Regulation of Ketogenic Enzyme HMGCS2 by Wnt/β-catenin/PPARγ Pathway in Intestinal Cells
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 t...
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MDPI AG
2019-09-01
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| Online Access: | https://www.mdpi.com/2073-4409/8/9/1106 |
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| author | Ji Tae Kim Chang Li Heidi L. Weiss Yuning Zhou Chunming Liu Qingding Wang B. Mark Evers |
| author_facet | Ji Tae Kim Chang Li Heidi L. Weiss Yuning Zhou Chunming Liu Qingding Wang B. Mark Evers |
| author_sort | Ji Tae Kim |
| collection | DOAJ |
| description | 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, <i>FABP2</i> and <i>PLIN2</i>, 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. |
| first_indexed | 2024-03-12T19:43:48Z |
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| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-12T19:43:48Z |
| publishDate | 2019-09-01 |
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| record_format | Article |
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| spelling | doaj.art-f6afb483b3854cb5ae70ed263e3c2fab2023-08-02T03:41:23ZengMDPI AGCells2073-44092019-09-0189110610.3390/cells8091106cells8091106Regulation of Ketogenic Enzyme HMGCS2 by Wnt/β-catenin/PPARγ Pathway in Intestinal CellsJi Tae Kim0Chang Li1Heidi L. Weiss2Yuning Zhou3Chunming Liu4Qingding Wang5B. Mark Evers6Markey Cancer Center, University of Kentucky, Lexington, KY 40536 USADepartment of Surgery, University of Kentucky, Lexington, KY 40536 USAMarkey Cancer Center, University of Kentucky, Lexington, KY 40536 USAMarkey Cancer Center, University of Kentucky, Lexington, KY 40536 USAMarkey Cancer Center, University of Kentucky, Lexington, KY 40536 USAMarkey Cancer Center, University of Kentucky, Lexington, KY 40536 USAMarkey Cancer Center, University of Kentucky, Lexington, KY 40536 USAThe 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, <i>FABP2</i> and <i>PLIN2</i>, 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.https://www.mdpi.com/2073-4409/8/9/1106ketogenesisHMGCS2Wnt/β-catenin pathwayPPARγintestinal cellsβ-hydroxybutyrate |
| spellingShingle | Ji Tae Kim Chang Li Heidi L. Weiss Yuning Zhou Chunming Liu Qingding Wang B. Mark Evers Regulation of Ketogenic Enzyme HMGCS2 by Wnt/β-catenin/PPARγ Pathway in Intestinal Cells Cells ketogenesis HMGCS2 Wnt/β-catenin pathway PPARγ intestinal cells β-hydroxybutyrate |
| title | Regulation of Ketogenic Enzyme HMGCS2 by Wnt/β-catenin/PPARγ Pathway in Intestinal Cells |
| title_full | Regulation of Ketogenic Enzyme HMGCS2 by Wnt/β-catenin/PPARγ Pathway in Intestinal Cells |
| title_fullStr | Regulation of Ketogenic Enzyme HMGCS2 by Wnt/β-catenin/PPARγ Pathway in Intestinal Cells |
| title_full_unstemmed | Regulation of Ketogenic Enzyme HMGCS2 by Wnt/β-catenin/PPARγ Pathway in Intestinal Cells |
| title_short | Regulation of Ketogenic Enzyme HMGCS2 by Wnt/β-catenin/PPARγ Pathway in Intestinal Cells |
| title_sort | regulation of ketogenic enzyme hmgcs2 by wnt β catenin pparγ pathway in intestinal cells |
| topic | ketogenesis HMGCS2 Wnt/β-catenin pathway PPARγ intestinal cells β-hydroxybutyrate |
| url | https://www.mdpi.com/2073-4409/8/9/1106 |
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