Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

HFD activated FAO mediates intestinal stemness and tumorgenicity I

ABSTRACT: Obesity is an established risk factor for cancer in many tissues such as the gastrointestinal tract. In the mammalian intestine, a pro-obesity high fat diet (HFD) promotes tumorigenesis in part by enhancing intestinal stem cell (ISC) numbers, proliferation and function. Although Ppar (Peroxisome proliferator-activated receptor) nuclear receptor activity has been proposed to mediate some of these effects in HFD ISCs, the exact role that different Ppar family members play in this process is unclear. Here, we find that in loss-of-function in vivo models, both Ppar family members alpha and delta contribute to the HFD response in ISCs. Mechanistically, both PPARs do so by robustly inducing a downstream fatty acid oxidation (FAO) metabolic program. Notably, pharmacologic and genetic disruption of CPT1a (the rate limiting enzyme of FAO) blunts the HFD phenotype in ISCs. Furthermore, just as HFD ISCs depend on CPT1a-mediated FAO, inhibition of CPT1a dampens the pro-tumorigenic consequences of a HFD on early tumor incidence and progression in the intestine. These findings demonstrate that inhibition of a HFD activated FAO program creates a therapeutic opportunity to counter the effects of a HFD on ISCs and intestinal tumorigenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE151045 | GEO | 2021/06/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

HFD activated FAO mediates intestinal stemness and tumorgenicity II

Project description:Obesity is an established risk factor for cancer in many tissues such as the gastrointestinal tract. In the mammalian intestine, a pro-obesity high fat diet (HFD) promotes tumorigenesis in part by enhancing intestinal stem cell (ISC) numbers, proliferation and function. Although Ppar (Peroxisome proliferator-activated receptor) nuclear receptor activity has been proposed to mediate some of these effects in HFD ISCs, the exact role that different Ppar family members play in this process is unclear. Here, we find that in loss-of-function in vivo models, both Ppar family members alpha and delta contribute to the HFD response in ISCs. Mechanistically, both PPARs do so by robustly inducing a downstream fatty acid oxidation (FAO) metabolic program. Notably, pharmacologic and genetic disruption of CPT1a (the rate limiting enzyme of FAO) blunts the HFD phenotype in ISCs. Furthermore, just as HFD ISCs depend on CPT1a-mediated FAO, inhibition of CPT1a dampens the pro-tumorigenic consequences of a HFD on early tumor incidence and progression in the intestine. These findings demonstrate that inhibition of a HFD activated FAO program creates a therapeutic opportunity to counter the effects of a HFD on ISCs and intestinal tumorigenesis.

2021-06-01 | GSE151046 | GEO

High-fat diet activated fatty acid oxidation mediates intestinal stemness and tumorigenicity

2021-06-01 | GSE167996 | GEO

High-fat diet enhances stemness and tumorigenicity of intestinal progenitors

Project description:Little is known about how pro-obesity diets regulate tissue stem and progenitor cell function. Here we find that high fat diet (HFD)-induced obesity augments the numbers and function of Lgr5+ intestinal stem cells (ISCs) of the mammalian intestine. Like HFD, ex vivo treatment of intestinal organoid cultures with palmitic acid (PA), a constituent of the HFD, enhances the self-renewal potential of these organoid bodies. Mechanistically, HFD induces a robust peroxisome proliferator-activated receptor delta (PPAR-delta signature in intestinal stem and progenitor cells and pharmacologic activation of PPAR-delta recapitulates the effects that HFD has on these cells. Interestingly, HFD- and agonist-activated PPAR-delta signaling endows organoid-initiating capacity to non-stem cells and enforced PPAR-delta signaling permits these non-stem cells to form in vivo tumors upon loss of the tumor suppressor Apc. These findings highlight how diet-modulated PPAR-delta activation alters not only the function of intestinal stem and progenitor cells but also their capacity to initiate tumors. mRNA profiles of intestinal stem cells (GFP-Hi) and progenitors (GFP-Low) from WT or HFD fed mice were generated by deep sequencing using HiSeq 2000.

