Tuberous sclerosis complex 2 loss increases lysophosphatidylcholine synthesis in lymphangioleiomyomatosis

American Journal of Respiratory Cell and Molecular Biology
Carmen PrioloElizabeth P Henske

Abstract

Lymphangioleiomyomatosis (LAM) is a destructive lung disease affecting women. LAM is caused by mutations in the tuberous sclerosis complex (TSC) genes. The TSC protein complex inhibits the mechanistic/mammalian target of rapamycin complex 1 (mTORC1), which is a master regulator of cellular metabolism. Using mass spectrometry-based lipid profiling, we analyzed plasma from patients with LAM and discovered elevated levels of four lysophosphatidylcholine (LPC) species (C16:0, C18:0, C18:1, and C20:4) compared with those in healthy control women. To investigate whether these lipids are generated in a TSC2-dependent manner, we profiled in vitro preclinical models of TSC/LAM and found significant LPC accumulation in TSC2-deficient cells relative to TSC2-expressing control cells. These lysoglycerophospholipid changes occurred alongside changes in other phospholipid and neutral lipid species. Treatment with rapamycin or torin1 or down-regulation of sterol regulatory element-binding protein (SREBP), a lipogenic transcription factor, did not suppress LPC in TSC2-deficient cells. Inhibition of distinct isoforms of phospholipase A2 decreased the proliferation of TSC2-deficient cells. Collectively, these results demonstrate that TSC2-deficie...Continue Reading

References

Nov 12, 1998·The American Journal of Pathology·G MontrucchioG Camussi
May 24, 2000·Proceedings of the National Academy of Sciences of the United States of America·T CarsilloE P Henske
Nov 13, 2001·American Journal of Respiratory and Critical Care Medicine·J YuE P Henske
Apr 28, 2005·Current Pharmaceutical Design·M C MeyerJ McHowat
Sep 29, 2006·The New England Journal of Medicine·Peter B CrinoElizabeth Petri Henske
Oct 13, 2006·Lymphatic Research and Biology·Kuniaki SeyamaYoshinosuke Fukuchi
Jul 3, 2007·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Zhenwen ZhaoYan Xu
Jan 11, 2008·The New England Journal of Medicine·Lisa R YoungFrancis X McCormack
Sep 3, 2008·Cell Metabolism·Thomas PorstmannAlmut Schulze
Jan 20, 2009·The Journal of Biological Chemistry·Carson C ThoreenNathanael S Gray
Feb 13, 2009·Molecular Biology of the Cell·Nao HosokawaNoboru Mizushima
Apr 28, 2009·Autophagy·Carson C Thoreen, David M Sabatini
Jul 21, 2010·Cellular Microbiology·Amanda Linkous, Eugenia Yazlovitskaya
Jul 31, 2010·Molecular Cell·Katrin DüvelBrendan D Manning
Aug 24, 2010·Journal of the National Cancer Institute·Amanda G LinkousDennis E Hallahan
Mar 18, 2011·EMBO Molecular Medicine·Nicole A Neuman, Elizabeth Petri Henske
Aug 6, 2011·Cell·Timothy R PetersonDavid M Sabatini
Jul 14, 2012·American Journal of Physiology. Renal Physiology·Brian J SirokyJohn J Bissler
Aug 8, 2012·Biochimica Et Biophysica Acta·Ioanna SevastouVassilis Aidinis
Oct 19, 2012·Nature Reviews. Cancer·Jong Bae ParkSung Ho Ryu
Mar 19, 2013·American Journal of Respiratory and Critical Care Medicine·Kameswara Rao BadriXiaoning Zhe
Mar 30, 2013·Chest·Corey J CudziloLisa R Young
Jul 31, 2013·Clinical Chemistry·Mary K TownsendBrian M Wolpin
Dec 4, 2013·Molecular Cancer Research : MCR·Andrey A ParkhitkoElizabeth P Henske

❮ Previous
Next ❯

Citations

Nov 1, 2016·IUBMB Life·Katarzyna SwitonJacek Jaworski
Apr 11, 2020·Genes & Development·Shuxi QiaoLeif W Ellisen
Nov 25, 2017·Expert Review of Respiratory Medicine·Julie NijmehElizabeth P Henske
Sep 23, 2018·Scientific Reports·Harilaos FilippakisElizabeth P Henske
Sep 21, 2018·Nature Reviews. Nephrology·Hilaire C LamElizabeth P Henske
Jun 13, 2018·Proceedings of the National Academy of Sciences of the United States of America·Carmen PrioloElizabeth P Henske
Jul 29, 2018·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Eline E VerwerCarmen Priolo
Jul 16, 2017·Molecular Cancer Research : MCR·Chenggang LiJane J Yu
Feb 23, 2020·Life Sciences·Panpan LiuCong Peng
Sep 22, 2021·Proceedings of the National Academy of Sciences of the United States of America·Ji WangHilaire C Lam

❮ Previous
Next ❯

Related Concepts

Related Feeds

American Thoracic Association Journals

Discover the latest respiratory research published by the journals from the American Thoracic Society.