Intestinal lipid metabolism regulates absorption and surface of gut epithelium
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ABSTRACT:
PROVIDER: PRJNA638157 | ENA |
REPOSITORIES: ENA
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Project description:Intestinal surface changes in size and function in response to environmental conditions, but what propels these alterations and what are the metabolic consequences is not clear. Here we show that in mice gut surface enlarges by increasing food amount rather than caloric intake, contributing to an increased absorptive function, and that it can be reversed by reducing daily food amount. Genetic- and environment-induced gut enlargement due to overeating is principally supported by upregulation of the intestinal lipid metabolism and transport. Intestinal knock-out, and pharmacological inhibition of PPARα supress intestinal crypt formation and shorten villi in the small intestine of mice and in human intestinal biopsies, respectively, and diminish post-prandial triglyceride transport and nutrient uptake. PPARα inhibition limits lipid absorption and restricts lipid droplet growth and PLIN2 levels, critical for the droplet formation. This improves lipid metabolism, reduces body adiposity and liver steatosis, suggesting an alternative target for treating obesity.
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Project description:The intestinal microbiota is a key regulator of mammalian lipid absorption, metabolism, and storage. Here we show that the microbiota reprograms intestinal lipid metabolism in mice by repressing the expression of long non-coding RNA (lncRNA) Snhg9 in small intestinal epithelial cells. Snhg9 suppressed the activity of the transcription factor peroxisome proliferator–activated receptor γ (PPARγ) – a central regulator of lipid metabolism – by dissociating the PPARγ inhibitor Sirtuin 1 from cell cycle and apoptosis protein 2 (CCAR2). Forced expression of Snhg9 in the intestinal epithelium of conventional mice lowered dietary lipid absorption, reduced body fat, and protected against diet-induced obesity. The microbiota repressed Snhg9 expression through an immune cell signaling relay encompassing myeloid cells and innate lymphoid cells. Our findings thus identify an unanticipated role for a lncRNA in microbial control of host metabolism.
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2020-09-24 | GSE146131 | GEO
Project description:Triacylglyceride (TAG) synthesis in the small intestine determines the absorption of dietary fat, but the mechanisms underlying are largely unknown. Here, we report that the RNA-binding protein HuR (ELAVL1) promotes TAG synthesis in the small intestine. HuR associates with the 3’UTR of Dgat2 mRNA and the introns 1 of Mgat2 pre-mRNA. Association of HuR with Dgat2 3’UTR stabilizes Dgat2 mRNA, while association of HuR with intron 1 of Mgat2 pre-mRNA promotes the processing of Mgat2 pre-mRNA. Intestinal epithelium-specific HuR knockout reduces the expression of DGAT2 and MGAT2, thereby reducing the dietary fat absorption through TAG synthesis and mitigating high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) and obesity. Our findings highlight a critical role of HuR in promoting dietary fat absorption.
2024-01-10 | GSE252591 | GEO
Project description:Triacylglyceride (TAG) synthesis in the small intestine determines the absorption of dietary fat, but the mechanisms underlying are largely unknown. Here, we report that the RNA-binding protein HuR (ELAVL1) promotes TAG synthesis in the small intestine. HuR associates with the 3’UTR of Dgat2 mRNA and the introns 1 of Mgat2 pre-mRNA. Association of HuR with Dgat2 3’UTR stabilizes Dgat2 mRNA, while association of HuR with intron 1 of Mgat2 pre-mRNA promotes the processing of Mgat2 pre-mRNA. Intestinal epithelium-specific HuR knockout reduces the expression of DGAT2 and MGAT2, thereby reducing the dietary fat absorption through TAG synthesis and mitigating high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) and obesity. Our findings highlight a critical role of HuR in promoting dietary fat absorption.
