Disease relevance of SREBF1

• In contrast, upregulation of fatty acid metabolism during in vitro transformation of human mammary epithelial cells and in breast cancer cells was driven by increased MAP kinase and PI 3-kinase signaling, which increased SREBP-1 levels [1].
• Glial-like cells (GaMg glioma and CCF-STTG1 astrocytoma cell lines) displayed more pronounced drug-induced SREBP activation compared to the response in HCN2 human cortical neurons and SH-SY5Y neuroblastoma cells, indicating that antipsychotic-induced activation of lipogenesis is most prominent in glial cells [2].
• An immunohistochemical analysis of SREBP-1, FAS, and Ki-67 expression in 25 primary human colorectal carcinoma specimens showed colocalization in 22 of these [3].
• Human obesity and type 2 diabetes are associated with alterations in SREBP1 isoform expression that are reproduced ex vivo by tumor necrosis factor-alpha [4].
• Our results indicate a role of the SREBF-1 gene in genetic predisposition of metabolic diseases such as obesity, type 2 diabetes, and dyslipidemia [5].
• Following multivariate logistic regression analysis, hepatic SREBP-1c expression remained independently associated with fibrosis (p=0.008) and hepatic inflammation (p=0.005) [6].
• Hepatic expression of tumor necrosis factor-alpha increased in accordance with fibrosis progression, which was possibly related to the decrease in hepatic SREBP-1c expression [7].

Psychiatry related information on SREBF1

• Both classes of Rip are implicated in diseases that are important in modern societies, such as hyperlipidaemias (via the sterol regulatory element binding protein pathway) and Alzheimer's disease (via processing of the amyloid precursor protein.)[8]

High impact information on SREBF1

• Overexpression of INSIG-1 increases the sensitivity of cells to sterol-mediated inhibition of SREBP processing [9].
• Transport-dependent proteolysis of SREBP: relocation of site-1 protease from Golgi to ER obviates the need for SREBP transport to Golgi [10].
• The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor [11].
• Through expression cloning we have isolated a cDNA-encoding SREBP cleavage-activating protein (SCAP), which regulates cholesterol metabolism by stimulating cleavage of transcription factors SREBP-1 and -2, thereby releasing them from membranes [12].
• SREBP-1, a membrane-bound transcription factor released by sterol-regulated proteolysis [13].

Chemical compound and disease context of SREBF1

• Recently, we demonstrated that the antipsychotic drugs clozapine and haloperidol stimulate lipogenic gene expression in cultured glioma cells through activation of the sterol regulatory element-binding protein (SREBP) transcription factors [2].
• Using two independent prostate cancer cell lines (LNCaP and MDA-PCa-2a), we demonstrate that coordinated stimulation of lipogenic gene expression by androgens is a common phenomenon in androgen-responsive prostate tumor lines and involves activation of the sterol regulatory element-binding protein (SREBP) pathway [14].
• To determine whether increased lipogenesis contributes to human obesity, we measured (postabsorptive state), in lean and obese subjects, lipid synthesis (deuterated water method) and the mRNA concentration (RT-competitive PCR) in subcutaneous adipose tissue of fatty acid synthase (FAS) and sterol regulatory element-binding protein (SREBP)-1c [15].
• Gender-related difference in altered gene expression of a sterol regulatory element binding protein, SREBP-2, by lead nitrate in rats: Correlation with development of hypercholesterolemia [16].
• Using human hepatoma cells, we show that these compounds act through the sterol-responsive element of the LDLr promoter and activate the SCAP/SREBP pathway, leading to increased LDLr expression and activity, even in presence of excess of sterols [17].

Biological context of SREBF1

• The SREBF1 gene mapped to the proximal short arm of chromosome 17 (17p11.2), and the SREBF2 gene was localized to the long arm of chromosome 22 (22q13) [18].
• The 5'-flanking regions of SREBF2 and of two alternatively spliced forms of SREBF1, SREBF1a and SREBF1c, were sequenced, and the SREBF2 transcription start site was determined [19].
• We investigated whether PPARgamma expression is dependent on the activity of adipocyte differentiation and determination factor 1/sterol regulatory element binding protein 1 (ADD-1/SREBP-1), another transcription factor associated with both adipocyte differentiation and cholesterol homeostasis [20].
• These results suggest that PPARgamma expression can be controlled by the SREBP family of transcription factors and demonstrate new interactions between transcription factors that can regulate different pathways of lipid metabolism [20].
• These findings provide new insight into the overall process of transcriptional activation mediated by the SREBP family [21].

Anatomical context of SREBF1

• The chromosomal locations of human SREBF1 and SREBF2 were determined by analysis of human-rodent somatic cell hybrids and fluorescence in situ hybridization [18].
• Regulation of peroxisome proliferator-activated receptor gamma expression by adipocyte differentiation and determination factor 1/sterol regulatory element binding protein 1: implications for adipocyte differentiation and metabolism [20].
• SREBP-2 overexpression exerted stronger down-regulatory effects on WT-LRP1 than on SRE-MT-LRP1 promoter activity both in control, nLDL- and agLDL-exposed HeLa cells [22].
• Insulin and human chorionic gonadotropin cause a shift in the balance of sterol regulatory element-binding protein (SREBP) isoforms toward the SREBP-1c isoform in cultures of human granulosa cells [23].
• Polyunsaturated fatty acids decrease the expression of sterol regulatory element-binding protein-1 in CaCo-2 cells: effect on fatty acid synthesis and triacylglycerol transport [24].

