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

Miranda, Diego A.; Krause, William C.; Cazenave-Gassiot, Amaury; Suzawa, Miyuki; Escusa, Hazel; Foo, Juat Chin; Shihadih, Diyala S.; Stahl, Andreas; Fitch, Mark; Nyangau, Edna; Hellerstein, Marc K.; Wenk, Markus R.; Silver, David L.; Ingraham, Holly A.

doi:10.1172/jci.insight.96151

Cited by 46 publications

(36 citation statements)

References 55 publications

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“…Interestingly, deficiencies in Nr5a2 are linked to non-alcoholic fatty liver disease where it seems to have an anti-inflammatory role (Schwaderer et al, 2020). In addition, lack of Nr5a2 in the adult liver leads to disruption of hepatic lipid homeostasis and composition (Miranda et al, 2018). Our data implies that Nr5a2 could be important in circadian chromatin loop formation.…”

Section: Regulatory Elements Form Dynamic and Stable Chromatin Contacmentioning

confidence: 61%

The global and promoter-centric 3D genome organization temporally resolved during a circadian cycle

Ando-Kuri

Arzate-Mejía

Morf

et al. 2020

Preprint

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SummaryCircadian gene expression is essential for organisms to adjust cellular responses and anticipate daily changes in the environment. In addition to its physiological importance, the clock circuit represents an ideal, temporally resolved, system to study transcription regulation. Here, we analysed changes in spatial mouse liver chromatin conformation using genome-wide and promoter-capture Hi-C alongside daily oscillations in gene transcription in mouse liver. We found circadian topologically associated domains switched assignments to the transcriptionally active, open chromatin compartment and the inactive compartment at different hours of the day while their boundaries stably maintain their structure over time. Individual circadian gene promoters displayed maximal chromatin contacts at times of peak transcriptional output and the expression of circadian genes and contacted transcribed regulatory elements, or other circadian genes, was phase-coherent. Anchor sites of promoter chromatin loops were enriched in binding sites for liver nuclear receptors and transcription factors, some exclusively present in either rhythmic or stable contacts. The circadian 3D chromatin maps provided here identify the scales of chromatin conformation that parallel oscillatory gene expression and protein factors specifically associated with circadian or stable chromatin configurations.

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Section: Regulatory Elements Form Dynamic and Stable Chromatin Contacmentioning

confidence: 61%

The global and promoter-centric 3D genome organization temporally resolved during a circadian cycle

Ando-Kuri

Arzate-Mejía

Morf

et al. 2020

Preprint

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“…We identified dilauroyl‐phosphatidylcholine (DLPC), an unusual PC species with two saturated 12‐carbon fatty acid acyl chains, as an exogenous LRH‐1 agonist and showed that DLPC treatment could attenuate fatty liver and improve insulin sensitivity by repressing lipogenesis . In the opposite direction, LRH‐1 mRNA expression is strongly decreased in livers of human subjects with steatosis or nonalcoholic steatohepatitis, and a recent report confirms that acute knockout (KO) of LRH‐1 in mouse liver disrupts lipid metabolism and induces fat accumulation . Another report identifying glucokinase as a primary LRH‐1 target links LRH‐1 to glucose use and glycogen synthesis …”

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confidence: 83%

“…(4) In the opposite direction, LRH-1 mRNA expression is strongly decreased in livers of human subjects with steatosis or nonalcoholic steatohepatitis, (10) and a recent report confirms that acute knockout (KO) of LRH-1 in mouse liver disrupts lipid metabolism and induces fat accumulation. (11) Another report identifying glucokinase as a primary LRH-1 target links LRH-1 to glucose use and glycogen synthesis. (12) The nucleus contains a surprisingly large and dynamic endonuclear PC pool that is distinct from the nuclear membrane, (13) suggesting that PCs could act as endogenous agonists.…”

