Transcription factors SREBPs

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. 

Peterson, D.G., Matitashvili, E.A., and Bauman, D.E. 2003a. Diet-induced milk fat depression in dairy cows results in increased trans-10, cis-12 CLA in milk fat and coordinate suppression of mRNA abundance for mammary enzymes involved in milk fat synthesis. J. Nutr. 133, 3098-3102. Peterson, D.G., Matitashvili, E.A., and Bauman, D.E. 2003b. The inhibitory effect of /10, cl2 CLA on lipid synthesis in bovine mammary epithelial cells involves reduced proteolytic activation of the transcription factor SREBP-1. FASEB J. 17, 681.6. 

In mammals, the liver is the organ most active in lipids synthesis, and in this organelle, the transcription factors SREBPs (sterol-regulatory element binding protein) play crucial roles in lipids homeostasis. In addition to cholesterol,... 

The LDL receptor is a key component in the feedback-regulated maintenance of cholesterol homeostasis [1]. In fact, as an active interface between extracellular and intracellular cholesterol pools, it is itself subject to regulation at the cellular level (Fig. 2). LDL-derived cholesterol (generated by hydrolysis of LDL-bome cholesteryl esters) and its intracellularly generated oxidized derivatives mediate a complex series of feedback control mechanisms that protect the cell from over-accumulation of cholesterol. First, (oxy)sterols suppress the activities of key enzymes that determine the rate of cellular cholesterol biosynthesis. Second, the cholesterol activates the cytoplasmic enzyme acyl-CoA cholesterol acyltransferase, which allows the cells to store excess cholesterol in re-esterified form. Third, the synthesis of new LDL receptors is suppressed, preventing further cellular entry of LDL and thus cholesterol overloading. The coordinated regulation of LDL receptors and cholesterol synthetic enzymes relies on the sterol-modulated proteolysis of a membrane-bound transcription factor, SREBP, as described in Chapter 14. 

Gauthier, B., Robb, M., Gaudet, R, Ginsbutg, G.S., and McPherson, R. (1999) Characterization of a Cholesterol Response Element (CRE) in the Promoter of the Cholesteryl Ester Transfer Protein Gene Functional Role of the Transcription Factors SREBP-la, -2, and YYl, 7. UpidRes. 40,1284 1293. 

Brown MS, Goldstein JL. The SREBP pathway regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 1997 89 331-340. 

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. 

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. 

Figure 1 S2P contains conserved HEXXH and LOG motifs found in metaiioproteases. SREBP first is cieaved by SI P in the iuminai ioop. The regulatory domain (Reg) interacts with the choiesteroi-sensing SCAP to ensure that SI P proteoiysis oniy occurs when choiesteroi ieveis are iow. Subsequent intramembrane proteoiysis reieases this transcription factor for the expression of genes essentiai to choiesteroi and fatty acid synthesis.

The concentration of LDL-cholesteroi in the blood is a function of its rate of production and rate of removal from the bloixistream. Diet influences LDL-cho-lesterol by changing its rate of removal or clearance, according to the following scenario. Let us briefly return to the topics of proteins and DMA, A transcription factor called sterol response element binding protein (SREbP) binds to a stretch of DNA called the sterol response element. The sterol response element has the structure CACCCCAC. In discussing any sequence of DNA, it is conventional to... 

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