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SIRT1 Modulating Compounds from High-Throughput Screening as Anti-Inflammatory and Insulin-Sensitizing Agents
S*BIO PTE LTD, Singapore.
* To whom correspondence should be addressed. E-mail: walter_stunkel{at}sbio.com.
The nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase SIRT1 has been linked to fatty acid metabolism via suppression of peroxysome proliferator-activated receptor gamma (PPAR- Key Words: SIRT1, small-molecule activators, HTS, adipocyte differentiation assay
First published on November 12, 2006, doi:10.1177/1087057106294710 |
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) and to inflammatory processes by deacetylating the transcription factor NF-
B. First, modulation of SIRT1 activity affects lipid accumulation in adipocytes, which has an impact on the etiology of a variety of human metabolic diseases such as obesity and insulin-resistant diabetes. Second, activation of SIRT1 suppresses inflammation via regulation of cytokine expression. Using high-throughput screening, the authors identified compounds with SIRT1 activating and inhibiting potential. The biological activity of these SIRT1-modulating compounds was confirmed in cell-based assays using mouse adipocytes, as well as human THP-1 monocytes. SIRT1 activators were found to be potent lipolytic agents, reducing the overall lipid content of fully differentiated NIH L1 adipocytes. In addition, the same compounds have anti-inflammatory properties, as became evident by the reduction of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-
). In contrast, a SIRT1 inhibitory compound showed a stimulatory activity on the differentiation of adipocytes, a feature often linked to insulin sensitization.