SREBP activation

FIGURE 21-43 SREBP activation. Sterol regulatory element-binding proteins (SREBPs, shown in green) are embedded in the ER when first synthesized, in a complex with the protein SREBP cleavage-activating protein (SCAP, red). (N and C represent the amino and carboxyl termini of the proteins.) When bound to SCAP, SREBPs are inactive. When... 

Horton, J.D., Goldstein, J.L., Brown, M.S. 2002. SREBPs Activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Invest. 109, 1125-1131. 

Li Y, Xu S, Mihaylova MM, Zheng B, Hou X, Jiang B, Park O, Luo Z, Lefai E, Shyy JY, Gao B, Wierzbicki M, Verbeuren TJ, Shaw RJ, Cohen RA, Zang M (2011) AMPK phos-phorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metab 13(4) 376-388. doi 10.1016/j.cmet. 2011.03.009... 

A FIGURE 18-17 Model for cholesterol-sensitive control of SREBP activation mediated by insig-1 (2) and SCAP. The... 

SREBPs interact with several co-activators and act in conjunction with several other transcription factors (Bengoechea-Alonso and Ericsson, 2007 Weber et ah, 2004). This could lead to other signal-sensitive co-activation of SREBP activity. For instance, the peroxisome proliferator activated receptor general co-activator (3 (PGC-1 p) interacts with and stimulates SREBP-lc activity in the liver of mice fed a diet rich in saturated fatty acids (Lin et ah, 2005). Chromatin remodelling complexes have also recently been shown to interact with SREBP-lc and contribute to insulin sensitivity (Lee et ah, 2007). 

Nuclear SREBP activity is also controlled by several post-translational regulations including phosphorylation, acetylation, sumoylation and ubiquiti-nation (Bengoechea-Alonso and Ericsson, 2007 Eberle et ah, 2004). Several cross-talks with kinase-mediated signalling are likely to influence SREBP-lc in the liver in vivo. GSK3 is involved in the phosphorylation and subsequent ubiquitination of SREBP-lc (Punga et ah, 2006 Sundqvist et ah, 2005). PKA-dependent phosphorylation of SREBP-lc also reduces SREBP-lc activity (Lu and Shyy, 2006). Together with 26S proteasome, Erk-dependent pathways is involved in the reduction of nuclear SREBP-1 induced by docosahexaenoic acid (C22 6n-3) (Botolin et ah, 2006). 

In the nucleus, SREBPs activity is directly and indirectly controlled by post-translational modification (Eberle et al., 2004). SREBPs are modified by the small ubiquitin-related modifier (SUMO)-l. Sumoylation of SREBPs represses the activity of the transcription factor without modifying its degradation (Hirano et al., 2003). 

SREBPs Activate the Synthesis of Proteins That Regulate Phospholipid, Fatty Acid and Cholesterol But Not Sphingolipid Synthesis... 

Koch et al. (2007a) found that the dietary oxidized lipids cause upregulation of the insulin-induced gene (Insig)-l in the liver in a PPARa-dependent manner. Insigs are membrane proteins that reside in the endoplasmic reticulum and play a central role in the regulation of SREBP activation, because they prevent the translocation of inactive SREBPs from the endoplasmic reticulum to the Golgi, where proteolytic activation of SREBPs and subsequent release of transcriptionally active forms of SREBPs occur (Yabe et al. 2002). As a result, the synthesis of cholesterol declines in response to PPARa activation. 

Horton JD, Goldstein JL, Brown MS. SREBPs activators of the complete program of... 

Nakajima T, Ota N, Kodama T, Emi M. Isolation and radiation hybrid mapping of a highly polymorphic CA repeat sequence at the SREBP cleavage-activating protein (SCAP) locus. J Hum Genet 1999 44 350-351. 

Iwaki K, Nakajima T, Ota N, Emi M. A common Ile796Val polymorphism of the human SREBP cleavage-activating pro-... 

It is SREBPs which coordinate the expression of HMG CoA reductase and cell surface receptors for LDL. Cholesterol is an essential component of membranes so if delivery of cholesterol to the cell is limited by low concentrations of LDL-cholesterol, the expression of the genes for both the LDL receptor and HMG CoA reductase are up-regulated allowing the cell to extract as much as possible form the circulation and also to synthesize cholesterol, thus there is an inverse relationship between plasma LDL-cholesterol concentration and HMG CoA reductase activity. 

Peterson, D.G., Matitashvili, E.A., Bauman, D.E. 2004. The inhibitory effect of trans-10, cis-12 CLA on lipid synthesis in bovine mammary epithelial cells involves reduced proteolytic activation of the transcription factor SREBP-1. J. Nutr. 134, 2523-2527. 

OS are able to regulate key enzymes in CHOL turnover at transcriptional and post-transcriptional levels (Wolf, 1999 Bjorkhem, 2000 Tall et al., 2002). CHOL biosynthesis and homeostasis are regulated by two transcriptional factors steroid regulatory element-binding proteins (SREBP)-1 and -2. These become activated by proteolysis when the CHOL... 

Members of a family of nuclear transcription factors called sterol regulatory element-binding proteins (SREBP) are responsible for the regulation of these cholesterol feedback mechanisms. SREBP are able to activate a number of genes encoding for proteins involved in the homeostasis of cholesterol and other lipids, including the LDL receptor gene itself. 

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