Abstract
Lipoprotein lipase (LPL) is a key enzyme in lipoprotein and energy metabolism and, therefore, regulation of its expression could have an important bearing on these processes. We have identified an evolutionarily conserved 5′-CCTCCCCCC-3′ motif (from −91 to −83, CT element) in the human LPL gene promoter, deletion or mutation of which caused approximately 70–80% decrease in promoter activity. We found that Sp1 and Sp3 in THP-1 nuclear protein extracts bind specifically to this element. Co-transfection with Sp1 and Sp3 expression plasmids transactivated the LPL promoter via the CT element in Drosophila SL2 cells devoid of Sp proteins. Sp3 moderately repressed Sp1-mediated LPL promoter activation when both were co-expressed in SL2 cells. Furthermore, co-expression of an active sterol regulatory element binding protein (SREBP-1), with Sp1, but not with Sp3, synergistically activated the LPL promoter in SL2 cells. We previously reported a naturally occurring T→G substitution at position −93 of the human LPL promoter which reduces promoter activity by 40–50% in transient transfection assays. In this study, we showed that this substitution results in reduced binding affinity to Sp1/Sp3 and in diminished transactivation by Sp1/Sp3 alone and by the synergistic action of Sp1 and SREBP-1. In conclusion, recruitment of Sp1/Sp3 by the CT element may play an important role in expression of the human lipoprotein lipase gene. Synergistic transcriptional activation by Sp1 and SREBP-1 may provide a mechanism for cross-talk between cholesterol and triglyceride metabolic pathways.—Yang, W-S., and S. S. Deeb. Sp1 and Sp3 transactivate the human lipoprotein lipase gene promoter through binding to a CT element: synergy with the sterol regulatory element binding protein and reduced transactivation of a naturally occurring promoter variant. J. Lipid Res. 1998. 39: 2054–2064.
Highlights
Lipoprotein lipase (LPL) is a key enzyme in lipoprotein and energy metabolism and, regulation of its expression could have an important bearing on these processes
LPL dimers bind to glycosaminoglycans on the vascular endothelial surface and hydrolyze the Abbreviations: LPL, lipoprotein lipase; sterol regulatory element binding proteins (SREBP), sterol regulatory element binding protein; LDL receptor (LDLR), low density lipoprotein receptor; FAS, fatty acid synthase; ACC, acetyl coenzyme A carboxylase; EMSA, electrophoretic mobility shift assay; CT element, 5Ј-CCTCCCCCC-3Ј
The Oct-1 (Ϫ46 to Ϫ39) and nuclear factor (NF)-Y binding sites were previously shown to be critical for activity of the human LPL promoter [11,12,13,14]
Summary
Lipoprotein lipase (LPL) is a key enzyme in lipoprotein and energy metabolism and, regulation of its expression could have an important bearing on these processes. Co-expression of an active sterol regulatory element binding protein (SREBP-1), with Sp1, but not with Sp3, synergistically activated the LPL promoter in SL2 cells. Sp1 and Sp3 transactivate the human lipoprotein lipase gene promoter through binding to a CT element: synergy with the sterol regulatory element binding protein and reduced transactivation of a naturally occurring promoter variant. LP- (between Ϫ468 and Ϫ430), which bind hepatic nuclear factor (NF) 3-like proteins, were suggested to contribute to differentiation-dependent promoter activity during adipogenesis of 3T3-F442A cells [7]. Fibrates as well as the new class of anti-diabetic agents, thiazolidinediones, have been shown to induce rat LPL gene expression in liver and adipose tissue through their action on the peroxisome proliferator response element (from Ϫ169 to Ϫ157) of the LPL promoter [10]. Mutagenesis of the TATA-like element (from Ϫ27 to Ϫ23) did not affect promoter activity [14]
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