Ketogenesis contributes to intestinal cell differentiation

Wang, Qingding; Zhou, Yifeng; Rychahou, Piotr G.; Fan, Teresa W.‐M.; Lane, Andrew N.; Weiss, Heidi L.; Evers, B. Mark

doi:10.1038/cdd.2016.142

Cited by 97 publications

(102 citation statements)

References 52 publications

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“…Although it would be impossible to prove that all phenotypic characteristics of a human enterocyte require SLFN12, these results certainly suggest that some may. These SLFN12 effects may seem modest, but they are consistent in magnitude with changes in mucosal atrophy that others have observed in vivo [37, 38] and the effects of differentiating stimuli on Caco-2 cells in vitro [39–43]. Since many markers of enterocytic differentiation are enzymes or transport proteins, small changes in such proteins can catalyze greater downstream effects.…”

Section: Discussionsupporting

confidence: 78%

Schlafen 12 Interaction with SerpinB12 and Deubiquitylases Drives Human Enterocyte Differentiation

Basson

Wang

Chaturvedi

et al. 2018

Cell Physiol Biochem

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Background/Aims: Human enterocytic differentiation is altered during development, fasting, adaptation, and bariatric surgery, but its intracellular control remains unclear. We hypothesized that Schlafen 12 (SLFN12) regulates enterocyte differentiation. Methods: We used laser capture dissection of epithelium, qRT-PCR, and immunohistochemistry to evaluate SLFN12 expression in biopsies of control and fasting human duodenal mucosa, and viral overexpression and siRNA to trace the SLFN12 pathway in human Caco-2 and HIEC6 intestinal epithelial cells. Results: Fasting human duodenal mucosa expressed less SLFN12 mRNA and protein, accompanied by decreases in enterocytic markers like sucrase-isomaltase. SLFN12 overexpression increased Caco-2 sucrase-isomaltase promoter activity, mRNA, and protein independently of proliferation, and activated the SLFN12 putative promoter. SLFN12 coprecipitated Serpin B12 (SERPB12). An inactivating SLFN12 point mutation prevented both SERPB12 binding and sucrase-isomaltase induction. SERPB12 overexpression also induced sucrase-isomaltase, while reducing SERPB12 prevented the SLFN12 effect on sucrase-isomaltase. Sucrase-isomaltase induction by both SLFN12 and SERPB12 was attenuated by reducing UCHL5 or USP14, and blocked by reducing both. SERPB12 stimulated USP14 but not UCHL5 activity. SERPB12 coprecipitated USP14 but not UCHL5. Moreover, SLFN12 increased protein levels of the sucrase-isomaltase-promoter-binding transcription factor cdx2 without altering Cdx2 mRNA. This was prevented by reducing UCHL5 and USP14. We further validated this pathway in vitro and in vivo. SLFN12 or SERPB12 overexpression induced sucrase-isomaltase in human non-malignant HIEC-6 enterocytes. Conclusions: SLFN12 regulates human enterocytic differentiation by a pathway involving SERPB12, the deubiquitylases, and Cdx2. This pathway may be targeted to manipulate human enterocytic differentiation in mucosal atrophy, short gut or obesity.

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Section: Discussionsupporting

confidence: 78%

Schlafen 12 Interaction with SerpinB12 and Deubiquitylases Drives Human Enterocyte Differentiation

Basson

Wang

Chaturvedi

et al. 2018

Cell Physiol Biochem

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“…Recent study have showed that proliferative cells at the base of the intestinal crypt are characterized by a glycolytic metabolic phenotype, whereas differentiated cells have an oxidative phosphorylation phenotype, which is in line with the findings showed by sun et.al and Wang et.al, implying that nutritional states are closely associated with alteration of intestinal barrier function. Interesting, our previous study has revealed monocarboxylate transporter 4 (MCT4) expression is significantly increased in intestinal mucosal tissue of IBD patients, which is correlated with intestinal mucosal inflammation, and MCT4 is involved in establishment and maintenance of epithelial polarity and lactate transporters .…”

Section: Introductionsupporting

confidence: 87%

“…Wang et.al, 22 implying that nutritional states are closely associated with alteration of intestinal barrier function. Interesting, our previous study has revealed monocarboxylate transporter 4 (MCT4) expression is significantly increased in intestinal mucosal tissue of IBD patients, which is correlated with intestinal mucosal inflammation, 23 and MCT4 is involved in establishment and maintenance of epithelial polarity and lactate transporters.…”

Section: Andmentioning

confidence: 99%

Inhibition of CREB‐mediated ZO‐1 and activation of NF‐κB‐induced IL‐6 by colonic epithelial MCT4 destroys intestinal barrier function

