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Nuclear receptor subfamily 5 group A member 2 (NR5A2): role in health and diseases

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Abstract

Nuclear receptors are the regulatory molecules that mediate cellular signals as they interact with specific DNA sequences. NR5A2 is a member of NR5A subfamily having four members (Nr5a1–Nr5a4). NR5A2 shows involvement in diverse biological processes like reverse cholesterol transport, embryonic stem cell pluripotency, steroidogenesis, development and differentiation of embryo, and adult homeostasis. NR5A2 haploinsufficiency has been seen associated with chronic pancreatitis, pancreatic and gastrointestinal cancer. There is a close relationship between the progression of pancreatic cancer from chronic pancreatitis, NR5A2 serving a common link. NR5A2 activity is regulated by intracellular phospholipids, transcriptional coregulators and post-translational modifications. The specific ligand of NR5A2 is unknown hence called an orphan receptor, but specific phospholipids such as dilauroyl phosphatidylcholine and diundecanoyl phosphatidylcholine act as a ligand and they are established drug targets in various diseases. This review will focus on the NR5A2 structure, regulation of its activity, and role in biological processes and diseases. In future, need more emphasis on discovering small molecule agonists and antagonist, which act as a drug target for therapeutic applications.

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Abbreviations

NR:

Nuclear receptors

HREs:

Hormone response elements

MR:

Mineralocorticoid receptors

ER:

Estrogen receptors

PR:

Progesterone receptors

AR:

Androgen receptors

GR:

Glucocorticoid receptors

PXR:

Pregame X receptor

SXR:

Steroid xenobiotic receptor

CAR:

Constitutive androstane receptor

LXRs:

Liver X receptors

NR5A2:

Nuclear receptor subfamily 5 group A member 2

PPARγ :

Peroxisome proliferator-activated receptor gamma

FXR:

Farnesol X receptor

DLPC:

Dilauroyl phosphatidylcholine

DBD:

DNA binding domain

AF-1:

Activation function-1

LBD:

Ligand binding domain

AF-2:

Activation function-2

SF-1:

Steroidogenic factor 1

LRH-1:

Liver receptor homolog

DUPC:

Diundecanoyl phosphatidylcholine

SRC:

Steroid receptor coactivator

SHP:

Small heterodimer partner

Oct4:

Octamer-binding transcription factor 4

PGC-1α:

PPARγ co-activator 1α

MBF-1:

Multiprotein bridging factor

CREB:

CAMP response element-binding protein

C/EBPδ:

CCAAT/enhancer-binding protein δ

CBP:

Co-activators CREB binding protein

CYP7A1:

Cholesterol 7α-hydroxylase

Cyp 19:

Aromatase

DAX-1:

Dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1

PROX1:

Prospero-related homeobox 1

NCOR1:

Nuclear receptor corepressor-1

SMRT:

Silencing mediator for retinol and thyroid receptor

CYP8B1:

12α-Hydroxylase

HDAC3:

Histone deacetylase 3 complex

GPS2:

G protein pathway suppressor 2

PMA:

Phorbol 12-myristate 13-acetate

PKA:

Protein kinase A

SIRT1:

SHP-sirtuin 1

PML:

Promyelocytic leukemia protein

T1DM:

Type 1 diabetes mellitus

AFP:

α1-Fetoprotein

HNF:

Hepatocyte nuclear factor

Sox2:

SRY-Box transcription factor 2

ERRβ:

Estrogen related receptor, beta

iPS:

Induced pluripotent stem cells

LH:

Luteinizing hormone

FSH:

Follicular stimulating hormone

StAR:

Steroidogenic acute regulatory protein

HSD3B2:

3β-Hydroxy steroid dehydrogenase type II

CYP 17:

Cytochrome P450 17 α-hydroxylase

ChREBP:

Carbohydrate response element binding protein

ChoREs:

Carbohydrate response elements

GCK:

Glucokinase

RCT:

Reverse cholesterol transport

HDLs:

High density lipoproteins

CETP:

Cholesterol-ester-transfer protein

SR-B1:

Scavenger receptor class B type I

BSEP:

Bile salt export pump

ASBT:

Apical sodium dependent bile acid transporter

Ost α/β:

Organic solute transporter alpha–beta

MRP-3:

Multidrug resistance protein-3

ER:

Endoplasmic reticulum

IL-1RA:

Interleukin-1 receptor antagonist

UPR:

Unfolded protein response

PlK-3:

Polio-like kinase 3

CYPIIA1:

Steroidogenic cholesterol side chain cleavage enzyme P450Scc

CYPIIB1:

11β-Hydroxylase

NF-KB:

Nuclear factor kappa-light chain-enhancer of activated B cells

AP1:

Activator protein-1

CP:

Chronic pancreatitis

PTF-1:

Pancreas transcription factor

GWAS:

Genome wide association studies

PDX-1:

Pancreatic and duodenal homeobox 1

SNPs:

Single nucleotide polymorphisms

PDAC:

Pancreatic ductal adenocarcinoma

PanIN:

Pancreatic intraepithelial neoplasia

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  1. Department of Biochemistry, All India Institute of Medical Sciences (AIIMS) Rishikesh, Rishikesh, Uttarakhand, India

    Nikita Sandhu, Satyavati Rana & Kiran Meena

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  1. Nikita Sandhu
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  2. Satyavati Rana
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KM: gave ideas, formulation of subtopics, critical reviewed, comments, editing and final approval; NS written draft of the review article; SR: review this article.

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Correspondence to Kiran Meena.

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Sandhu, N., Rana, S. & Meena, K. Nuclear receptor subfamily 5 group A member 2 (NR5A2): role in health and diseases. Mol Biol Rep 48, 8155–8170 (2021). https://doi.org/10.1007/s11033-021-06784-1

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