SREBPs: the crossroads of physiological and pathological lipid homeostasis

Raghow, Rajendra; Yellaturu, Chandrahasa R.; Deng, Xiong; Park, Edwards A.; Elam, Marshall B.

doi:10.1016/j.tem.2007.10.009

Cited by 272 publications

(256 citation statements)

References 81 publications

Supporting

Mentioning

234

Contrasting

Unclassified

Order By: Relevance

“…We previously found that IL-4-stimulated EC contained activated SREBP-1, but not SREBP-2 [12], and now we found that FAS inhibitors abrogated induction of protection by IL-4. The SREBP-1 isoform controls FA and phospholipid synthesis, while SREBP-2 controls sterol synthesis [19,20]. Accordingly, in IL-4-treated cells, we found increased FA and phospholipids, including cardiolipin, but not cholesterol, in the absence of increased EC proliferation.…”

Section: Discussionmentioning

confidence: 54%

IL‐4 induces protection of vascular endothelial cells against killing by complement and melittin through lipid biosynthesis

et al. 2010

View full text Add to dashboard Cite

We have shown previously that cytokines IL-4 and IL-13 induce protection in porcine vascular endothelial cells (EC) against killing by the membrane attack complex (MAC) of human complement. This protection is intrinsic, not due to changes in complement regulatory proteins, and requires activation of Akt and sterol receptor element binding protein-1 (SREBP-1), which regulates fatty acid and phospholipid synthesis. Here we report that, compared to EC incubated in medium, IL-4-treated EC had a profound reduction in complement-mediated ATP loss and in killing assessed by vital dye uptake, but only a slight reduction in permeability disruption measured by calcein release. While controls exposed to complement lost mitochondrial membrane potential and subsequently died, protected EC maintained mitochondrial morphology and membrane potential, and remained alive. SREBP-1 and fatty acid synthase activation were required for protection and fatty acid and phospholipid synthesis, including cardiolipin, were increased after IL-4 stimulation, without increase in cholesterol content or cell proliferation. IL-4 also induced protection of EC from killing by the channel forming protein melittin, similar to protection observed for the MAC. We conclude that IL-4 induced activation of Akt/SREBP-1/lipid biosynthesis in EC, resulting in protection against MAC and melittin, in association with mitochondrial protection. IntroductionThe vascular endothelium has critically important physiologic functions [1] and, if injured, pathologic states such as atherosclerosis, ischemia reperfusion, and vasculopathy, as observed in vascularized allo-and xenograft rejection, may result. The vascular endothelium is directly exposed to complement, complement activation may take place in blood secondary to various physiologic and pathologic events, and activated complement may influence vascular endothelial physiology [2,3]. Among products derived from complement activation, the membrane attack complex (MAC) of human complement is known to have multiple effects on the vascular endothelium and the vasculature as a whole, including activation, production of inflammatory cytokines, expression of adhesion molecules, loss of endothelial anticoagulant properties, gain of procoagulant properties, cell retraction and detachment from the basement membrane, and cell death [2,3]. Consequently, the MAC may initiate or contribute to ischemia or to acute and chronic inflammation, becoming a major pathophysiologic mediator in vascular diseases, autoimmune diseases, and graft rejection. Cells possess at least three control mechanisms for protection against injury from the MAC. First, the membrane proteins decayaccelerating factor (CD55) and membrane cofactor protein (CD46) inhibit progression of complement activation at the C3 and C5 activation stages, and CD59 inhibits MAC assembly by blocking C9 binding to C5b-8 [4]. Second, complement proteins bound to a cell membrane may be removed from the membrane by exocytosis or endocytosis [5]. Third, nucleated cells may be in...

show abstract

Section: Discussionmentioning

confidence: 54%

IL‐4 induces protection of vascular endothelial cells against killing by complement and melittin through lipid biosynthesis

et al. 2010

View full text Add to dashboard Cite

show abstract

“…31 SREBPs are a family of master transcription factors that controls the expression of lipogenic enzymes. [40][41][42][43] Second, our microarray analysis revealed altered expression of genes whose products were involved in regulating lipid metabolism when CDK8 is overexpressed ( Fig. 3E and F).…”

Section: Overexpression Of Cdk8 Inhibits Growth Of Human Endometrial mentioning

confidence: 90%

Tumor-suppressive effects of CDK8 in endometrial cancer cells

Wang

et al. 2013

Cell Cycle

View full text Add to dashboard Cite

“…Cellular cholesterol levels are normally highly regulated via a complex interplay between several processes: transport (influx and efflux), de novo synthesis, trafficking, storage, and recycling (Goldstein et al, 2006;Ikonen, 2008;Raghow et al, 2008). In general, the SREBP transcriptional regulator proteins activate genes for cholesterol synthesis and influx, and the Liver X Receptor, (LXR) nuclear receptors activate cholesterol efflux; however, both also regulate different aspects of fatty acid metabolism (Abildayeva et al, 2006;Wang et al, 2008b;Raychaudhuri and Prinz, 2010).…”

Section: Cholesterol Homeostasis Overviewmentioning

confidence: 99%

The Bladder Tumor Suppressor Protein TERE1 (UBIAD1)Modulates Cell Cholesterol: Implications for Tumor Progression

Fredericks

McGarvey

Wang

et al. 2011

DNA and Cell Biology

View full text Add to dashboard Cite

Convergent evidence implicates the TERE1 protein in human bladder tumor progression and lipid metabolism. Previously, reduced TERE1 expression was found in invasive urologic cancers and inhibited cell growth upon re-expression. A role in lipid metabolism was suggested by TERE1 binding to APOE, a cholesterol carrier, and to TBL2, a candidate protein in triglyceride disorders. Natural TERE1 mutations associate with Schnyder's corneal dystrophy, characterized by lipid accumulation. TERE1 catalyzes menaquinone synthesis, known to affect cholesterol homeostasis. To explore this relationship, we altered TERE1 and TBL2 dosage via ectopic expression and interfering RNA and measured cholesterol by Amplex red. Protein interactions of wild-type and mutant TERE1 with GST-APOE were evaluated by binding assays and molecular modeling. We conducted a bladder tumor microarray TERE1 expression analysis and assayed tumorigenicity of J82 cells ectopically expressing TERE1. TERE1 expression was reduced in a third of invasive specimens. Ectopic TERE1 expression in J82 bladder cancer cells dramatically inhibited nude mouse tumorigenesis. TERE1 and TBL2 proteins inversely modulated cellular cholesterol in HEK293 and bladder cancer cells from 20% to 50%. TERE1 point mutations affected APOE interactions, and resulted in cholesterol levels that differed from wild type. Elevated tumor cell cholesterol is known to affect apoptosis and growth signaling; thus, loss of TERE1 in invasive bladder cancer may represent a defect in menaquinone-mediated cholesterol homeostasis that contributes to progression.

show abstract

SREBPs: the crossroads of physiological and pathological lipid homeostasis

Cited by 272 publications

References 81 publications

IL‐4 induces protection of vascular endothelial cells against killing by complement and melittin through lipid biosynthesis

IL‐4 induces protection of vascular endothelial cells against killing by complement and melittin through lipid biosynthesis

Tumor-suppressive effects of CDK8 in endometrial cancer cells

The Bladder Tumor Suppressor Protein TERE1 (UBIAD1)Modulates Cell Cholesterol: Implications for Tumor Progression

Contact Info

Product

Resources

About