Influence of CYP3A4, CYP3A5, and NR3C1 genes polymorphism on the effectiveness of glucocorticoid therapy in patients with endocrine ophthalmopathy

Brovkina, A F; Сычев, Д. А.; Toropova, O.S.

doi:10.17116/oftalma2020136062125

Cited by 3 publications

(2 citation statements)

References 45 publications

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“…The rs6190 SNP case is fascinating because a theoretically inconsequential coding variant (conservative replacement R->K in position 23) associated with lower levels of fasting insulin and HOMA-IR [22], increased lean mass and muscle strength as young adults [25], and prolonged survival as older adults [53]. The proposed mechanism of “glucocorticoid resistance”, based on limited in vitro observations [54], was largely unreproducible in many other association studies [24; 55-60]. Thus, the extent to which the coding rs6190 GR variant is sufficient to directly regulate insulin sensitivity, as well as the underlying mechanism, remain unknown.…”

Section: Discussionmentioning

confidence: 99%

The human genetic variant rs6190 unveils Foxc1 and Arid5a as novel pro-metabolic targets of the glucocorticoid receptor in muscle.

Prabakaran,

Chung,

McFarland

et al. 2024

Preprint

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Genetic variations in the glucocorticoid receptor (GR) gene NR3C1 can impact metabolism. The single nucleotide polymorphism (SNP) rs6190 (p.R23K) has been associated in humans with enhanced metabolic health, but the SNP mechanism of action remains completely unknown. We generated a transgenic knock-in mice genocopying this polymorphism to elucidate how the mutant GR impacts metabolism. Compared to non-mutant littermates, mutant mice showed increased muscle insulin sensitivity and strength on regular chow and high-fat diet, blunting the diet-induced adverse effects on weight gain and exercise intolerance. Overlay of RNA-seq and ChIP-seq profiling in skeletal muscle revealed increased transactivation of Foxc1 and Arid5A genes by the mutant GR. Using adeno-associated viruses for in vivo overexpression in muscle, we found that Foxc1 was sufficient to transcriptionally activate the insulin response pathway genes Insr and Irs1. In parallel, Arid5a was sufficient to transcriptionally repress the lipid uptake genes Cd36 and Fabp4, reducing muscle triacylglycerol accumulation. Collectively, our findings identify a muscle-autonomous epigenetic mechanism of action for the rs6190 SNP effect on metabolic homeostasis, while leveraging a human nuclear receptor coding variant to unveil Foxc1 and Arid5a as novel epigenetic regulators of muscle metabolism.

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Section: Discussionmentioning

confidence: 99%

The human genetic variant rs6190 unveils Foxc1 and Arid5a as novel pro-metabolic targets of the glucocorticoid receptor in muscle.

Prabakaran,

Chung,

McFarland

et al. 2024

Preprint

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“…In vivo, glucocorticoids were mostly metabolized and inactivated by the liver microsomal cytochrome P450 enzyme system, resulting in low bioavailability. For example, hydrocortisone can be metabolized by P4503a (CYP3A) to 6β-hydroxy hydrocortisone, which is easily excreted from urine [ 7 , 8 ]. Glycyrrhizic acid is a saponin component extracted from the traditional Chinese medicine licorice [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

A novel biomimetic nanomedicine system with anti-inflammatory and anti-osteoporosis effects improves the therapy efficacy of steroid-resistant nephrotic syndrome

Zhao

Xiang

et al. 2021

J Nanobiotechnol

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Clinically, steroid-resistant nephrotic syndrome (SRNS) is always prolonged and difficult to treat and easily develops into end-stage renal disease, resulting in a low survival rate. Strategies to reverse steroid resistance and reduce the long-term use of high doses of steroid medicines are urgently needed. In this study, a novel nanoparticle drug system (Pm-GCH) with a core–shell structure was designed. Metal–organic frameworks, synthesized by glycyrrhizic acid (G) and calcium ions (Ca2+) loaded with hydrocortisone (H) were the core of the nanoparticles. Platelet membrane vesicles were the shells. The natural platelet membrane endows Pm-GCH with good biocompatibility and the ability to promote immune escape. In addition, under the chemotaxis of inflammatory factors, platelet membranes assist Pm-GCH in nonspecific targeting of the inflammatory sites of the kidney. Under an inflammatory acid environment, GCH slowly degrades and releases glycyrrhizic acid and hydrocortisone. Glycyrrhizic acid inhibits the inactivation of hydrocortisone, jointly inhibits the activity of phospholipase A2 (PLA2) and the classic activation pathway of complement C2, blocks the production of inflammatory factors, plays an anti-inflammatory role, and enhances the efficacy of hydrocortisone in the treatment of SRNS. Moreover, glycyrrhizic acid alleviates osteoporosis induced by long-term use of glucocorticoids. These results indicate that Pm-GCH is a promising treatment strategy for SRNS. Graphical Abstract

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The human glucocorticoid receptor variant rs6190 promotes blood cholesterol and atherosclerosis

Durumutla,

Haller,

Noble

et al. 2024

Preprint

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Elevated cholesterol poses a significant cardiovascular risk, particularly in older women. The glucocorticoid receptor (GR), a crucial nuclear transcription factor that regulates the metabolism of virtually all major nutrients, harbors a still undefined role in cholesterol regulation. Here, we report that a coding single nucleotide polymorphism (SNP) in the gene encoding the GR, rs6190, associated with increased cholesterol levels in women according to UK Biobank and All Of Us datasets. In SNP-genocopying transgenic mice, we found that the rs6190 SNP enhanced hepatic GR activity to transactivate Pcsk9 and Bhlhe40, negative regulators of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) receptors in liver respectively. Accordingly, in mice the rs6190 SNP was sufficient to elevate circulating cholesterol levels across all lipoprotein fractions and the risk and severity of atherosclerotic lesions on the pro-atherogenic hAPOE*2/*2 background. The SNP effect on atherosclerosis was blocked by in vivo knockdown of Pcsk9 and Bhlhe40 in liver. Remarkably, we found that this mechanism was conserved in human hepatocyte-like cells using CRISPR-engineered, SNP-genocopying human induced pluripotent stem cells (hiPSCs). Taken together, our study leverages a non-rare human variant to uncover a novel GR-dependent mechanism contributing to atherogenic risk, particularly in women.

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Influence of CYP3A4, CYP3A5, and NR3C1 genes polymorphism on the effectiveness of glucocorticoid therapy in patients with endocrine ophthalmopathy

Cited by 3 publications

References 45 publications

The human genetic variant rs6190 unveils Foxc1 and Arid5a as novel pro-metabolic targets of the glucocorticoid receptor in muscle.

The human genetic variant rs6190 unveils Foxc1 and Arid5a as novel pro-metabolic targets of the glucocorticoid receptor in muscle.

A novel biomimetic nanomedicine system with anti-inflammatory and anti-osteoporosis effects improves the therapy efficacy of steroid-resistant nephrotic syndrome

The human glucocorticoid receptor variant rs6190 promotes blood cholesterol and atherosclerosis

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