Sterol regulatory element-binding protein (SREBP)-1-mediated lipogenesis is involved in cell senescence.
Increased cell mass is one of the characteristics of senescent cells, but this event has not been clearly defined. When subcellular organellar mass was estimated with organelle-specific fluorescence dyes, we observed that most membranous organelles progressively increase in mass during cell senescence. This increase was accompanied by an increase in membrane lipids and augmented expression of lipogenic enzymes, such as fatty acid synthase (FAS), ATP citrate lyase, and acetyl-CoA carboxylase. The mature form of sterol regulatory element-binding protein (SREBP)-1 was also elevated. Increased expression of these lipogenic effectors was further observed in the liver tissues of aging Fischer 344 rats. Ectopic expression of mature form of SREBP-1 in both Chang cells and primary young human diploid fibroblasts was enough to induce senescence. Blocking lipogenesis with FAS inhibitors (cerulenin and C75) and via siRNA-mediated silencing of SREBP-1 and ATP citrate lyase significantly attenuated H(2)O(2)-induced senescence. Finally, old human diploid fibroblasts were effectively reversed to young-like cells by challenging with FAS inhibitors. Our results suggest that enhanced lipogenesis is not only a common event, but also critically involved in senescence via SREBP-1 induction, thereby contributing to the increase in organelle mass (as a part of cell mass), a novel indicator of senescence.
Kim
You-Mie
YM
Department of Biochemistry and Molecular Biology, School of Medicine, Ajou University, Suwon 443-721, Korea.
Shin
Hyun-Taek
HT
Seo
Yong-Hak
YH
Byun
Hae-Ok
HO
Yoon
Soo-Han
SH
Lee
In-Kyu
IK
Hyun
Dong-Hoon
DH
Chung
Hae-Young
HY
Yoon
Gyesoon
G
D001275:ATP Citrate (pro-S)-Lyase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D002855:Chromatography, Thin Layer; D003676:Deferoxamine / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D050155:Lipogenesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D008563:Membrane Lipids / Q000378:metabolism; D015388:Organelles / Q000187:drug effects / Q000378:metabolism; D034741:RNA, Small Interfering; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*
D008563:Membrane Lipids; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D006861:Hydrogen Peroxide; D001275:ATP Citrate (pro-S)-Lyase; D003676:Deferoxamine