplicini
Andrea
A
Dalla Man
Chiara
C
Cobelli
Claudio
C
Fadini
Gian Paolo
GP
Avogaro
Angelo
A
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D050197:Atherosclerosis / Q000235:genetics / Q000473:pathology; D002339:Carotid Arteries / Q000473:pathology; D015536:Down-Regulation; D005947:Glucose / Q000494:pharmacology; D005951:Glucose Tolerance Test; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D008136:Longevity; D024821:Metabolic Syndrome / Q000235:genetics* / Q000473:pathology; D009000:Monocytes / Q000502:physiology; D019308:Palmitic Acid / Q000494:pharmacology; D012016:Reference Values; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000235:genetics*; D013267:Stilbenes / Q000494:pharmacology; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology; D017540:Tunica Media / Q000187:drug effects / Q000473:pathology
D020533:Angiogenesis Inhibitors; D013267:Stilbenes; D019308:Palmitic Acid; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D005947:Glucose; D000077185:Resveratrol