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Open AccessArticle

Regulation of Ketogenic Enzyme HMGCS2 by Wnt/β-catenin/PPARγ Pathway in Intestinal Cells

1
Markey Cancer Center, University of Kentucky, Lexington, KY 40536 USA
2
Department of Surgery, University of Kentucky, Lexington, KY 40536 USA
3
Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536-0509, USA
*
Authors to whom correspondence should be addressed.
Cells 2019, 8(9), 1106; https://doi.org/10.3390/cells8091106
Received: 22 August 2019 / Revised: 10 September 2019 / Accepted: 17 September 2019 / Published: 19 September 2019
(This article belongs to the Section Cell Signaling and Regulated Cell Death)
The Wnt/β-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 β-hydroxybutyrate (βHB), contributes to the regulation of intestinal cell differentiation. Here, we have shown that HMGCS2 is a novel target of Wnt/β-catenin/PPARγ signaling in intestinal epithelial cancer cell lines and normal intestinal organoids. Inhibition of the Wnt/β-catenin pathway resulted in increased protein and mRNA expression of HMGCS2 and βHB production in human colon cancer cell lines LS174T and Caco2. In addition, Wnt inhibition increased expression of PPARγ and its target genes, FABP2 and PLIN2, in these cells. Conversely, activation of Wnt/β-catenin signaling decreased protein and mRNA levels of HMGCS2, βHB production, and expression of PPARγ and its target genes in LS174T and Caco2 cells and mouse intestinal organoids. Moreover, inhibition of PPARγ reduced HMGCS2 expression and βHB production, while activation of PPARγ increased HMGCS2 expression and βHB synthesis. Furthermore, PPARγ bound the promoter of HMGCS2 and this binding was enhanced by β-catenin knockdown. Finally, we showed that HMGCS2 inhibited, while Wnt/β-catenin stimulated, glycolysis, which contributed to regulation of intestinal cell differentiation. Our results identified HMGCS2 as a downstream target of Wnt/β-catenin/PPARγ signaling in intestinal epithelial cells. Moreover, our findings suggest that Wnt/β-catenin/PPARγ signaling regulates intestinal cell differentiation, at least in part, through regulation of ketogenesis. View Full-Text
Keywords: ketogenesis; HMGCS2; Wnt/β-catenin pathway; PPARγ; intestinal cells; β-hydroxybutyrate ketogenesis; HMGCS2; Wnt/β-catenin pathway; PPARγ; intestinal cells; β-hydroxybutyrate
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Kim, J.T.; Li, C.; Weiss, H.L.; Zhou, Y.; Liu, C.; Wang, Q.; Evers, B.M. Regulation of Ketogenic Enzyme HMGCS2 by Wnt/β-catenin/PPARγ Pathway in Intestinal Cells. Cells 2019, 8, 1106.

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