%0 Journal Article
%T Regulation of Ketogenic Enzyme HMGCS2 by Wnt/¦Â-catenin/PPAR¦Ã Pathway in Intestinal Cells
%J Cells | An Open Access Journal from MDPI
%D 2019
%R https://doi.org/10.3390/cells8091106
%X The Wnt/¦Â-catenin pathway plays a crucial role in development and renewal of the intestinal epithelium. Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), a rate-limiting ketogenic enzyme in the synthesis of ketone body ¦Â-hydroxybutyrate (¦ÂHB), contributes to the regulation of intestinal cell differentiation. Here, we have shown that HMGCS2 is a novel target of Wnt/¦Â-catenin/PPAR¦Ã signaling in intestinal epithelial cancer cell lines and normal intestinal organoids. Inhibition of the Wnt/¦Â-catenin pathway resulted in increased protein and mRNA expression of HMGCS2 and ¦ÂHB production in human colon cancer cell lines LS174T and Caco2. In addition, Wnt inhibition increased expression of PPAR¦Ã and its target genes, FABP2 and PLIN2, in these cells. Conversely, activation of Wnt/¦Â-catenin signaling decreased protein and mRNA levels of HMGCS2, ¦ÂHB production, and expression of PPAR¦Ã and its target genes in LS174T and Caco2 cells and mouse intestinal organoids. Moreover, inhibition of PPAR¦Ã reduced HMGCS2 expression and ¦ÂHB production, while activation of PPAR¦Ã increased HMGCS2 expression and ¦ÂHB synthesis. Furthermore, PPAR¦Ã bound the promoter of HMGCS2 and this binding was enhanced by ¦Â-catenin knockdown. Finally, we showed that HMGCS2 inhibited, while Wnt/¦Â-catenin stimulated, glycolysis, which contributed to regulation of intestinal cell differentiation. Our results identified HMGCS2 as a downstream target of Wnt/¦Â-catenin/PPAR¦Ã signaling in intestinal epithelial cells. Moreover, our findings suggest that Wnt/¦Â-catenin/PPAR¦Ã signaling regulates intestinal cell differentiation, at least in part, through regulation of ketogenesis. View Full-Tex
%U https://www.mdpi.com/2073-4409/8/9/1106