SREBP-1: gene regulatory key to syndrome X?
Combined appearance of different cardiovascular risk factors seems to be more prevalent in individuals with decreased insulin sensitivity and increased visceral obesity, thereby being components of the so-called metabolic syndrome or syndrome X. Alterations in the abundance and activity of transcription factors lead to complex dysregulation of gene expression, which might be a key to understand insulin resistance-associated clinical clustering of coronary risk factors at the cellular or gene regulatory level. Recent examples are members of the nuclear hormone receptor superfamily-for example, peroxisome proliferator-activated receptors (PPARs) and sterol regulatory element-binding proteins (SREBPs). Besides their regulation by metabolites and nutrients, these transcription factors are also targets of hormones (like insulin and leptin), growth factors, inflammatory signals, and drugs. Major signaling pathways coupling transcription factors to extracellular stimuli are the MAP kinase cascades. We have recently shown that SREBPs appear to be substrates of MAP kinases and propose that SREBP-1 might play a role in the development of cellular features belonging to lipid toxicity and possibly syndrome X. Thus, the metabolic syndrome appears to be not only a disease or state of altered glucose tolerance, plasma lipid levels, blood pressure, and body fat distribution, but rather a complex clinical phenomenon of dysregulated gene expression.
Müller-Wieland
Dirk
D
Klinische Biochemie und Pathobiochemie, Deutsches Diabetes-Forschungsinstitut, Heinrich-Heine Universität Düsseldorf, Germany. mueller-wieland@ddfi.uni-duesseldorf.de
Kotzka
Jörg
J
D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D006801:Humans; D024821:Metabolic Syndrome / Q000235:genetics*; D051379:Mice; D012307:Risk Factors; D051780:Sterol Regulatory Element Binding Protein 1; D013329:Structure-Activity Relationship; D014157:Transcription Factors
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; C497387:SREBF1 protein, human; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors