Ketogenesis contributes to intestinal cell differentiation

• Published in: Cell death and differentiation 2017-03, Vol.24 (3), p.458-468
• Main Authors: Wang, Qingding, Zhou, Yuning, Rychahou, Piotr, Fan, Teresa W-M, Lane, Andrew N, Weiss, Heidi L, Evers, B Mark
• Format: Article
• Language: English
• Subjects: 13; 13/106; 13/109; 3-Hydroxybutyric Acid - pharmacology; 38; 38/90; 631/337; 96; 96/1; 96/106; 96/109; 96/63; 96/95; Alkaline Phosphatase - metabolism; Animals; Apoptosis; Biochemistry; Biomedical and Life Sciences; Caco-2 Cells; Cancer; CDX2 Transcription Factor - metabolism; Cell Biology; Cell Cycle Analysis; Cell death; Cell Differentiation - drug effects; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Diet, Ketogenic; Enzymes; Fatty acids; Glucose; Homeostasis; HT29 Cells; Humans; Hydroxymethylglutaryl-CoA Synthase - antagonists & inhibitors; Hydroxymethylglutaryl-CoA Synthase - genetics; Hydroxymethylglutaryl-CoA Synthase - metabolism; Keratin-20 - metabolism; Life Sciences; Male; Mechanistic Target of Rapamycin Complex 1 - antagonists & inhibitors; Mechanistic Target of Rapamycin Complex 1 - metabolism; Metabolism; Metabolites; Mice; Mice, Inbred C57BL; Mucin-2 - metabolism; Original Paper; Signal Transduction - drug effects; Sirolimus - pharmacology; Stem Cells; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2016.142

The intestinal epithelium undergoes a continual process of proliferation, differentiation and apoptosis. Previously, we have shown that the PI3K/Akt/mTOR pathway has a critical role in intestinal homeostasis. However, the downstream targets mediating the effects of mTOR in intestinal cells are not known. Here, we show that the ketone body β -hydroxybutyrate ( β HB), an endogenous inhibitor of histone deacetylases (HDACs) induces intestinal cell differentiation as noted by the increased expression of differentiation markers (Mucin2 (MUC2), lysozyme, IAP, sucrase-isomaltase, KRT20, villin, Caudal-related homeobox transcription factor 2 (CDX2) and p21 Waf1 ). Conversely, knockdown of the ketogenic mitochondrial enzyme hydroxymethylglutaryl CoA synthase 2 (HMGCS2) attenuated spontaneous differentiation in the human colon cancer cell line Caco-2. Overexpression of HMGCS2, which we found is localized specifically in the more differentiated portions of the intestinal mucosa, increased the expression of CDX2, thus further suggesting the contributory role of HMGCS2 in intestinal differentiation. In addition, mice fed a ketogenic diet demonstrated increased differentiation of intestinal cells as noted by an increase in the enterocyte, goblet and Paneth cell lineages. Moreover, we showed that either knockdown of mTOR or inhibition of mTORC1 with rapamycin increases the expression of HMGCS2 in intestinal cells in vitro and in vivo , suggesting a possible cross-talk between mTOR and HMGCS2/ β HB signaling in intestinal cells. In contrast, treatment of intestinal cells with β HB or feeding mice with a ketogenic diet inhibits mTOR signaling in intestinal cells. Together, we provide evidence showing that HMGCS2/ β HB contributes to intestinal cell differentiation. Our results suggest that mTOR acts cooperatively with HMGCS2/ β HB to maintain intestinal homeostasis.