New insights into the activation of sterol regulatory element-binding proteins by proteolytic processing

2013 ◽  
Vol 4 (4) ◽  
pp. 417-423 ◽  
Author(s):  
Jun Inoue ◽  
Ryuichiro Sato
Keyword(s):  
Endoplasmic Reticulum ◽  
Small Molecules ◽  
Recent Progress ◽  
Binding Proteins ◽  
Regulatory Element ◽  
Acid Synthesis ◽  
Proteolytic Processing ◽  
Endoplasmic Reticulum Membrane ◽  
Post Translational Modification ◽  
Sterol Regulatory Element

AbstractSterol regulatory element-binding proteins (SREBPs) are transcription factors that regulate a wide variety of genes involved in cholesterol and fatty acid synthesis. After transcription, SREBPs are controlled at multiple post-transcriptional levels, including proteolytic processing and post-translational modification. Among these, proteolytic processing is a crucial regulatory step that activates SREBPs, which are synthesized as inactive endoplasmic reticulum membrane proteins. In this review, we focus on recent progress with regard to signaling pathways and small molecules that affect activation of SREBPs by proteolytic processing.

scholarly journals Effects of fish oil and conjugated linoleic acids on expression of target genes of PPARα and sterol regulatory element-binding proteins in the liver of laying hens

2008 ◽  
Vol 100 (2) ◽  
pp. 355-363 ◽  
Author(s):  
Bettina König ◽  
Julia Spielmann ◽  
Kati Haase ◽  
Corinna Brandsch ◽  
Holger Kluge ◽  
...  
Keyword(s):  
Fish Oil ◽  
Binding Proteins ◽  
Target Genes ◽  
Laying Hens ◽  
Regulatory Element ◽  
Acid Synthesis ◽  
Control Fish ◽  
Mrna Levels ◽  
Conjugated Linoleic Acids ◽  
Sterol Regulatory Element

In mammals, (n-3) PUFA and conjugated linoleic acids (CLA) act as activators of PPARα and alter nuclear concentrations of sterol regulatory element-binding proteins (SREBP) in the liver, and thereby influence hepatic lipid catabolism and synthesis. In this study, we investigated the hypothesis that (n-3) PUFA and CLA exert similar effects in the liver of laying hens. Thirty hens (64 weeks old) were fed diets containing 30 g/kg of sunflower oil (control), fish oil (salmon oil) or CLA in TAG form (containing predominantlycis-9,trans-11 CLA andtrans-10,cis-12 CLA) for 5 weeks. Hens fed fish oil had a higher expression of some PPARα target genes and a lower nuclear concentration of SREBP-2 in the liver and lower concentrations of cholesterol and TAG in plasma than control hens. Nuclear concentration of SREBP-1 and its target genes involved in lipogenesis were not altered in hens fed fish oil. Hens fed CLA had increased concentrations of TAG and cholesterol in the liver. However, their mRNA levels of PPARα target genes and nuclear concentrations of SREBP-1 and SREBP-2 as well as mRNA levels of their target genes in the liver were largely unchanged compared to control hens. The results of this study suggest that (n-3) PUFA cause a moderate activation of PPARα and lower cholesterol synthesis but do not impair fatty acid synthesis in the liver of laying hens. CLA lead to an accumulation of TAG and cholesterol in the liver of hens by mechanisms to be elucidated in further studies.

scholarly journals Regulation of the CDP-choline pathway by sterol regulatory element binding proteins involves transcriptional and post-transcriptional mechanisms

2003 ◽  
Vol 372 (3) ◽  
pp. 811-819 ◽  
Author(s):  
Neale D. RIDGWAY ◽  
Thomas A. LAGACE
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Transcriptional Activation ◽  
Binding Proteins ◽  
Regulatory Element ◽  
Acid Synthesis ◽  
Transcriptional Level ◽  
Ctp:Phosphocholine Cytidylyltransferase ◽  
Sterol Regulatory Element

The synthesis of phosphatidylcholine (PtdCho) by the CDP-choline pathway is under the control of the rate-limiting enzyme CTP:phosphocholine cytidylyltransferase (CCT). Sterol regulatory element binding proteins (SREBPs) have been proposed to regulate CCT at the transcriptional level, or via the synthesis of lipid activators or substrates of the CDP-choline pathway. To assess the contributions of these two mechanisms, we examined CCTα expression and PtdCho synthesis by the CDP-choline pathway in cholesterol and fatty acid auxotrophic CHO M19 cells inducibly expressing constitutively active nuclear forms of SREBP1a or SREBP2. Induction of either SREBP resulted in increased expression of mRNAs for sterol-regulated genes, elevated fatty acid and cholesterol synthesis (>10–50-fold) and increased PtdCho synthesis (2-fold). CCTα mRNA was increased 2-fold by enforced expression of SREBP1a or SREBP2. The resultant increase in CCTα protein and activity (2-fold) was restricted primarily to the soluble fraction of cells, and increased CCTα activity in vivo was not detected. Inhibition of the synthesis of fatty acids or their CoA esters by cerulenin or triacsin C respectively following SREBP induction effectively blocked the accompanying elevation in PtdCho synthesis. Thus PtdCho synthesis was driven by increased synthesis of fatty acids or a product thereof. These data show that transcriptional activation of CCTα is modest relative to that of other SREBP-regulated genes, and that stimulation of PtdCho synthesis by SREBPs in CHO cells is due primarily to increased fatty acid synthesis.

A role for smooth endoplasmic reticulum membrane cholesterol ester in determining the intracellular location and regulation of sterol-regulatory-element-binding protein-2

2001 ◽  
Vol 358 (2) ◽  
pp. 415-422 ◽  
Author(s):  
Christopher R. IDDON ◽  
Jane WILKINSON ◽  
Andrew J. BENNETT ◽  
Julie BENNETT ◽  
Andrew M. SALTER ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cholesterol Ester ◽  
Smooth Endoplasmic Reticulum ◽  
Regulatory Element ◽  
Membrane Cholesterol ◽  
Endoplasmic Reticulum Membrane ◽  
Cellular Cholesterol ◽  
Element Binding Protein ◽  
Sterol Regulatory Element ◽  
Coa Reductase

Cellular cholesterol homoeostasis is regulated through proteolysis of the membrane-bound precursor sterol-regulatory-element-binding protein (SREBP) that releases the mature transcription factor form, which regulates gene expression. Our aim was to identify the nature and intracellular site of the putative sterol-regulatory pool which regulates SREBP proteolysis in hamster liver. Cholesterol metabolism was modulated by feeding hamsters control chow, or a cholesterol-enriched diet, or by treatment with simvastatin or with the oral acyl-CoA:cholesterol acyltransferase inhibitor C1-1011 plus cholesterol. The effects of the different treatments on SREBP activation were confirmed by determination of the mRNAs for the low-density lipoprotein receptor and hydroxymethylglutaryl-CoA (HMG-CoA) reductase and by measurement of HMG-CoA reductase activity. The endoplasmic reticulum was isolated from livers and separated into subfractions by centrifugation in self-generating iodixanol gradients. Immunodetectable SREBP-2 accumulated in the smooth endoplasmic reticulum of cholesterol-fed animals. Cholesterol ester levels of the smooth endoplasmic reticulum membrane (but not the cholesterol levels) increased after cholesterol feeding and fell after treatment with simvastatin or C1-1011. The results suggest that an increased cellular cholesterol load causes accumulation of SREBP-2 in the smooth endoplasmic reticulum and, therefore, that membrane cholesterol ester may be one signal allowing exit of the SREBP-2/SREBP-cleavage-regulating protein complex to the Golgi.

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