Associations of SREBF1 with chemical compounds

• In addition, cholesterol depletion, a condition known to result in proteolytic activation of transcription factors of the SREBP family, induced PPARgamma expression and improved PPRE-driven transcription [20].
• The abundance of mature SREBP-2 but not SREBP-1 was increased following mevalonate depletion [25].
• The isoforms of sterol regulatory element-binding proteins (SREBP) (1a, 1c, and 2) are key transcriptional regulators of lipid biosynthesis [23].
• Cyclic adenosine 5'-monophosphate-dependent sphingosine-1-phosphate biosynthesis induces human CYP17 gene transcription by activating cleavage of sterol regulatory element binding protein 1 [26].
• SREBP1 and SREBP2 are 47% identical, and they share a novel structure comprising a transcriptionally active NH2-terminal basic helix-loop-helix-leucine zipper (bHLH-Zip) domain followed by a membrane attachment domain [18].
• We report that the activation of SREBP-1 by insulin or cholesterol in mouse liver and primary human hepatocytes inhibits the transcriptional effects in PXR and CAR [27].
• The up-regulation of both SREBP and FAS by NS4B protein required phosphatidylinositol 3-kinase activity [28].
• Insulin fails to enhance the levels of mature SREBP1 in cells lacking Fbw7 [29].

Physical interactions of SREBF1

• Deletion of the major SREBP binding site from the FAS promoter abrogated transcription in transformed MCF-10a cells [30].
• This region contains a sterol regulatory element (SRE) that interacted with the recombinant active form of SRE binding protein-1c (SREBP-1c) in electrophoretic mobility shift assays, and, using chromatin immunoprecipitation assay, we showed that endogenous SREBP-1 interacted directly with the promoter region of the HKII gene in human muscle cells [31].
• In contrast to CREB, SREBP interacts with CBP in the absence of phosphorylation [32].
• The C-terminal domain of SREBP interacts with the C-terminal domain of SREBP-cleavage-activating protein (SCAP) [33].
• 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 [34].

Enzymatic interactions of SREBF1

• MAP kinases Erk1/2 phosphorylate sterol regulatory element-binding protein (SREBP)-1a at serine 117 in vitro [35].

Regulatory relationships of SREBF1

• Expression of FAS has previously been shown to be regulated by the SREBP family of transcription factors [36].
• Chromatin immunoprecipitation assays revealed that Bt2cAMP and S1P increased acetylation of histone H3 and promoted binding of SREBP1 to the -520/-331 region of the CYP17 promoter [26].
• In addition, overexpression of active SREBP-1 directly stimulated SCD-1 and FAS [37].
• Proteolytic activation of sterol regulatory element-binding protein induced by cellular stress through depletion of Insig-1 [38].
• Whether SCA/CPP32 participates in vivo in the sterol-regulated activation of SREBP, or whether it activates SREBPs during apoptosis, remains to be determined [39].

Other interactions of SREBF1

• Nuclear SREBPs interacted with the SUMO-1-conjugating enzyme Ubc9, and overexpression of a dominant negative form of Ubc9 increased the mRNA levels of SREBP-responsive genes [40].
• We now demonstrate that SREBP-2 is the predominant SREBP in human keratinocytes and murine epidermis, while SREBP-1 is not detected [41].
• In CaCo-2 cells, polyunsaturated fatty acids decrease gene and protein expression of SREBP-1 and FAS mRNA, probably through interference with LXR activity [24].
• Overexpression of SUMO-1 reduced whereas its dominant negative form increased mRNA levels of SREBP-responsive genes [40].
• In summary, our studies demonstrate a role for sphingolipid metabolism and SREBP1 in ACTH-dependent CYP17 regulation and steroidogenesis [26].

Analytical, diagnostic and therapeutic context of SREBF1

• Spatial distribution and function of sterol regulatory element-binding protein 1a and 2 homo- and heterodimers by in vivo two-photon imaging and spectroscopy fluorescence resonance energy transfer [21].
• Gel mobility shift assays showed that recombinant SREBP-2-NT protein (1-468) binds to a double-stranded LRP1 DNA fragment (215 to 245) containing a wild-type (wt) SRE sequence but not to a mutated SRE (mt) sequence (5-GAATTCGA-3') [22].
• The decrease in hepatic expression of SREBP-1 and FAS associated with PUFA ingestion was mimicked by supplementing the fat-free diet with the PPARalpha-activator, WY 14, 643 [42].
• METHODS: Expression levels of C-4 sterol methyl oxidase gene (ERG25), sterol regulatory element binding protein (SREBP)-1 and -2 were evaluated in porcine aortic endothelial cells (PAEC), porcine and human smooth muscle cells (SMC) and in the vascular wall from normolipemic and hyperlipemic pigs by RT-PCR [43].
• Lack of correlation between SREBF1 genotype and hyperlipidemia in individuals treated with highly active antiretroviral therapy [44].

References