Abstract
Polyunsaturated fatty acids affect gene expression mainly through peroxisome proliferator-activated receptors (PPARs) and sterol regulatory element binding proteins (SREBPs), but how monounsaturated fatty acids affect gene expression is poorly understood. In HepG2 cells, oleate supplementation has been shown to increase secretion of hepatic lipase (HL). We hypothesized that oleate affects HL gene expression at the transcriptional level. To test this, we studied the effect of oleate on HL promoter activity using HepG2 cells and the proximal HL promoter region (700 bp). Oleate increased HL expression and promoter activity 1.3–2.1 fold and reduced SREBP activity by 50%. Downregulation of SREBP activity by incubation with cholesterol+25-hydroxycholesterol had no effect on HL promoter activity. Overexpression of SREBP2, but not SREBP1, reduced HL promoter activity, which was effected mainly through the USF1 binding site at -307/-312. Oleate increased the nuclear abundance of USF1 protein 2.7 ± 0.6 fold, while USF1 levels were reduced by SREBP2 overexpression. We conclude that oleate increases HL gene expression via USF1. USF1 may be an additional fatty acid sensor in liver cells.
Highlights
Polyunsaturated fatty acids (PUFAs) affect gene expression through interaction with specific transcription factors, notably peroxisome proliferator-activated receptors (PPARs) and sterol regulatory element binding proteins (SREBPs) [1,2]
Our results show that supplementation of HepG2 cells with oleate increases the nuclear abundance of USF1, which may at least in part explain the stimulatory effect of oleate on hepatic lipase (HL) promoter activity [33]
We have previously shown by chromatin immunoprecipitation assays that USF1 is bound to the proximal region of the human HL gene in HepG2 cells [31,32], that the degree of binding correlates with HL gene expression levels [31], and that co-transfection of HepG2 cells with USF1expression plasmids results in strong upregulation of HL expression [23,31]
Summary
Polyunsaturated fatty acids (PUFAs) affect gene expression through interaction with specific transcription factors, notably peroxisome proliferator-activated receptors (PPARs) and sterol regulatory element binding proteins (SREBPs) [1,2]. PUFAs are ligands for PPARs, and binding results in the formation of an active transcription factor [3]. SREBP1 and −2 are cholesterol-sensitive transcription factors that are involved predominantly in regulation of fatty acid synthesis and cholesterol homeostasis, respectively [4]. PUFAs reduce SREBP activity or nSREBP1 protein in rat and mouse liver in vivo [8,9,10,11], rat hepatocytes [10,11] and human HepG2 hepatoma cell lines [6,12]
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