Abstract
The essential function of sterol regulatory element-binding proteins (SREBPs) in cellular lipid metabolism and homeostasis has been recognized for a long time, and the basic biological pathway involving SREBPs has been well described; however, a rapidly growing number of studies reveal the complex regulation of these SREBP transcription factors at multiple levels. This regulation allows the integration of signals of diverse pathways involving nutrients, contributing to cellular lipid and energy homeostasis. This review attempts to integrate this knowledge. The description of the SREBP pathway is Web-linked as it refers to the online version of the pathway on wikipathways.org, which is interactively linked to genomics databases and literature. This allows a more extensive study of the pathway through reviewing these links.
Highlights
Sterol regulatory element-binding proteins (SREBPs) play an important role in the regulation of the intracellular cholesterol concentration and in overall lipid homeostasis
The essential function of sterol regulatory element-binding proteins (SREBPs) in cellular lipid metabolism and homeostasis has been recognized for a long time, and the basic biological pathway involving SREBPs has been well described; a rapidly growing number of studies reveal the complex regulation of these SREBP transcription factors at multiple levels
It should be noticed that this study made use of a different system based on HEK293 cells (Dif et al 2006). cAMP, which can be activated by glucagon, and the cAMP-dependent kinase, protein kinase A (PKA) have been shown to suppress SREBP-1c transcription by phosphorylation of liver X receptors (LXRs), which inhibits the DNA binding activity by inhibiting LXR/retinoid X receptors (RXRs) dimerization, decreases recruitment of a coactivator, and enhances the recruitment of a corepressor (Yamamoto et al 2007). It has been shown in HepG2 cells that PKA can phosphorylate SREBP-1a at Ser338, which reduces DNA binding of SREBP-1c (Lu and Shyy 2006). These results indicate a role for the cAMP/PKA pathway in mediating SREBP-1 and hepatic lipogenesis
Summary
The basic signaling pathway affected by SREBPs has been elucidated in great detail. Regulation of SREBPs themselves is proven to be very complex. It has been described that SREBP has a role in several physiological cellular processes not directly related with lipid homeostasis, like cell growth and innate immunity (Jeon and Osborne 2012). As the insight in the SREBP pathway becomes more and more complex, integration of the different aspects of this knowledge is vital. We will describe the SREBP protein and its isoforms, to continue with a description of the current view on the molecular basis of the SREBP pathway, its complex regulation and its physiological function. We are applying a pathway approach to investigate the function and regulation of the SREBP proteins in lipid-metabolism-related pathways
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