scholarly journals PCSK9: A Key Target for the Treatment of Cardiovascular Disease (CVD)

2020 ◽  
Vol 10 (4) ◽  
pp. 502-511
Author(s):  
Saeideh Sobati ◽  
Amir Shakouri ◽  
Mahdi Edalati ◽  
Daryoush Mohammadnejad ◽  
Reza Parvan ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Gene Silencing ◽  
Regulatory Element ◽  
New Method ◽  
Lipid Homeostasis ◽  
Transcriptional Level ◽  
Ldl Receptors ◽  
Sterol Regulatory Element ◽  
Pcsk9 Inhibition

Proprotein convertase subtilisin/kexin type 9 (PCSK9), as a vital modulator of low-densitylipoprotein cholesterol (LDL-C) , is raised in hepatocytes and released into plasma where it bindsto LDL receptors (LDLR), leading to their cleavage. PCSK9 adheres to the epidermal growthfactor-like repeat A (EGF-A) domain of the LDLR which is confirmed by crystallography. LDLRexpression is adjusted at the transcriptional level through sterol regulatory element bindingprotein 2 (SREBP-2) and at the post translational stages, specifically through PCSK9, and theinducible degrader of the LDLR PCSK9 inhibition is an appealing new method for reducing theconcentration of LDL-C. In this review the role of PCSK9 in lipid homeostasis was elucidated, theeffect of PCSK9 on atherosclerosis was highlighted, and contemporary therapeutic techniquesthat focused on PCSK9 were summarized. Several restoration methods to inhibit PCSK9 havebeen proposed which concentrate on both extracellular and intracellular PCSK9, and theyinclude blockage of PCSK9 production by using gene silencing agents and blockage of it’sbinding to LDLR through antibodies and inhibition of PCSK9 autocatalytic processes by tinymolecule inhibitors.

scholarly journals TNF-α interferes with lipid homeostasis and activates acute and proatherogenic processes

2007 ◽  
Vol 31 (2) ◽  
pp. 216-227 ◽  
Author(s):  
Klementina Fon Tacer ◽  
Drago Kuzman ◽  
Matej Seliškar ◽  
Denis Pompon ◽  
Damjana Rozman
Keyword(s):  
Regulatory Element ◽  
Hdl Cholesterol ◽  
Acid Synthesis ◽  
Farnesoid X Receptor ◽  
Lipid Homeostasis ◽  
Transcriptional Level ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Element Binding Protein ◽  
Cytokine Tumor Necrosis Factor

The interaction between disrupted lipid homeostasis and immune response is implicated in the pathogenesis of several diseases, but the molecular bridges between the major players are still a matter of controversy. Our systemic study of the inflammatory cytokine tumor necrosis factor-alpha (TNF-α) in the livers of mice exposed to 20-h cytokine/fasting for the first time shows that TNF-α interferes with adaptation to fasting and activates harmful proatherogenic pathways, partially through interaction with the insulin-Insig-sterol regulatory element binding protein (Srebp) signaling pathway. In addition to the increased expression of acute-phase inflammatory genes, the most prominent alterations represent modified lipid homeostasis observed on the gene expression and metabolite levels. These include reduction of HDL-cholesterol, increase of LDL-cholesterol, and elevated expression of cholesterogenic genes, accompanied by increase of potentially harmful precholesterol metabolites and suppression of cholesterol elimination through bile acids, likely by farnesoid X receptor-independent mechanisms. On the transcriptional level, a shift from fatty oxidation toward fatty acid synthesis is observed. The concept of the influence of TNF-α on the Srebp regulatory network, followed by downstream effects on sterol metabolism, is novel. Observed acute alterations in lipid metabolism are in agreement with chronic disturbances found in patients.

scholarly journals SCAP/SREBP pathway is required for the full steroidogenic response to cyclic AMP

2016 ◽  
Vol 113 (38) ◽  
pp. E5685-E5693 ◽  
Author(s):  
Masami Shimizu-Albergine ◽  
Brian Van Yserloo ◽  
Martin G. Golkowski ◽  
Shao-En Ong ◽  
Joseph A. Beavo ◽  
...  
Keyword(s):  
Cyclic Amp ◽  
Leydig Cells ◽  
De Novo ◽  
Regulatory Element ◽  
De Novo Synthesis ◽  
Intracellular Lipid ◽  
Element Binding Protein ◽  
Short Palindromic Repeat ◽  
Sterol Regulatory Element

Luteinizing hormone (LH) stimulates steroidogenesis largely through a surge in cyclic AMP (cAMP). Steroidogenic rates are also critically dependent on the availability of cholesterol at mitochondrial sites of synthesis. This cholesterol is provided by cellular uptake of lipoproteins, mobilization of intracellular lipid, and de novo synthesis. Whether and how these pathways are coordinated by cAMP are poorly understood. Recent phosphoproteomic analyses of cAMP-dependent phosphorylation sites in MA10 Leydig cells suggested that cAMP regulates multiple steps in these processes, including activation of the SCAP/SREBP pathway. SCAP [sterol-regulatory element-binding protein (SREBP) cleavage-activating protein] acts as a cholesterol sensor responsible for regulating intracellular cholesterol balance. Its role in cAMP-mediated control of steroidogenesis has not been explored. We used two CRISPR (clustered regularly interspaced short palindromic repeat)-Cas9 (CRISPR associated protein 9) knockout approaches to test the role of SCAP in steroidogenesis. Our results demonstrate that SCAP is required for progesterone production induced by concurrent inhibition of the cAMP phosphodiesterases PDE4 and PDE8. These inhibitors increased SCAP phosphorylation, SREBP2 activation, and subsequent expression of cholesterol biosynthetic genes, whereas SCAP deficiency largely prevented these effects. Reexpression of SCAP in SCAP-deficient cells restored SREBP2 protein expression and partially restored steroidogenic responses, confirming the requirement of SCAP–SREBP2 in steroidogenesis. Inhibitors of 3-hydroxy-3-methylglutaryl-Coenzyme A reductase and isoprenylation attenuated, whereas exogenously provided cholesterol augmented, PDE inhibitor-induced steroidogenesis, suggesting that the cholesterol substrate needed for steroidogenesis is provided by both de novo synthesis and isoprenylation-dependent mechanisms. Overall, these results demonstrate a novel role for LH/cAMP in SCAP/SREBP activation and subsequent regulation of steroidogenesis.

scholarly journals Role of Sterol Regulatory Element Binding Proteins in the Regulation of Gα i2 Expression in Cultured Atrial Cells

2002 ◽  
Vol 91 (1) ◽  
pp. 32-37 ◽  
Author(s):  
Ho-Jin Park ◽  
Ulrike Begley ◽  
Dequan Kong ◽  
Haiyan Yu ◽  
Liya Yin ◽  
...  
Keyword(s):  
Binding Proteins ◽  
Regulatory Element ◽  
Atrial Cells ◽  
Sterol Regulatory Element

The Potential Role of Sterol Regulatory Element Binding Protein Transcription Factors in Renal Injury

2007 ◽  
Vol 17 (1) ◽  
pp. 62-65 ◽  
Author(s):  
Marek Szolkiewicz ◽  
Michal Chmielewski ◽  
Anna Nogalska ◽  
Ewa Stelmanska ◽  
Julian Swierczynski ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Renal Injury ◽  
Potential Role ◽  
Binding Protein ◽  
Regulatory Element ◽  
Element Binding Protein ◽  
Sterol Regulatory Element ◽  
Protein Transcription

Molecular regulation of SREBP function: the Insig-SCAP connection and isoform-specific modulation of lipid synthesis

2004 ◽  
Vol 82 (1) ◽  
pp. 201-211 ◽  
Author(s):  
Ruth McPherson ◽  
Andre Gauthier
Keyword(s):  
Acid Metabolism ◽  
Regulatory Element ◽  
Lipid Synthesis ◽  
Molecular Regulation ◽  
New Information ◽  
Ubiquitin Proteasome ◽  
Sterol Regulatory Element ◽  
Membrane Bound ◽  
Proteasome Pathway

Sterol regulatory element binding proteins (SREBPs) are a family of membrane-bound transcription factors that play a unique and fundamental role in both cholesterol and fatty acid metabolism, relevant to human disease. There are three SREBPs that regulate the expression of over 30 genes. SREBPs are subject to regulation at three levels: proteolytic cleavage, rapid degradation by the ubiquitin-proteasome pathway, and sumoylation. Recently, there have been exciting advances in our understanding of the molecular mechanism of SREBP trafficking and processing with new information on the role of insulin-induced genes and the differential role and regulation of SREBP-1c and -2, which may ultimately lead to novel strategies for the treatment of dyslipidemia and insulin resistance.Key words: SREBP, Insig, SCAP, cholesterol synthesis, lipid metabolism.

Modulation of human Niemann-Pick C1-like 1 gene expression by sterol: role of sterol regulatory element binding protein 2

2007 ◽  
Vol 292 (1) ◽  
pp. G369-G376 ◽  
Author(s):  
Waddah A. Alrefai ◽  
Fadi Annaba ◽  
Zaheer Sarwar ◽  
Alka Dwivedi ◽  
Seema Saksena ◽  
...  
Keyword(s):  
Promoter Activity ◽  
Binding Protein ◽  
Regulatory Element ◽  
Cholesterol Absorption ◽  
Cholesterol Depletion ◽  
Element Binding Protein ◽  
Sterol Regulatory Element ◽  
Niemann Pick ◽  
Coa Reductase

Niemann-Pick C1-like 1 (NPC1L1) is an essential intestinal component of cholesterol absorption. However, little is known about the molecular regulation of intestinal NPC1L1 expression and promoter activity. We demonstrated that human NPC1L1 mRNA expression was significantly decreased by 25-hydroxycholesterol but increased in response to cellular cholesterol depletion achieved by incubation with Mevinolin (an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase) in human intestinal Caco-2 cells. We also showed that a −1741/+56 fragment of the NPC1L1 gene demonstrated high promoter activity in Caco-2 cells that was reduced by 25-hydroxycholesterol and stimulated by cholesterol depletion. Interestingly, we showed that the NPC1L1 promoter is remarkably transactivated by the overexpression of sterol regulatory element (SRE) binding protein (SREBP)-2, suggesting its involvement in the sterol-induced alteration in NPC1L1 promoter activity. Finally, we identified two putative SREs in the human NPC1L1 promoter and established their essential roles in mediating the effects of cholesterol on promoter activity. Our study demonstrated the modulation of human NPC1L1 expression and promoter activity by cholesterol in a SREBP-2-dependent mechanism.

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