2016-02-16 | E-GEOD-67324 | biostudies-arrayexpress

High-fat diet enhances stemness and tumorigenicity of intestinal progenitors

2016-02-16 | GSE67324 | GEO

HFD activated FAO mediates intestinal stemness and tumorgenicity

Project description:HFD activated FAO mediates intestinal stemness and tumorgenicity

| PRJNA634505 | ENA

HFD activated FAO mediates intestinal stemness and tumorgenicity I

Project description:HFD activated FAO mediates intestinal stemness and tumorgenicity I

| PRJNA634508 | ENA

HFD activated FAO mediates intestinal stemness and tumorgenicity II

Project description:HFD activated FAO mediates intestinal stemness and tumorgenicity II

| PRJNA634507 | ENA

Low-density Lipoprotein Regulates Intestinal Stem Cell Homeostasis via PPAR Pathway

Project description:Epidemiological studies have highlighted a strong association between hyperlipidemia and an increased risk of cancer in the gut. Intestinal stem cells (ISCs) have been demonstrated as the cells of origin for tumorigenesis in the gut. However, the impact of hyperlipidemia on ISC homeostasis remains unclear. Here, we show that hyperlipidemia induced by low-density lipoprotein receptor (Ldlr) deficiency enhances ISC proliferation in vivo. Additionally, LDL treatment impairs organoid survival but increases ISC stemness ex vivo, as evidenced by the formation of poorly differentiated spheroid and higher ISC self-renewal capacity. Mechanistically, LDL treatment activates PPAR pathways, and pharmacological inhibition of PPAR and its downstream targets, including CPT1A and PDK4, mitigates the effect of LDL on ISCs. Furthermore, although Ldlr-/- intestines exhibit increased susceptibility to irradiation-induced crypt damage, they regenerate completely within a similar timeframe as controls. These findings demonstrate that hyperlipidemia modulates ISC homeostasis, providing new insights into the mechanism linking hyperlipidemia with tumorigenesis in the gut.

2024-12-05 | GSE269253 | GEO

Dietary suppression of MHC-II expression in intestinal epithelial cells enhances intestinal tumorigenesis

Project description:Little is known about how interactions between diet, intestinal stem cells (ISCs) and immune cells impact the early steps of intestinal tumorigenesis. Here, we show that a high fat diet (HFD) reduces the expression of the major histocompatibility complex II (MHC-II) genes in intestinal epithelial cells including ISCs. This decline in epithelial MHC-II expression in a HFD correlates with reduced diversity of the intestinal microbiome and is recapitulated in antibiotic treated and germ-free mice on a control diet. Mechanistically, pattern recognition receptor (PRR) and IFN g signaling regulate epithelial MHC-II expression where genetic ablation of these signaling pathways dampen MHC-II epithelial expression. Interestingly, upon loss of the tumor suppressor gene Apc in a HFD, MHC-II- ISCs harbor greater in vivo tumor-initiating capacity than their MHC-II+ counterparts when transplanted into immune-component hosts but not immune-deficient hosts, thus implicating a role for epithelial MHC-II-mediated immune surveillance in suppressing tumorigenesis. Finally, ISC-specific genetic ablation of MHC-II in engineered Apc-mediated intestinal tumor models increases tumor burden in a cell autonomous manner. These findings highlight how a HFD perturbs a microbiome – stem cell – immune cell crosstalk in the intestine and contributes to tumor initiation through the dampening of MHC-II expression in pre-malignant ISCs.

2021-08-16 | GSE180949 | GEO

FDXR Drives Primary and Endocrine Resistant Tumor Cell Growth in ER+ Breast Cancer via CPT1A-Mediated Fatty Acid Oxidation

Project description:The majority of breast cancers (BCs) harboring estrogen receptor (ER) have shown endocrine resistance. Our previous study has demonstrated that ferredoxin reductase (FDXR) promotes mitochondrial function and ER+ breast tumorigenesis. Here, integrative analyses of targeted metabolomics assay and gene expression profiling show that FDXR potentiates fatty acid oxidation (FAO) through positive regulation of carnitine palmitoyltransferase 1A (CPT1A) expression. Treatment with ER antagonist (tamoxifen) or degrader (fulvestrant) leads to increased expression of FDXR and CPT1A. In line with this finding, we find that FDXR-CPT1A-FAO axis is required for primary and endocrine resistant breast cancer cell growth. Therapeutically,combining endocrine therapy with FAO inhibitor synergistically reduces primary and endocrine resistant breast cancer cell growth, thus providing a potential combinatory treatment for ER+ breast cancer. We used microarrays to be able to elucidate to some extent the gene regulatory mechanisms of FDXR regulating breast cancer metabolism.

2023-05-24 | GSE217902 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data