SREBP nuclear regulation

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. 

SREBPs are transcription factors that bind to the sterol regulatory element DNA sequence TCACNCCAC. Unactivated SREBPs are attached to the nuclear envelope and endoplasmic reticulum membranes. In cells with low levels of sterols, SREBPs are cleaved to a water-soluble N-terminal domain that is translocated to the nucleus. These activated SREBPs then bind to specific sterol regulatory element DNA sequences, thus up-regulating the synthesis of enzymes involved in sterol biosynthesis. Sterols in turn inhibit the cleavage of SREBPs and therefore synthesis of additional sterols is reduced through a negative-feedback loop. 

In addition to SREBPs, several members of the nuclear receptor superfamily regulate lipid metabolism. Nuclear receptors are transcription factors that are generally activated when bound to specific small-molecule ligands (Chapter 11). Certain nuclear receptors influence whole-body lipid metabolism by regulating the absorption of dietary lipids, cellular synthesis of lipids, transport protein-mediated import and export of lipids, levels of lipoproteins and their receptors, and catabolism of lipids (e.g., fatty acid oxidation in the peroxisome) and their secretion from the body. 

The signalling pathways involved in the control of SREBP-lc expression are not clearly understood. However, Protein Kinase B (PKB) (Fleischmann and lynedjian, 2000 Porstmann et al., 2005) and Protein Kinase C X (Matsumoto et al., 2003 Taniguchi et al., 2006) are likely to be involved (Fleischmann and lynedjian, 2000). Moreover, the Liver X Receptor, a nuclear receptor highly expressed in the liver, also contributes to regulate SREBP-lc expression (Peet et al., 1998 Repa et al., 2000). In the last part of this chapter, we will see how PKB and LXR might be involved in the control of SREBP-lc expression in response to the dietary status. 

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). 

Botolin, D., Wang, Y., Christian, B., and Jump, D. B. Docosahexaneoic acid (22 6,n-3) regulates rat hepatocyte SREBP-1 nuclear abundance by Erk- and 26S proteasome-dependent pathways. J Lipid Res 47 (2006) 181-192. 

Further studies have demonstrated that, of the n-3 PUFAs, DHA is the most potent fatty acid regulator of SREBP (reviewed by Jump, 2008). The mechanism by which DHA seems to work is by lowering SREBP-1 nuclear content (reviewed by Jump, 2008). Other n-3 and n-6 PUFAs sean to suppress SREBP-1 by regulating SREBP-lc gene transcription and by decreasing the stability of SREBP-1 mRNA (reviewed by Jump, 2008 Xu et al., 1999). More research specific to MUFA and ALA is needed in the future. 

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