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LRH-1 coordinates metabolic and epigenetic programs that establish luteal cell identity [ChIP-seq]

ABSTRACT: Despite advances in assisted reproductive technology, success rates remain modest, largely due to implantation failure and inadequate support of early pregnancy. Corpus luteum function and consequent progesterone secretion are essential for these processes. Large luteal cells are the primary source of progesterone production, yet the transcriptional programs that define their identity remain unclear. Here, we identify the nuclear receptor Liver receptor homolog-1 as a key regulator of large luteal cell function. Loss of Liver receptor homolog-1 disrupts lipid droplet accumulation and downregulates key steroidogenic genes. Mechanistically, Liver receptor homolog-1 undergoes chromatin-binding reprogramming during luteinization, establishing regulatory regions that couple lipid metabolism to steroidogenesis. Large luteal cells integrate energy metabolism with steroid hormone production and promote nuclear acetyl-coenzyme A synthesis via Acyl-CoA synthetase short-chain family member 2, linking metabolic reprogramming to epigenetic control. These findings establish Liver receptor homolog-1 and Acyl-CoA synthetase short-chain family member 2 as key regulators coordinating lipid homeostasis, chromatin regulation and fertility.

ORGANISM(S): Mus musculus

PROVIDER: GSE322887 | GEO | 2026/09/22

REPOSITORIES: GEO

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Project description:vanEunen2013 - Network dynamics of fatty acid β-oxidation (steady-state model) Lipid metabolism plays an important role in the development of metabolic syndrome, a major risk factor for cardiovascular disease and diabetes. This model gives insights into the response of lipid oxidation to dietart and medical interventions. The model predicts the rate of lipid oxidation and the time course of most acyl carnitines. There are two models described in the paper, (i) steady-state model [ BIOMD0000000505 ], (ii) time-course model [ BIOMD0000000506 ]. This model corresponds to the steady-state model. This model is described in the article: Biochemical competition makes fatty-acid β-oxidation vulnerable to substrate overload. van Eunen K, Simons SM, Gerding A, Bleeker A, den Besten G, Touw CM, Houten SM, Groen BK, Krab K, Reijngoud DJ, Bakker BM. PLoS Comput Biol. 2013;9(8):e1003186. Abstract: Fatty-acid metabolism plays a key role in acquired and inborn metabolic diseases. To obtain insight into the network dynamics of fatty-acid β-oxidation, we constructed a detailed computational model of the pathway and subjected it to a fat overload condition. The model contains reversible and saturable enzyme-kinetic equations and experimentally determined parameters for rat-liver enzymes. It was validated by adding palmitoyl CoA or palmitoyl carnitine to isolated rat-liver mitochondria: without refitting of measured parameters, the model correctly predicted the β-oxidation flux as well as the time profiles of most acyl-carnitine concentrations. Subsequently, we simulated the condition of obesity by increasing the palmitoyl-CoA concentration. At a high concentration of palmitoyl CoA the β-oxidation became overloaded: the flux dropped and metabolites accumulated. This behavior originated from the competition between acyl CoAs of different chain lengths for a set of acyl-CoA dehydrogenases with overlapping substrate specificity. This effectively induced competitive feedforward inhibition and thereby led to accumulation of CoA-ester intermediates and depletion of free CoA (CoASH). The mitochondrial [NAD⁺]/[NADH] ratio modulated the sensitivity to substrate overload, revealing a tight interplay between regulation of β-oxidation and mitochondrial respiration. This model is hosted on BioModels Database and identified by: BIOMD0000000505 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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LRH-1 coordinates metabolic and epigenetic programs that establish luteal cell identity [ChIP-seq]

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