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Transcriptional analysis of adult LRH-1 knockout livers reveals a novel role for LRH-1 in hepatic lipid homeostasis and phospholipid remodeling

ABSTRACT: Transcriptional analysis of adult LRH-1 knockout livers reveals a novel role for LRH-1 in hepatic lipid homeostasis and phospholipid remodeling

PROVIDER: PRJNA430872 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6496830.fastq.gz	Fastqsanger.gz
	SRR6496831.fastq.gz	Fastqsanger.gz
	SRR6496832.fastq.gz	Fastqsanger.gz
	SRR6496833.fastq.gz	Fastqsanger.gz
	SRR6496834.fastq.gz	Fastqsanger.gz

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Transcriptional analysis of adult LRH-1 knockout livers reveals a novel role for LRH-1 in hepatic lipid homeostasis and phospholipid remodeling

Project description:Purpose: To identify novel LRH-1 target genes in adult knockout livers.

2020-01-01 | GSE109431 | GEO

Global hepatic transcript data from LRH-1 WT and LRH-1 K289R livers

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Global hepatic transcript data from LRH-1 hep+/+ and LRH-1 hep-/- livers

Project description:Transcript data from LRH-1 hep+/+ and LRH-1 hep-/- livers from mice fed ad libitum and sacrificed at 7 am We used microarrays to detail the global programme of gene expression underlying hepatic function in ad libitum fed mice. 17-19-week-old mice were fed ad libitum, sacrificed at 7 am, and livers snap-frozen in liquid nitorgen for RNA extraction and hybridization on Affymetrix microarrays.

2014-07-11 | E-GEOD-59305 | biostudies-arrayexpress

Global hepatic transcript data from LRH-1 WT and LRH-1 K289R livers

Project description:Transcript data from LRH-1 WT and LRH-1 K289R livers from mice fed ad libitum and sacrificed at 7 am We used microarrays to detail the global programme of gene expression underlying hepatic function in ad libitum fed mice. 17-19-week-old mice were fed ad libitum, sacrificed at 7 am, and livers snap-frozen in liquid nitorgen for RNA extraction and hybridization on Affymetrix microarrays.

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Global transcript analysis of livers of Lrh-1 K289R knockin mice under refed conditions

Project description:Transcript data from liver receptor homolog-1 (LRH-1) WT and LRH-1 K289R livers from mice fasted for 24h followed by 6h refed. We used microarrays to detail the global program of gene expression underlying hepatic function under refed conditions.

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Global hepatic transcript data from LRH-1 WT and LRH-1 K289R jejunums

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LRH-1 regulates hepatic lipid homeostasis and maintains arachidonoyl phospholipid pools critical for phospholipid diversity.

Project description:Excess lipid accumulation is an early signature of nonalcoholic fatty liver disease (NAFLD). Although liver receptor homolog 1 (LRH-1) (encoded by NR5A2) is suppressed in human NAFLD, evidence linking this phospholipid-bound nuclear receptor to hepatic lipid metabolism is lacking. Here, we report an essential role for LRH-1 in hepatic lipid storage and phospholipid composition based on an acute hepatic KO of LRH-1 in adult mice (LRH-1AAV8-Cre mice). Indeed, LRH-1-deficient hepatocytes exhibited large cytosolic lipid droplets and increased triglycerides (TGs). LRH-1-deficient mice fed high-fat diet displayed macrovesicular steatosis, liver injury, and glucose intolerance, all of which were reversed or improved by expressing wild-type human LRH-1. While hepatic lipid synthesis decreased and lipid export remained unchanged in mutants, elevated circulating free fatty acid helped explain the lipid imbalance in LRH-1AAV8-Cre mice. Lipidomic and genomic analyses revealed that loss of LRH-1 disrupts hepatic phospholipid composition, leading to lowered arachidonoyl (AA) phospholipids due to repression of Elovl5 and Fads2, two critical genes in AA biosynthesis. Our findings reveal a role for the phospholipid sensor LRH-1 in maintaining adequate pools of hepatic AA phospholipids, further supporting the idea that phospholipid diversity is an important contributor to healthy hepatic lipid storage.

| S-EPMC5922282 | biostudies-literature

Global hepatic transcript data from LRH-1 WT and LRH-1 K289R jejunums

Project description:Transcript data from LRH-1 WT and LRH-1 K289R jejunums from mice fed ad libitum and sacrificed at 7 am We used microarrays to detail the global programme of gene expression underlying jejunal function in ad libitum fed mice. 19-21-week-old mice were fed ad libitum, sacrificed at 7 am, and jejunums snap-frozen in liquid nitorgen for RNA extraction and hybridization on Affymetrix microarrays.

2014-07-11 | E-GEOD-59303 | biostudies-arrayexpress

Differential modulation of nuclear receptor LRH-1 through targeting buried and surface regions of the binding pocket

Project description:Liver receptor homolog-1 (LRH-1) is a phospholipid-sensing nuclear receptor that has shown promise as a target for alleviating intestinal inflammation and disease states characterized by metabolic dysregulation in the liver. LRH-1 contains an unusually large ligand binding pocket but generating synthetic modulators has been challenging. Leveraging a hexahydropentalene (6HP) core, we have had recent success in generating potent and efficacious agonists through two distinct strategies. We targeted residues deep within the pocket to enhance compound binding, while residues at the mouth of the pocket were targeted to mimic interactions made by endogenous phospholipids. Here, we unite these two designs into one hybrid molecule to synthesize the most potent LRH-1 agonist to date. Through a combination of global transcriptomic, biochemical, and structural studies, we show that selective modulation can be driven through contacting deep vs. surface polar regions in the pocket. While deep pocket contacts convey high-affinity, contacts with the pocket mouth dominate allostery and provide a phospholipid-like transcriptional response in cultured cells.

2022-05-10 | GSE199060 | GEO

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