SIRT1 modulating compounds from high-throughput screening as anti-inflammatory and insulin-sensitizing agents.
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-gamma) and to inflammatory processes by deacetylating the transcription factor NF-kappaB. 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-alpha). In contrast, a SIRT1 inhibitory compound showed a stimulatory activity on the differentiation of adipocytes, a feature often linked to insulin sensitization.
Nayagam
Vasantha M
VM
S*BIO PTE LTD, Singapore.
Wang
Xukun
X
Tan
Yong Cheng
YC
Poulsen
Anders
A
Goh
Kee Chuan
KC
Ng
Tony
T
Wang
Haishan
H
Song
Hong Yan
HY
Ni
Binhui
B
Entzeroth
Michael
M
Stünkel
Walter
W
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001665:Binding Sites; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D007328:Insulin; D050155:Lipogenesis / Q000187:drug effects; D051379:Mice; D015394:Molecular Structure; D011810:Quinoxalines / Q000737:chemistry*; D056564:Sirtuin 1; D037761:Sirtuins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D007328:Insulin; D011810:Quinoxalines; D014409:Tumor Necrosis Factor-alpha; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins