SREBP regulation

Mullen, E., Brown, R. M., Osborne, T. R, Shay, N. F. (2004). Soy isoflavones affect sterol regulatory element binding proteins (SREBPs) and SREBP-regulated genes in HepG2 cells. J. Nutr., 134, 2942-2947. 

Multiple SREBPs Regulate Expression of Numerous Lipid-Metabolizing Proteins... 

Two Treatments for Atherosclerosis Are Based on SREBP-Regulated Cellular Cholesterol Metabolism... 

D. melanogaster. SREBP is also found in C. elegans and Giardia lamblia (Dobrosotskaya et al., 2002 Kunte et al., 2006 McKay et al., 2003 Worgall et al., 2004b). In G. lamblia, SREBP regulates the transcription of the cyst wall... 

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

Osborne TF. Sterol regulatory element binding protein (SREBPs) Key regulators of nutritional homeostasis and insulin action. J Biol Chem 2000 275 32379-32382. 

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. 

Includes a timely new discussion on the regulation of cholesterol metabolism at the genetic level, with consideration of sterol regulatory element-binding proteins (SREBPs). 

Regulation of HMG CoA reductase. SRE = sterol regulatory element SREBP = sterol regulatory elementbinding protein. 

Shimano, H. 2001. Sterol regulatory element-binding proteins (SREBPs) transcriptional regulators of lipid synthetic genes. Prog. Lipid Res. 40, 439-452. 

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. 

An opposite effect is at the basis of the up-regulation of LDL receptors in response to treatments with bile acid sequestrants, intestinal cholesterol absorption inhibitors, and HMG-CoA reductase inhibitors. The first class of drugs inhibits the intestinal reabsorption of bile acids, thus promoting increased conversion of cholesterol to bile acids in the liver. The increased demand for cholesterol results in activation of the SREBP system and upregulation of LDL receptor synthesis (as well as cholesterol synthesis via upregulation of HMG-CoA reductase). Similarly, inhibition of intestinal cholesterol absorption with ezetimibe results in a reduction in the hepatic cholesterol pool... 

What are SREBP and SCAP What role do they play in the regulation of cholesterol homeostasis ... 

Kim, H. J.,Takahashi, M., and Ezaki, 0.1999. Fish oil feeding decreases mature sterol regulatory element-binding protein 1 (SREBP-1) by down-regulation of SREBP-lc mRNA in mouse liver a possible mechanism for down-regulation of lipogenic enzyme mRNAs. J. Biol. Chem.,274, 25892-25898. 

Fatty acid synthase is transcriptionally regulated by upstream stimulatory factor and sterol regulatory element binding protein Ic (SREBP-lc), in response to feeding/insulin. 

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. 

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