Identification of Sp1 as a Transcription Activator to Regulate Fibroblast Growth Factor 21 Gene Expression

Abstract

Fibroblast growth factor 21 (FGF21) is a metabolic hormone with multiple beneficial effects on lipid and glucose homeostasis. Previous study demonstrated that FGF21 might be one of the Sp1 target genes. However, the transcriptional role of Sp1 on FGF21 in adipose tissue and liver has not been reported. In this study, we found that the proximal promoter of mouse FGF21 is located between −63 and −20 containing two putative Sp1-binding sites. Sp1 is a mammalian transcription factor involved in the regulation of many genes during physiological and pathological processes. Our study showed that overexpression of Sp1 or suppressing Sp1 expression resulted in increased or reduced FGF21 promoter activity, respectively. Mutation analysis demonstrated that the Sp1-binding site located between −46 and −38 plays a primary role in transcription of FGF21. Electrophoretic mobility shift assay and chromatin immunoprecipitation analysis indicated that Sp1 specifically bound to this region. Furthermore, the binding activity of Sp1 was significantly increased in adipose tissues of HFD-induced obese mouse and liver of DEN-treated mouse. Thus, our results demonstrate that Sp1 positively regulates the basal transcription of FGF21 in the liver and adipose tissue and contributes to the obesity-induced FGF21 upregulation in mouse adipose tissue and hepatic FGF21 upregulation in hepatocarcinogenesis.

FOXO1 represses PPARα-Mediated induction of FGF21 gene expression

“…Since the identification of FGF21 as a new member of the FGF family back in 2000 [51], the FGF21 promoter has been exhaustively characterized. Besides the description of the PPARa binding site (PPRE) present in FGF21 regulatory sequences [14], several other transcription factors have been identified to bind to particular promoter sequences and to induce transcriptional activity, such as activating transcription factor 2 (ATF2) [52], ATF4 [53], Sp1 [54], among several others [55]. Contradictory results on Bmal1/Clockmediated activation of the Fgf21 promoter have been previously reported.…”

The ovine HIAT1 gene: mRNA expression, InDel mutations, and growth trait associations

“…The regulation of SP1 with regards to target genes is achieved by binding of the DNA binding domain to GC-rich motifs in the promoter region of the target gene, thereby regulating cellular processes such as autophagy, apoptosis, proliferation, differentiation and angiogenesis ( 36 , 37 ). Chen et al ( 38 ) found that Sp1 binding sites in the core promoter region are essential for positive regulation of FGF21 ( Fibroblast growth factor 21 ) through gene transcription in both hepatic and adipose tissue ( 38 ). Furthermore, a recent study found that an SNP g.133A>C located within the SCD ( Stearoyl CoA desaturase ) promoter generated overall higher Sp1 binding affinity to the SCD promoter, which consequently affected gene expression ( 39 ).…”

Th2 Cytokines Increase the Expression of Fibroblast Growth Factor 21 in the Liver

“…Moreover, the regulator involved in Fgf21 induction might be modulated differently in different tissues. Indeed, Sp1, a mammalian transcriptional factor, binds to the Fgf21 promoter and increases the expression of Fgf21 [ 58 ]. Interestingly, Sp1 protein expression in mice with diet-induced obesity was much higher in white adipose tissue than in the liver.…”