Transcriptional activities of nuclear SREBP-1a, -1c, and -2 to different target promoters of lipogenic and cholesterogenic genes

Abstract

Recent studies on the in vivo roles of the sterol regulatory element binding protein (SREBP) family indicate that SREBP-2 is more specific to cholesterogenic gene expression whereas SREBP-1 targets lipogenic genes. To define the molecular mechanism involved in this differential regulation, luciferase-reporter gene assays were performed in HepG2 cells to compare the transactivities of nuclear SREBP-1a, -1c, and -2 on a battery of SREBP-target promoters containing sterol regulatory element (SRE), SRE-like, or E-box sequences. The results show first that cholesterogenic genes containing classic SREs in their promoters are strongly and efficiently activated by both SREBP-1a and SREBP-2, but not by SREBP-1c. Second, an E-box containing reporter gene is much less efficiently activated by SREBP-1a and -1c, and SREBP-2 was inactive in spite of its ability to bind to the E-box. Third, promoters of lipogenic enzymes containing variations of SRE (SRE-like sequences) are strongly activated by SREBP-1a, and only modestly and equally by both SREBP-1c and -2. Finally, substitution of the unique tyrosine residue within the basic helix-loop-helix (bHLH) portion of nuclear SREBPs with arginine, the conserved residue found in all other bHLH proteins, abolishes the transactivity of all SREBPs for SRE, and conversely results in markedly increased activity of SREBP-1 but not activity of SREBP-2 for E-boxes.These data demonstrate the different specificity and affinity of nuclear SREBP-1 and -2 for different target DNAs, explaining a part of the mechanism behind the differential in vivo regulation of cholesterogenic and lipogenic enzymes by SREBP-1 and -2, respectively.

Docosahexaenoic Acid Activates Some SREBP‐2 Targets Independent of Cholesterol and ER Stress in SW620 Colon Cancer Cells

“…UFAs could also possibly affect co-factors or regulate repressors that are involved in SREBP-2 target gene transcription [46,47]. The SREBP-1a transcription factor has also been demonstrated to be involved in the regulation of genes involved in cholesterol biosynthesis [10,36,37]. We have previously observed reduced levels of mSREBP-1 in DHA-treated SW620 cells [27].…”

“…The active transcription factor is translocated to the nucleus where it induces expression of target genes, including the SREBP transcription factors themselves [3,5]. SREBP target genes contain a sterol regulatory element (SRE) sequence or modified forms of this sequence in their promoters, while SREBP-1c target genes mainly contain E-boxes or E-box like sequences [9,10]. The SREBP transcription factors have weak transcriptional domains, and require co-factors like NF-Y or Sp1 to activate target genes [9,11].…”

Bile acid‐binding activity of young persimmon (Diospyros kaki) fruit and its hypolipidemic effect in mice

“…CYP7A1 is the rate-limiting enzyme in bile acid biosynthesis (Russell and Setchell, 1992), and it was reported previously that dietary YP signifi cantly up-regulated the expression of the hepatic CYP7A1 gene (Matsumoto et al, 2006). SREBP-1 and SREBP-2 regulate the expression of several lipogenic and cholesterogenic enzymes after proteolytic cleavage (Amemiya-Kudo et al, 2002;Espenshade and Hughes, 2007). The LDL receptor, which is regulated by SREBP-2, plays an important role in the uptake of LDLparticles, thus controlling serum cholesterol levels (Amemiya-Kudo et al, 2002).…”

Perturbation of Intracellular Cholesterol and Fatty Acid Homeostasis During Flavivirus Infections

“…Infection was accompanied by redirecting cholesterol from the plasma membrane to virus replication sites (12). In mammalian cells cholesterol homeostasis is tightly regulated in a feedback mechanism via transcription factors that sense intracellular cholesterol levels (57,58). These transcription factors are termed SREBPs that associate tightly with the sterol-sensing SREBP cleavage-activating protein (SCAP) within the ER membrane, via an additional interaction with the ER-resident protein Insig, which functions as an inhibitor of SREBP (59,60).…”