FXR Regulates Intestinal Cancer Stem Cell Proliferation

Fu, Ting; Coulter, Sally; Yoshihara, Eiji; Oh, Tae Gyu; Fang, Sungsoon; Cayabyab, Fritz; Zhu, Quanyin; Zhang, Tong; Leblanc, Mathias; Liu, Sihao; He, Min; Waizenegger, Wanda; Gasser, Emanuel; Schnabl, Bernd; Atkins, Annette R.; Yu, Ruth T.; Knight, Rob; Liddle, Christopher; Downes, Michael; Evans, Ronald M.

doi:10.1016/j.cell.2019.01.036

Cited by 343 publications

(324 citation statements)

References 58 publications

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“…In line with our result, it has been shown that FXR signaling is associated with DCA‐inhibited proliferation of intestinal epithelial cell 27 . In addition, a recent study has indicated that the intestinal FXR activation inhibits the proliferation of intestinal cancer stem cells 37 . With regard to TGR5, it has been reported that overexpression of TGR5 could reverse LPS‐induced inhibition of Caco‐2 cell proliferation, whereas knockdown of TGR5 had the opposite effect, 38 indicating a critical role of TGR5 in intestinal epithelial cell proliferation.…”

Section: Discussionsupporting

confidence: 91%

Hyodeoxycholic acid (HDCA) suppresses intestinal epithelial cell proliferation through FXR‐PI3K/AKT pathway, accompanied by alteration of bile acids metabolism profiles induced by gut bacteria

et al. 2020

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Bile acids (BAs) have been implicated in regulation of intestinal epithelial signaling and function. This study aimed to investigate the effects of hyodeoxycholic acid (HDCA) on intestinal epithelial cell proliferation and explore the underlying mechanisms. IPEC‐J2 cells and weaned piglets were treated with HDCA and the contributions of cellular signaling pathways, BAs metabolism profiles and gut bacteria were assessed. In vitro, HDCA suppressed IPEC‐J2 proliferation via the BAs receptor FXR but not TGR5. In addition, HDCA inhibited the PI3K/AKT pathway, while knockdown of FXR or constitutive activation of AKT eliminated the inhibitory effects of HDCA, suggesting that FXR‐dependent inhibition of PI3K/AKT pathway was involved in HDCA‐suppressed IPEC‐J2 proliferation. In vivo, dietary HDCA inhibited intestinal expression of proliferative markers and PI3K/AKT pathway in weaned piglets. Meanwhile, HDCA altered the BAs metabolism profiles, with decrease in primary BA and increase in total and secondary BAs in feces, and reduction of conjugated BAs in serum. Furthermore, HDCA increased abundance of the gut bacteria associated with BAs metabolism, and thereby induced BAs profiles alternation, which might indirectly contribute to HDCA‐suppressed cell proliferation. Together, HDCA suppressed intestinal epithelial cell proliferation through FXR‐PI3K/AKT signaling pathway, accompanied by alteration of BAs metabolism profiles induced by gut bacteria.

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Section: Discussionsupporting

confidence: 91%

Hyodeoxycholic acid (HDCA) suppresses intestinal epithelial cell proliferation through FXR‐PI3K/AKT pathway, accompanied by alteration of bile acids metabolism profiles induced by gut bacteria

et al. 2020

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“…As stem cells are considered to be more prone to acquire oncogenic mutations, this increase in "stemness" is proposed to be a mechanism contributing to the increase of tumor incidence observed upon HFD (Beyaz et al, 2016). Moreover, it was recently shown that HFD alters bile acids, which also contribute to drive malignant transformation of ISCs with dysregulated Wnt signaling (Fu et al, 2019). In Drosophila, increased dietary cholesterol influences the differentiation of ISCs by modulating Notch signaling, which leads to an increase of secretory entero-endocrine cells in the posterior midgut (Obniski et al, 2018).…”

Section: Dietmentioning

confidence: 99%

Lipid Mediated Regulation of Adult Stem Cell Behavior

Clémot

Demarco

Jones

2020

Front. Cell Dev. Biol.

