title: Akt acutely activates the cholesterogenic transcription factor SREBP-2.
abstract: Akt is an essential protein kinase for cell growth, proliferation, and survival. Perturbed Akt regulation is associated with a number of human diseases, such as cancer and diabetes. Recently, evidence has emerged that Akt is involved in the regulation of the sterol-regulatory element binding proteins, which are master transcriptional regulators of lipid metabolism. This offers a means by which synthesis of new membrane can be coordinated with cell growth and proliferation. However, the link between Akt and sterol-regulatory element binding protein-2, the major isoform participating in cholesterol regulation, is relatively unexplored. In the present study, we employed insulin-like growth factor-1 as an inducer of Akt signalling, and showed that it increased sterol-regulatory element binding protein-2 activation acutely (within 1h). This insulin-like growth factor-1-induced sterol-regulatory element binding protein-2 activation was blunted when Akt was inhibited pharmacologically or molecularly with small interfering RNA. Furthermore, we employed a rapalog heterodimerisation system to specifically and rapidly activate Akt, and found that sterol-regulatory element binding protein-2 activation was increased in response to Akt activation. Together, this study provides compelling evidence that Akt contributes to the acute regulation of cholesterol metabolism through activating sterol-regulatory element binding protein-2.
authors: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia.
authors: Winnie
authors: W
authors: Luu
authors: Laura J
authors: LJ
authors: Sharpe
authors: Julian
authors: J
authors: Stevenson
authors: Andrew J
authors: AJ
authors: Brown
mesh_terms: D000818:Animals; D016466:CHO Cells; D002784:Cholesterol / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D004789:Enzyme Activation; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D002784:Cholesterol; D007334:Insulin-Like Growth Factor I; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D051782:Sterol Regulatory Element Binding Protein 2; C102196:SREBP cleavage-activating protein