Rapamycin down-regulates LDL-receptor expression independently of SREBP-2.
As a key regulator of cholesterol homeostasis, sterol-regulatory element binding protein-2 (SREBP-2) up-regulates expression of genes involved in cholesterol synthesis (e.g., 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) Reductase) and uptake (the low density lipoprotein (LDL)-receptor). Previously, we showed that Akt, a critical kinase in cell growth and proliferation, contributes to SREBP-2 activation. However, the specific Akt target involved is unknown. A potential candidate is the mammalian target of rapamycin, mTOR. Rapamycin can cause hyperlipidaemia clinically, and we hypothesised that this may be mediated via an effect of mTOR on SREBP-2. Herein, we found that SREBP-2 activation and HMG-CoA Reductase gene expression were unaffected by rapamycin treatment. However, LDL-receptor gene expression was decreased by rapamycin, suggesting that this may contribute to the hyperlipidaemia observed in rapamycin-treated patients. Rapamycin did not affect mRNA stability, so the decrease in LDL-receptor gene expression is likely to be occurring at the transcriptional level, although independently of SREBP-2.
Sharpe
Laura J
LJ
BABS, School of Biotechnology and Biomolecular Sciences, Biosciences Building D26, University of New South Wales, Sydney, NSW 2052, Australia.
Brown
Andrew J
AJ
D000818:Animals; D016466:CHO Cells; D002784:Cholesterol / Q000096:biosynthesis* / Q000235:genetics; D006224:Cricetinae; D003412:Cricetulus; D015536:Down-Regulation; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation; D006056:Golgi Apparatus / Q000378:metabolism; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D020871:RNA Stability / Q000187:drug effects; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases
D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011973:Receptors, LDL; C102196:SREBP cleavage-activating protein; D051782:Sterol Regulatory Element Binding Protein 2; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D011494:Protein Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus