A physiologically-based model of bile acid metabolism in mice
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ABSTRACT:
PROVIDER: PRJEB58856 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR10763622_1.fastq.gz | Fastqsanger.gz | |||
| ERR10763622_2.fastq.gz | Fastqsanger.gz | |||
| ERR10763623_1.fastq.gz | Fastqsanger.gz | |||
| ERR10763623_2.fastq.gz | Fastqsanger.gz | |||
| ERR10763624_1.fastq.gz | Fastqsanger.gz |
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Project description:Insulin regulation of hepatic gene expression is critical for controlling metabolism and preventing diabetes, atherosclerosis and NAFLD; yet, how insulin regulates gene expression in the spatial context of the liver lobule is largely unexplored. Here, we find that insulin regulates bile acid metabolism by segregating CYP8B1, the enzyme that catalyzes the 12α-hydroxylation of bile acids, from the other enzymes required for bile acid synthesis. When insulin signaling is disrupted, Cyp8b1 and the other bile acid synthesis genes become co-localized within the same zone, and 12α-hydroxylated bile acids, which drive atherosclerosis and NAFLD, are increased. Novel zone-specific genetic manipulations of Cyp8b1 that mimic the effects of insulin result in a more benign bile salt profile. Mechanistically, the zonal effects of insulin are not due to gradients of insulin concentration or signaling, but through insulin crosstalk with positional Wnt signals: Wnt and insulin act together to determine the complement of transcription factors active in the pericentral hepatocytes and thereby regulate Cyp8b1 zonation. Taken together, these data show that by repatterning gene expression in the liver lobule, insulin can transcriptionally regulate the outputs of a metabolic pathway. The spatial dimension of transcriptional regulation represents a novel lens with which to view the control of metabolism that may ultimately lead us to more precise therapies.
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Project description:Gut microbiota rewires host mRNA m6A epitranscriptomic landscape via bile acid metabolism
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Project description:Alterations in the gastrointestinal microbiota have been implicated in obesity in mice and humans, but the conserved microbial functions that influence host energy metabolism and adiposity have not been determined. Here we show that bacterial bile salt hydrolase (BSH) controls a microbe-host dialogue which functionally regulates host lipid metabolism and weight gain. Expression of cloned BSH enzymes in the GI tract of gnotobiotic or conventional mice significantly altered plasma bile acid signatures and regulated transcription of key genes involved in lipid metabolism (PPARgamma angptl4), cholesterol metabolism (abcg5/8), gastrointestinal homeostasis (regIIIgamma) and circadian rhythm (dbp, per1/2) in the liver or small intestine. High-level expression of BSH in conventionally raised mice resulted in significant reduction of host weight-gain, plasma cholesterol and liver triglycerides. We demonstrate that bacterial BSH activity significantly impacts systemic metabolic processes and adiposity in the host, and represents a key mechanistic target for the control of obesity and hypercholesterolaemia. Germ free Swiss Webster mice were monocolonised with EC containing the bacterial gene, Bile salt hydroalse. The treatment groups and relevant controls were; 1. Germ Free(GF) n=4 , 2. GF and EC n=4, 3. GF and EC +BSH1 n=4, 4. GF and EC+ BSH2 n=4, 5. GF re-conventionalised (CONV-D) n= 5. The Ileum and Liver were removed and the RNA extracted (RNAeasy plus universal kit (Qiagen), quantified and Microarrays were carried out using mouse Exon ST1.0 arrays (Affymetrix) by Almac Group, Craigavon, Northern Ireland. Analysis and pathway mapping was carried out by ALMAC and using Subio Platform software (Subio Inc) and Genesis Software.
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