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Intestinal epithelial cell NCoR deficiency ameliorates obesity and metabolic syndrome

ABSTRACT: Obesity has emerged as a common disease worldwide. Risks of developing other metabolic diseases, such as Type 2 diabetes are also higher in obese population. However, current treatment options are limited. Here we discovered a new approach for mitigating obesity and metabolic disorders by targeting intestinal nuclear receptor corepressor (NCoR). In mice with diet-induced obesity, NCoR deficiency in intestinal epithelial cells (IECs) improved obesity, insulin resistance, and glucose intolerance, corrected atherogenic dyslipidemia, and reduced hepatic steatosis. These effects were mediated through regulation of energy expenditure, energy harvest, and gut hormone secretion. Mechanistically, NCoR deficiency in IECs stimulated peroxisome proliferator-activated receptor α (PPARα) signaling pathway-mediated succinate production and thermogenesis. Intestinal cholesterol excretion was induced by derepression of intestinal liver X receptor (LXR), and triglyceride and fatty acid absorption in the upper intestine was reduced by disrupted bile acid synthesis and altered bile acid composition. In the distal intestine, increased fatty acid uptake stimulated glucagon-like peptide-1 (GLP-1) secretion and improved glycemic control.

ORGANISM(S): Mus musculus

PROVIDER: GSE237833 | GEO | 2024/08/01

REPOSITORIES: GEO

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Immunoglobulin-like domain receptor 1 mediates fat-stimulated cholecystokinin secretion.

Project description:Cholecystokinin (CCK) is a satiety hormone produced by discrete enteroendocrine cells scattered among absorptive cells of the small intestine. CCK is released into blood following a meal; however, the mechanisms inducing hormone secretion are largely unknown. Ingested fat is the major stimulant of CCK secretion. We recently identified a novel member of the lipoprotein remnant receptor family known as immunoglobulin-like domain containing receptor 1 (ILDR1) in intestinal CCK cells and postulated that this receptor conveyed the signal for fat-stimulated CCK secretion. In the intestine, ILDR1 is expressed exclusively in CCK cells. Orogastric administration of fatty acids elevated blood levels of CCK in wild type but not ILDR1-deficient mice, although the CCK secretory response to trypsin inhibitor was retained. The uptake of fluorescently labeled lipoproteins in ILDR1-transfected CHO cells and release of CCK from isolated intestinal cells required a unique combination of fatty acid plus HDL. CCK secretion secondary to ILDR1 activation is associated with increased [Ca2+]i consistent with regulated hormone release. These findings demonstrate that ILDR1 regulates CCK release through a mechanism dependent on fatty acids and lipoproteins and that absorbed fatty acids regulate gastrointestinal hormone secretion. GFP positive cells from CCK-EGFP transgenic mice were isolated by FACS and the expression profile was compared with an equal number of non-fluorescent intestinal cells.

2013-05-23 | E-GEOD-47196 | biostudies-arrayexpress

Next Generation Sequencing Analysis of Pparafl/fl and PparaΔIE intestinal transcriptomes

Project description:Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic diseases globally and nonalcoholic steatohepatitis is its progressive stage with limited therapeutic options. Here a role for intestinal peroxisome proliferator-activated receptor α (PPARα)-fatty acid binding protein 1 (FABP1) in obesity-associated metabolic syndrome, fatty liver and nonalcoholic steatohepatitis via modulating dietary fat absorption was uncovered. Intestinal PPARα is highly activated accompanied by marked upregulation of FABP1 by high-fat diet (HFD) in mice and obese humans. Intestine-specific PPARα or FABP1 disruption in mice decreases HFD-induced obesity, fatty liver and nonalcoholic steatohepatitis and intestinal PPARα disruption fails to further decrease obesity and NASH. Chemical PPARα antagonism improves metabolic disorders depending on the presence of intestinal PPARα or FABP1. Translationally, GW6471 decreases human PPARα-driven intestinal fatty acid uptake and therapeutically improves obesity in PPARA-humanized, but not Ppara-null, mice. These results suggest that intestinal PPARα-FABP1 axis could be a therapeutic target for NASH.

2022-09-01 | GSE190140 | GEO

Deletion of intestinal Hdac3 remodels the lipidome of enterocytes and protects mice from diet-induced obesity

Project description:Histone deacetylase 3 (Hdac3) regulates the expression of lipid metabolism genes in multiple tissues, however its role in regulating lipid metabolism in the intestinal epithelium is unknown. Here we demonstrate that intestine-specific deletion of Hdac3 (Hdac3IKO) protects mice from diet induced obesity. Intestinal epithelial cells (IECs) from Hdac3IKO mice display co-ordinate induction of genes and proteins involved in mitochondrial and peroxisomal b-oxidation, have an increased rate of fatty acid oxidation, and undergo marked remodelling of their lipidome, particularly a reduction in long chain triglycerides. Many HDAC3-regulated fatty oxidation genes are transcriptional targets of the PPAR family of nuclear receptors, Hdac3 deletion enhances their induction by PPAR-agonists, and pharmacological HDAC3 inhibition induces their expression in enterocytes. These findings establish a central role for HDAC3 in co-ordinating PPAR-regulated lipid oxidation in the intestinal epithelium, and identify intestinal HDAC3 as a potential therapeutic target for preventing obesity and related diseases.

2019-10-12 | GSE138775 | GEO

Immunoglobulin-like domain receptor 1 mediates fat-stimulated cholecystokinin secretion.

2013-05-23 | GSE47196 | GEO

An early-life microbiota metabolite protects against obesity via intestinal PPAR-gamma

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2022-06-03 | ST002186 | MetabolomicsWorkbench

Corepressors NCOR1 and SMRT regulate metabolism via intestinal regulation of carbohydrate transport

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2024-08-12 | GSE268594 | GEO

EFHD2 Suppresses Intestinal Inflammation by Blocking Intestinal Epithelial Cell TNFR1 Internalization and Cell Death

Project description:Death of intestinal epithelial cells (IECs) is important in the pathological process of intestinal inflammatory diseases. TNF acts as one pathogenic driver for inducing IEC death and substantial intestinal inflammation. However, the physiological protective mechanisms for suppressing TNF-induced IEC death remain poorly understood. Here, we report that EF-hand domain-containing protein D2 (EFHD2), highly expressed in normal intestine tissues but decreased in intestinal biopsy samples of ulcerative colitis patients, protects the intestinal epithelium from TNF-induced IEC apoptosis. EFHD2 inhibits TNF-induced apoptosis in primary IECs and intestinal organoids (enteroids). Mice deficient of Efhd2 in IECs exhibit excessive IEC death and exacerbated experimental colitis. Mechanistically, EFHD2 interacts with Cofilin to suppress the phosphorylation of Cofilin, leading to the inhibition of TNF receptor Ⅰ (TNFR1) internalization and TNF-induced apoptosis. Our findings define EFHD2 as an endogenous suppressor of IEC death to protect intestine inflammation, providing new insight to the regulation of death receptor signaling and control of intestinal inflammatory diseases.

2024-01-14 | PXD048587 | iProX

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Project description:Recent studies reveal that bile acid metabolite composition and its metabolism are changed in metabolic disorders, such as obesity, type 2 diabetes and metabolic associated fatty liver disease (MAFLD), yet its role and the mechanism remain largely unknown. Hepatic whole transcriptome analysis identified glycoursodeoxycholic acid (GUDCA), glycine-conjugated bile acid produced from intestinal bacteria, differentially regulated 189 genes involved in biological processes including sterol, cholesterol and steroid biosynthesis, lipid metabolism, circadian rhythm and regulation, and the cellular component in cytosol, cytoplasm and endoplasmic reticulum, and molecular function including catalytic activity and platelet-derived growth factor binding.

2024-03-09 | GSE168822 | GEO

Genome-wide analysis of PPARα activation in murine small intestine

Project description:The peroxisome proliferator-activated receptor alpha (PPARα) is a fatty acid-activated transcription factor that governs a variety of biological processes. Little is known about the role of PPARα in the small intestine. Since this organ is frequently exposed to high levels of PPARα ligands via the diet, we set out to characterize the function of PPARα in small intestine using functional genomics experiments and bioinformatics tools. PPARα was expressed at high levels in both human and murine small intestine. Detailed analyses showed that PPARα was expressed highest in villus cells of proximal jejunum. Microarray analyses of total tissue samples revealed, that in addition to genes involved in fatty acid and triacylglycerol metabolism, transcription factors and enzymes connected to sterol and bile acid metabolism, including FXR and SREBP1, were specifically induced. In contrast, genes involved in cell cycle and differentiation, apoptosis, and host defense were repressed by PPARα activation. Additional analyses showed that intestinal PPARα dependent gene regulation occurred in villus cells. Functional implications of array results were corroborated by morphometric data. The repression of genes involved in proliferation and apoptosis was accompanied by a 22% increase in villus height, and a 34% increase in villus area of wild-type animals treated with WY14643. This is the first report providing a comprehensive overview of processes under control of PPARα in the small intestine. We show that PPARα is an important transcriptional regulator in small intestine, which may be of importance for the development of novel foods and therapies for obesity and inflammatory bowel diseases. Keywords: identification of target genes

2007-06-28 | GSE5475 | GEO

Expression data from fatty acid and bile acid receptor agonist treated liver sinusoidal endothelial cells

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