2024-04-03 | GSE262777 | GEO
Project description:Because of the epidemic rise of obesity worldwide, the identification of novel target genes for pharmacological treatment of obesity and related disorders is becoming of high importance. IFRD1 and IFRD2 are members of a novel transcriptional regulators family. Intestinal over-expression of mouse homologue of IFRD1 promoted intestinal triglyceride uptake and induced whole body adiposity in mice. To further elucidate the role of IFRD1 and IFRD2 in vivo, we generated mice lacking both mouse homologues of IFRD1 (TIS7) and IFRD2 (SKMc15) genes. Here, we report that mice deficient in TIS7 and SKMc15 genes, despite normal calorie intake had severely reduced amount of adipose tissue, were resistant to diet-induced obesity and displayed high glucose tolerance. Lower dietary fat entry into the circulation suggested that this phenotype resulted from impaired intestinal lipid transport. We identified down-regulation of CD36, a fatty acid transporter, both on RNA and protein levels. Reporter assays indicated that TIS7 and SKMc15 transcriptionally regulated CD36 expression and CD36 overexpression partially restored fatty acid uptake in vitro. Hence, our study suggested that TIS7 and SKMc15 play an important role in the regulation of the lipid metabolism and might represent a novel strategy for treatment of disorders caused by excess fat intake. To determine whether decreased intestinal lipid absorption might be caused by changes in expression of lipid processing and transport molecules, we performed Affymetrix microarray analyses of total RNA samples isolated from the jejunum of HFD-fed WT type and dKO animals. The moderated t-test was used to calculate p-values for significance of differential gene expression between 3 dKO and 3 wild type mice. These raw p-values were adjusted for multiple hypothesis testing using the method from Benjamini and Hochberg for a strong control of the false discovery rate (FDR) and genes with thus adjusted p-values < 0.05 were considered significant. Age-matched (7-10 week old) male wild type and TIS7 (Ifrd1) SKMc15 (Ifrd2) double knock out mice (C57Bl6 background) were caged individually and maintained from 3 weeks up to 8 weeks on a synthetic high saturated fat (HFD) diet (Ssniff). Small intestines (jejunum) were harvested for total RNA isolation. RNAs from 3 WT and 3 dKO mice were subjected to Affymetrix based whole genome gene expression analysis (Mouse 430.2 GeneChip).
2012-07-31 | E-GEOD-27019 | biostudies-arrayexpress
Project description:Macrophages Maintain Epithelium Integrity by Limiting Fungal Product Absorption
| PRJNA609356 | ENA
Project description:Because of the epidemic rise of obesity worldwide, the identification of novel target genes for pharmacological treatment of obesity and related disorders is becoming of high importance. IFRD1 and IFRD2 are members of a novel transcriptional regulators family. Intestinal over-expression of mouse homologue of IFRD1 promoted intestinal triglyceride uptake and induced whole body adiposity in mice. To further elucidate the role of IFRD1 and IFRD2 in vivo, we generated mice lacking both mouse homologues of IFRD1 (TIS7) and IFRD2 (SKMc15) genes. Here, we report that mice deficient in TIS7 and SKMc15 genes, despite normal calorie intake had severely reduced amount of adipose tissue, were resistant to diet-induced obesity and displayed high glucose tolerance. Lower dietary fat entry into the circulation suggested that this phenotype resulted from impaired intestinal lipid transport. We identified down-regulation of CD36, a fatty acid transporter, both on RNA and protein levels. Reporter assays indicated that TIS7 and SKMc15 transcriptionally regulated CD36 expression and CD36 overexpression partially restored fatty acid uptake in vitro. Hence, our study suggested that TIS7 and SKMc15 play an important role in the regulation of the lipid metabolism and might represent a novel strategy for treatment of disorders caused by excess fat intake. To determine whether decreased intestinal lipid absorption might be caused by changes in expression of lipid processing and transport molecules, we performed Affymetrix microarray analyses of total RNA samples isolated from the jejunum of HFD-fed WT type and dKO animals. The moderated t-test was used to calculate p-values for significance of differential gene expression between 3 dKO and 3 wild type mice. These raw p-values were adjusted for multiple hypothesis testing using the method from Benjamini and Hochberg for a strong control of the false discovery rate (FDR) and genes with thus adjusted p-values < 0.05 were considered significant.
2012-08-01 | GSE27019 | GEO
Project description:The pyruvate kinase M2 isoform (PKM2) is preferentially expressed in cancer to regulate anabolic metabolism. However, the metabolic requirements of PKM2 in tumorigenesis have yielded contradictory results. Herein we discovered that this glycolytic enzyme regulates lipid homeostasis in cancer cell autonomous manner and at systemic levels. Transmembrane protein 33 (TMEM33) was identified as a downstream effector of PKM2, whose expression level positively correlates with plasma total cholesterol level in vivo. Loss of PKM2 leads to up-regulation of TMEM33, which recruits ring finger protein 5 (RNF5) to promote SCAP ubiquitination and degradation, thereby inhibiting Golgi translocation and activation of sterol regulatory element binding protein 1 (SREBP1). Moreover, global PKM2 knockout promoted allografted tumor growth, at least partially attributes to the elevated plasma cholesterol level caused by increased intestinal Niemann-Pick C1-Like 1 (NPC1L1) to facilitate cholesterol absorption. Collectively, PKM2-TMEM33 axis modulates cell autonomous lipid metabolism by regulating SREBP activation. PKM2 in small intestine plays critical functions in controlling systemic cholesterol level. Overall, our results underscore unappreciated functions of PKM2 in lipid homeostasis and imply that combining an allosteric activator of PKM2 with NPC1L1 inhibitor represents a therapeutic invention for cancer treatment.
2021-08-06 | PXD026434 | Pride
Project description: Not available
| S-EPMC8639731 | biostudies-literature