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2017 ; 24
(3
): 458-468
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Ketogenesis contributes to intestinal cell differentiation
#MMPMID27935584
Wang Q
; Zhou Y
; Rychahou P
; Fan TW
; Lane AN
; Weiss HL
; Evers BM
Cell Death Differ
2017[Mar]; 24
(3
): 458-468
PMID27935584
show ga
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 ?-hydroxybutyrate (?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/?HB signaling in intestinal cells. In contrast, treatment of
intestinal cells with ?HB or feeding mice with a ketogenic diet inhibits mTOR
signaling in intestinal cells. Together, we provide evidence showing that
HMGCS2/?HB contributes to intestinal cell differentiation. Our results suggest
that mTOR acts cooperatively with HMGCS2/?HB to maintain intestinal homeostasis.
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