Liver receptor homolog-1 regulates mouse superoxide dismutase 2

Lee, Jun Su; Bae, Sijeong; Kang, Hye Suk; Im, Seung Soon; Moon, Young Ah

doi:10.1016/j.bbrc.2017.05.144

Cited by 8 publications

(10 citation statements)

References 34 publications

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“…Simultaneously, upregulating factors involved in general stress responses LRH-1 enables the protection from environmental threats as well as increasing intrinsic stress that highly proliferating cancer cells are commonly facing. 100,123,148,151 Most of the LRH-1-regulated processes promoting the survival of tumor cells are associated with mitochondrial functions. To begin with, increasing evidence suggests that LRH-1 induces the expression of antiapoptotic proteins, such as Bcl-xL and Bcl-2.…”

Section: Discussionmentioning

confidence: 99%

“…The pharmacological activation of LRH-1 was reported to increase SOD2 expression, while simultaneously reducing ROS production. 148 A protein stabilizing SOD2 polymorphism has been implicated in the development of various cancer types 149 and its expression levels are associated with a poor prognosis of ovarian cancer. 150 Thus, enhanced expression as well as activity of LRH-1 that increase SOD2 levels may contribute to the development of ROS resistance in certain cancer cells.…”

Section: Protection From Er Stress and Oxidative And Dna Damagementioning

confidence: 99%

“…Superoxide dismutase 2 (SOD2), which is a key antioxidant enzyme located within the mitochondria, was shown to be a direct transcriptional target of LRH‐1. The pharmacological activation of LRH‐1 was reported to increase SOD2 expression, while simultaneously reducing ROS production 148 . A protein stabilizing SOD2 polymorphism has been implicated in the development of various cancer types 149 and its expression levels are associated with a poor prognosis of ovarian cancer 150 .…”

Section: Lrh‐1 As a Regulator Of Cell Survival And Mitochondrial Apopmentioning

confidence: 99%

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Nuclear‐mitochondrial crosstalk: On the role of the nuclear receptor liver receptor homolog‐1 (NR5A2) in the regulation of mitochondrial metabolism, cell survival, and cancer

Michalek

Brunner

2020

IUBMB Life

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Liver receptor homolog-1 (LRH-1, NR5A2) is an orphan nuclear receptor with widespread activities in the regulation of development, stemness, metabolism, steroidogenesis, and proliferation. Many of the LRH-1-regulated processes target the mitochondria and associated activities. While under physiological conditions, a balanced LRH-1 expression and regulation contribute to the maintenance of a physiological equilibrium, deregulation of LRH-1 has been associated with inflammation and cancer. In this review, we discuss the role and mechanism(s) of how LRH-1 regulates metabolic processes, cell survival, and cancer in a nuclear-mitochondrial crosstalk, and evaluate its potential as a pharmacological target.

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Section: Discussionmentioning

confidence: 99%

Section: Protection From Er Stress and Oxidative And Dna Damagementioning

confidence: 99%

Section: Lrh‐1 As a Regulator Of Cell Survival And Mitochondrial Apopmentioning

confidence: 99%

See 1 more Smart Citation

Nuclear‐mitochondrial crosstalk: On the role of the nuclear receptor liver receptor homolog‐1 (NR5A2) in the regulation of mitochondrial metabolism, cell survival, and cancer

Michalek

Brunner

2020

IUBMB Life

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“…The next day, 100 µM DLPC was administered to the cells, which were incubated for 24 h. Finally, cells were lysed in reporter lysis buffer (Promega corporation, Madison, WI 53711 USA) and luciferase assays were performed. The luciferase activity was normalized by β-galactosidase activity [22].…”

Section: Plasmid Dna Design and Transient Transfectionmentioning

confidence: 99%

LRH-1 Ameliorates Hepatic Triglyceride Accumulation via Regulation of Perilipin 5 in the Liver

Pantha¹,

J²,

Bae³

et al. 2021

Preprint

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Liver receptor homolog-1 (LRH-1) has emerged as a regulator of hepatic glucose, bile acid, and mitochondrial metabolism. However, the functional mechanism underlying the effect of LRH-1 on lipid mobilization has not been addressed. This study investigated the regulatory function of LRH-1 in lipid metabolism during fasting. The wild-type (WT) and LRH-1 liver-specific knockout (LKO) mice were either fed or fasted for 24 h, and the liver and serum were isolated. During fasting, the LRH-1 LKO mice showed greater accumulation of triglycerides in the liver compared to that in WT mice. Interestingly, LRH-1 LKO liver decreased the perilipin 5 (PLIN5) expression and genes involved in β-oxidation. Additionally, the LRH-1 agonist dialauroylphosphatidylcholine also enhanced PLIN5 expression in human cultured HepG2 cells. To identify new target genes of LRH-1, these findings directed to analyze the PLIN5 promoter sequence, which revealed −1620/−1614 to be a putative binding site for LRH-1. This was confirmed by promoter activity and chromatin immuno-precipitation assays. Moreover, fasted WT primary hepatocytes showed increased co-localization of PLIN5 in lipid droplets (LDs) compared to that in fasted LRH-1 LKO primary hepatocytes. Overall, these findings suggest that PLIN5 might be a novel target of LRH-1 to mobilize LDs and manage the cellular needs.

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“…The compound RJW100 (Fig. 1a) is one of the few reported chemical scaffolds shown to activate these receptors and has been used by several groups to probe LRH-1 and SF-1 biology 16,[27][28][29][30][31][32][33] .…”

mentioning

confidence: 99%

Enantiomer-specific activities of an LRH-1 and SF-1 dual agonist

Mays

Stec

Liu

et al. 2020

Sci Rep

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Chirality is an important consideration in drug development: it can influence recognition of the intended target, pharmacokinetics, and off-target effects. Here, we investigate how chirality affects the activity and mechanism of action of RJW100, a racemic agonist of the nuclear receptors liver receptor homolog-1 (LRH-1) and steroidogenic factor-1 (SF-1). LRH-1 and SF-1 modulators are highly sought as treatments for metabolic and neoplastic diseases, and RJW100 has one of the few scaffolds shown to activate them. However, enantiomer-specific effects on receptor activation are poorly understood. We show that the enantiomers have similar binding affinities, but RR-RJW100 stabilizes both receptors and is 46% more active than SS-RJW100 in LRH-1 luciferase reporter assays. We present an LRH-1 crystal structure that illuminates striking mechanistic differences: SS-RJW100 adopts multiple configurations in the pocket and fails to make an interaction critical for activation by RR-RJW100. In molecular dynamics simulations, SS-RJW100 attenuates intramolecular signalling important for coregulator recruitment, consistent with previous observations that it weakly recruits coregulators in vitro. These studies provide a rationale for pursuing enantiomerically pure RJW100 derivatives: they establish RR-RJW100 as the stronger LRH-1 agonist and identify a potential for optimizing the SS-RJW100 scaffold for antagonist design.

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Liver receptor homolog-1 regulates mouse superoxide dismutase 2

Cited by 8 publications

References 34 publications

Nuclear‐mitochondrial crosstalk: On the role of the nuclear receptor liver receptor homolog‐1 (NR5A2) in the regulation of mitochondrial metabolism, cell survival, and cancer

Nuclear‐mitochondrial crosstalk: On the role of the nuclear receptor liver receptor homolog‐1 (NR5A2) in the regulation of mitochondrial metabolism, cell survival, and cancer

LRH-1 Ameliorates Hepatic Triglyceride Accumulation via Regulation of Perilipin 5 in the Liver

Enantiomer-specific activities of an LRH-1 and SF-1 dual agonist

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