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confidence: 99%

Methyl‐Sensing Nuclear Receptor Liver Receptor Homolog‐1 Regulates Mitochondrial Function in Mouse Hepatocytes

et al. 2019

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Background and Aims Liver receptor homolog‐1 (LRH‐1; NR5A2) is a nuclear receptor that regulates metabolic homeostasis in the liver. Previous studies identified phosphatidylcholines as potential endogenous agonist ligands for LRH‐1. In the liver, distinct subsets of phosphatidylcholine species are generated by two different pathways: choline addition to phosphatidic acid through the Kennedy pathway and trimethylation of phosphatidylethanolamine through phosphatidylethanolamine N‐methyl transferase (PEMT). Approach and Results Here, we report that a PEMT–LRH‐1 pathway specifically couples methyl metabolism and mitochondrial activities in hepatocytes. We show that the loss of Lrh‐1 reduces mitochondrial number, basal respiration, beta‐oxidation, and adenosine triphosphate production in hepatocytes and decreases expression of mitochondrial biogenesis and beta‐oxidation genes. In contrast, activation of LRH‐1 by its phosphatidylcholine agonists exerts opposite effects. While disruption of the Kennedy pathway does not affect the LRH‐1‐mediated regulation of mitochondrial activities, genetic or pharmaceutical inhibition of the PEMT pathway recapitulates the effects of Lrh‐1 knockdown on mitochondria. Furthermore, we show that S‐adenosyl methionine, a cofactor required for PEMT, is sufficient to induce Lrh‐1 transactivation and consequently mitochondrial biogenesis. Conclusions A PEMT–LRH‐1 axis regulates mitochondrial biogenesis and beta‐oxidation in hepatocytes.

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“…In adult mammals, expression of the NR was originally detected in the liver, intestine, ovaries and exocrine pancreas [74]. In the liver, LRH-1/NR5A2 regulates expression of genes involved in cholesterol and bile acid metabolism as well as in glucose and lipid homeostasis while in ovaries it controls genes implicated in steroidogenesis [74,75]. In the exocrine pancreas, LRH-1/ NR5A2 along with PTF1-L cooperatively regulates expression of genes such as Cel, Ela1 and Cpa1 involved in digestive function [76].…”

Section: Lrh-1/nr5a2 a Pleiotropic Nuclear Receptor With Prime Assetsmentioning

confidence: 99%

Time for a paradigm shift in treating type 1 diabetes mellitus: coupling inflammation to islet regeneration

Cobo-Vuilleumier

Gauthier

2020

Metabolism

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Type 1 diabetes mellitus (T1DM) is an autoimmune disease that targets the destruction of islet beta-cells resulting in insulin deficiency, hyperglycemia and death if untreated. Despite advances in medical devices and longer-acting insulin, there is still no robust therapy to substitute and protect beta-cells that are lost in T1DM. Attempts to refrain from the autoimmune attack have failed to achieve glycemic control in patients highlighting the necessity for a paradigm shift in T1DM treatment. Paradoxically, beta-cells are present in T1DM patients indicating a disturbed equilibrium between the immune attack and beta-cell regeneration reminiscent of unresolved wound healing that under normal circumstances progression towards an anti-inflammatory milieu promotes regeneration. Thus, the ultimate T1DM therapy should concomitantly restore immune self-tolerance and replenish the beta-cell mass similar to wound healing. Recently the agonistic activation of the nuclear receptor LRH-1/ NR5A2 was shown to induce immune self-tolerance, increase beta-cell survival and promote regeneration through a mechanism of alpha-to-beta cell phenotypic switch. This trans-regeneration process appears to be facilitated by a pancreatic anti-inflammatory environment induced by LRH-1/NR5A2 activation. Herein, we review the literature on the role of LRH1/NR5A2 in immunity and islet physiology and propose that a cross-talk between these cellular compartments is mandatory to achieve therapeutic benefits.

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

Cited by 46 publications

References 55 publications

The global and promoter-centric 3D genome organization temporally resolved during a circadian cycle

The global and promoter-centric 3D genome organization temporally resolved during a circadian cycle

Methyl‐Sensing Nuclear Receptor Liver Receptor Homolog‐1 Regulates Mitochondrial Function in Mouse Hepatocytes

Time for a paradigm shift in treating type 1 diabetes mellitus: coupling inflammation to islet regeneration

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