Zhang

Wang

et al. 2019

Cell Proliferation

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Objective Inflammatory bowel disease (IBD) is a disorder intestinal inflammation and impaired barrier function, associated with increased epithelial expression of monocarboxylate transporter 4 (MCT4). However, the specific non‐metabolic function and clinical relevance of MCT4 in IBD remain to be fully elucidated. Methods Lentivirus‐mediated overexpression of MCT4 was used to assess the role of MCT4 in transcriptionally regulating ZO‐1 and IL‐6 expression by luciferase assays, WB and ChIP. IP was used to analyse the effect of MCT4 on the interaction NF‐κB‐CBP or CREB‐CBP, and these MCT4‐mediated effects were confirmed in vivo assay. Results We showed that ectopic expression of MCT4 inhibited ZO‐1 expression, while increased pro‐inflammatory factors expression, leading to destroy intestinal epithelial barrier function in vitro and in vivo. Mechanistically, MCT4 contributed NF‐κB p65 nuclear translocation and increased the binding of NF‐κB p65 to the promoter of IL‐6, which is attributed to MCT4 enhanced NF‐κB‐CBP interaction and dissolved CREB‐CBP complex, resulting in reduction of CREB activity and CREB‐mediated ZO‐1 expression. In addition, treatment of experimental colitis with MCT4 inhibitor α‐cyano‐4‐hydroxycinnamate (CHC) ameliorated mucosal intestinal barrier function, which was due to attenuation of pro‐inflammation factors expression and enhancement of ZO‐1 expression. Conclusion These findings suggested a novel role of MCT4 in controlling development of IBD and provided evidence for potential targets of IBD.

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“…In the developing brain, ketone bodies generated from leucine may also act as a substrate for the oxidative generation of energy. Furthermore, ketone bodies are known to play a regulatory roles in the differentiation of intestinal epithelial cells . A study showed that a ketogenic diet induced the expression of HMGCS2 during the differentiation and proliferation of intestinal epithelium, suggesting that HMGCS2 was regulated by ketone bodies .…”

Section: Discussionmentioning

confidence: 99%

Comparative Proteomic Analysis Reveals the Upregulation of Ketogenesis in Cardiomyocytes Differentiated from Induced Pluripotent Stem Cells

et al. 2019

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Diverse metabolic pathways, such as the tricarboxylic acid cycle, pyruvate metabolism, and oxidative phosphorylation, regulate the differentiation of induced pluripotent stem cells (iPSCs) to cells of specific lineages and organs. Here, the protein dynamics during cardiac differentiation of human iPSCs into cardiomyocytes (CMs) are characterized. The differentiation is induced by N-(6-methyl-2-benzothiazolyl)-2-[(3,4,6,7-tetrahydro-4-oxo-3-phenylthieno[3,2d]pyrimidin-2-yl)thio]-acetamide, a Wnt signaling inhibitor, and confirmed by the mRNA and protein expression of cTnT and MLC2A in CMs.For comparative proteomics, cells from three stages, namely, hiPSCs, cardiac progenitor cells, and CMs, are prepared using the three-plex tandem mass tag labeling approach. In total, 3970 proteins in triplicate analysis are identified. As the result, the upregulation of proteins associated with branched chain amino acid degradation and ketogenesis by the Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis are observed. The levels of 3-hydroxymethyl-3-methylglutaryl-CoA lyase, 3-hydroxymethyl-3-methylglutaryl-CoA synthase 2, and 3-hydroxybutyrate dehydrogenase 1, involved in ketone body metabolism, are determined using western blotting, and the level of acetoacetate, the final product of ketogenesis, is higher in CMs. Taken together, these observations indicate that proteins required for the production of diverse energy sources are naturally self-expressed during cardiomyogenic differentiation. Furthermore, acetoacetate concentration might act as a regulator of this differentiation.

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Ketogenesis contributes to intestinal cell differentiation

Cited by 97 publications

References 52 publications

Schlafen 12 Interaction with SerpinB12 and Deubiquitylases Drives Human Enterocyte Differentiation

Schlafen 12 Interaction with SerpinB12 and Deubiquitylases Drives Human Enterocyte Differentiation

Inhibition of CREB‐mediated ZO‐1 and activation of NF‐κB‐induced IL‐6 by colonic epithelial MCT4 destroys intestinal barrier function

Comparative Proteomic Analysis Reveals the Upregulation of Ketogenesis in Cardiomyocytes Differentiated from Induced Pluripotent Stem Cells

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