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Adult stem cells constitute an important reservoir of self-renewing progenitor cells and are crucial for maintaining tissue and organ homeostasis. The capacity of stem cells to self-renew or differentiate can be attributed to distinct metabolic states, and it is now becoming apparent that metabolism plays instructive roles in stem cell fate decisions. Lipids are an extremely vast class of biomolecules, with essential roles in energy homeostasis, membrane structure and signaling. Imbalances in lipid homeostasis can result in lipotoxicity, cell death and diseases, such as cardiovascular disease, insulin resistance and diabetes, autoimmune disorders and cancer. Therefore, understanding how lipid metabolism affects stem cell behavior offers promising perspectives for the development of novel approaches to control stem cell behavior either in vitro or in patients, by modulating lipid metabolic pathways pharmacologically or through diet. In this review, we will first address how recent progress in lipidomics has created new opportunities to uncover stem-cell specific lipidomes. In addition, genetic and/or pharmacological modulation of lipid metabolism have shown the involvement of specific pathways, such as fatty acid oxidation (FAO), in regulating adult stem cell behavior. We will describe and compare findings obtained in multiple stem cell models in order to provide an assessment on whether unique lipid metabolic pathways may commonly regulate stem cell behavior. We will then review characterized and potential molecular mechanisms through which lipids can affect stem cell-specific properties, including self-renewal, differentiation potential or interaction with the niche. Finally, we aim to summarize the current knowledge of how alterations in lipid homeostasis that occur as a consequence of changes in diet, aging or disease can impact stem cells and, consequently, tissue homeostasis and repair.

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“…Up to now, it Is generally accepted that FXR plays a critical role in the regulation of intestinal tumorigenesis. 94 Inactivation of Apc inhibited FXR gene expression through CpG hypermethylation, resulting in disruption of BA homeostasis and increased expression of COX-2 and c-MYC, which contributed to colon tumorigenesis. 90 An immunohistochemical evaluation found that low expression of FXR is also accompanied by poor clinical outcome.…”

Section: Bile Acids-activated Receptorsmentioning

confidence: 99%

“…On the contrary, selective activation of FXR with Fexaramine D (FexD) and Obeticholic acid (OCA) inhibited the abnormal growth of Lgr5 + cells and the progression of CRC. 94 Inactivation of Apc inhibited FXR gene expression through CpG hypermethylation, resulting in disruption of BA homeostasis and increased expression of COX-2 and c-MYC, which contributed to colon tumorigenesis. 95 From the terminal ileum to the rectosigmoidal junction, the expression of FXR gradually decreased, and this concurs with a gradient of bile exposure along the intestinal axis.…”

Section: Bile Acids-activated Receptorsmentioning

confidence: 99%

The gut microbiota at the intersection of bile acids and intestinal carcinogenesis: An old story, yet mesmerizing

Song

Khan

et al. 2019

Intl Journal of Cancer

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The prevalence of colorectal cancer (CRC) has markedly increased worldwide in the last decade. Alterations of bile acid metabolism and gut microbiota have been reported to play vital roles in intestinal carcinogenesis. About trillions of bacteria have inhabited in the human gut and maintained the balance of host metabolism. Bile acids are one of numerous metabolites that are synthesized in the liver and further metabolized by the gut microbiota, and are essential in maintaining the normal gut microbiota and lipid digestion. Multiple receptors such as FXR, GPBAR1, PXR, CAR and VDR act as sensors of bile acids have been reported. In this review, we mainly discussed interplay between bile acid metabolism and gut microbiota in intestinal carcinogenesis. We then summarized the critical role of bile acids receptors involving in CRC, and also addressed the rationale of multiple interventions for CRC management by regulating bile acids–microbiota axis such as probiotics, metformin, ursodeoxycholic acid and fecal microbiota transplantation. Thus, by targeting the bile acids–microbiota axis may provide novel therapeutic modalities in CRC prevention and treatment.

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FXR Regulates Intestinal Cancer Stem Cell Proliferation

Abstract: Highlights d Genetic and dietary risk factors for colorectal cancer converge on the BA-FXR axis d FXR controls proliferating Lgr5 + intestinal stem cells d FXR agonists curtail colorectal cancer progression

Cited by 343 publications

References 58 publications

Hyodeoxycholic acid (HDCA) suppresses intestinal epithelial cell proliferation through FXR‐PI3K/AKT pathway, accompanied by alteration of bile acids metabolism profiles induced by gut bacteria

Hyodeoxycholic acid (HDCA) suppresses intestinal epithelial cell proliferation through FXR‐PI3K/AKT pathway, accompanied by alteration of bile acids metabolism profiles induced by gut bacteria

Lipid Mediated Regulation of Adult Stem Cell Behavior

The gut microbiota at the intersection of bile acids and intestinal carcinogenesis: An old story, yet mesmerizing

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