In:
Journal of Cellular Physiology, Wiley, Vol. 230, No. 9 ( 2015-09), p. 2224-2232
Abstract:
Patatin‐like phospholipase domain containing 3 (PNPLA3) is a non‐secreted protein primarily expressed in liver and adipose tissue. Recently, numerous genetic studies have shown that PNPLA3 is a major susceptibility gene for nonalcoholic fatty liver disease (NAFLD). However, the mechanism involved in transcriptional regulation of the PNPLA3 gene remains unknown. We performed a detailed analysis of the human PNPLA3 gene promoter and identified two novel cis ‐acting elements (SRE and NFY binding motifs) located at −97/−88 and −26/−22 bp, respectively. Overexpression of SREBP‐1c in HepG2 cells significantly increased PNPLA3 promoter activity. Mutation of either of the putative SRE or NFY binding motifs blocked the transactivation effects of SREBP‐1c on the promoter. Overexpression of SREBP‐1c and NFY together increased PNPLA3 promoter activity twice as much as that of SREBP‐1c or NFY expression alone. This result suggests that SREBP‐1c and NFY synergistically transactivate the human PNPLA3 gene. The ability of SREBP‐1c and NFY to bind these cis ‐elements was confirmed using gel shift analysis. Putative SRE and NFY motifs also mediated synergistic insulin‐induced transactivation of the PNPLA3 promoter in HepG2 cells. Additionally, the ability of SREBP‐1c to bind to the PNPLA3 promoter was increased by insulin in a dose‐dependent manner. Moreover, the treatment of HepG2 cells with the PI3K inhibitor LY294002 led to reduced insulin promoter‐activating ability accompanied by a decrease in PNPLA3 and SREBP‐1c protein expression. These results demonstrate that SREBP‐1c is a direct activator of the human PNPLA3 gene and insulin transactivates the PNPLA3 gene via the PI3K‐SREBP‐1c/NFY pathway in HepG2 cells. J. Cell. Physiol. 230: 2224–2232, 2015. © 2015 Wiley Periodicals, Inc.
Type of Medium:
Online Resource
ISSN:
0021-9541
,
1097-4652
Language:
English
Publisher:
Wiley
Publication Date:
2015
detail.hit.zdb_id:
1478143-8
SSG:
12
