PUBLICATION

Vitamin D regulates insulin pathway and glucose metabolism in zebrafish (Danio rerio)

Authors

Shao, R., Liao, X., Lan, Y., Zhang, H., Jiao, L., Du, Q., Han, D., Ai, Q., Mai, K., Wan, M.

ID

ZDB-PUB-220428-3

Date

2022

Source

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 36: e22330 (Journal)

Registered Authors

Han, Dong

Keywords

1,25(OH)2D3, diabetes, glucose homeostasis, hyperglycemia, insulin, insulin receptor, vitamin D3

MeSH Terms

Animals
Glucose/metabolism
Insulin/metabolism
Vitamin D*/metabolism
Vitamins
Zebrafish*/metabolism

(all 6)

PubMed

35474468 Full text @ FASEB J.

Abstract

1,25-dihydroxyvitamin D₃ [1,25(OH)₂ D₃ ], the most active vitamin D (VD) metabolite, is a steroid hormone playing an important role in many physiological functions in addition to maintaining mineral homeostasis. In this study, we explored the mechanism that the VD regulated insulin pathway and glucose metabolism in zebrafish in vitro and in vivo. Our results show that 1,25(OH)₂ D₃ significantly enhances the expression of insulin receptor a (insra), insulin receptor substrate 1 (irs1) and glucose transporter 2 (glut2), and promotes glycolysis and glycogenesis, while suppressing gluconeogenesis in zebrafish liver cell line (ZFL) under the condition of high glucose (20 mM), instead of the normal glucose (10 mM). Moreover, consistent results were obtained from the zebrafish fed with VD₃ -deficient diet, as well as the cyp2r1^-/- zebrafish, in which endogenous VD metabolism is blocked. Furthermore, results from dual-luciferase reporting system exhibited that 1,25(OH)₂ D₃ directly activated the transcription of insra, rather than insrb in zebrafish by binding to vitamin D response element (VDRE) located at -181 to -167 bp in the promoter region of insra. Importantly, the 1,25(OH)₂ D₃ treatment significantly alleviated the symptoms of hyperglycemia in diabetic zebrafish. In conclusion, our study demonstrated that VD activates VDRE located in the promoter area of insra in zebrafish to promote insulin/insra signaling pathway, thereby contributing to the maintenance of glucose homeostasis.

Genes / Markers

Marker	Marker Type	Name
cyp24a1	GENE	cytochrome P450, family 24, subfamily A, polypeptide 1
cyp27b1	GENE	cytochrome P450, family 27, subfamily B, polypeptide 1
cyp2r1	GENE	cytochrome P450, family 2, subfamily R, polypeptide 1
fbp1a	GENE	fructose-1,6-bisphosphatase 1a
g6pc1a.1	GENE	glucose-6-phosphatase catalytic subunit 1a, tandem duplicate 1
gck	GENE	glucokinase (hexokinase 4)
gys1	GENE	glycogen synthase 1 (muscle)
gys2	GENE	glycogen synthase 2
hk1	GENE	hexokinase 1
il1b	GENE	interleukin 1, beta

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Figures

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Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
fbp1a	cyp2r1^{ihb153/ihb153}	chemical treatment by injection: D-glucose	Days 45-89	liver	RTPCR	Fig. 4
fbp1a	cyp2r1^{ihb153/ihb153}	control	Days 45-89	liver	RTPCR	Fig. 4
fbp1a	WT	chemical treatment by diet: D3 vitamins	Days 45-89	liver	RTPCR	Fig. 3
fbp1a	WT	chemical treatment by injection: D-glucose	Days 45-89	liver	RTPCR	Fig. 3
fbp1a	WT	control	Days 45-89	liver	RTPCR	Fig. 3
fbp1a	WT	chemical treatment by diet: D3 vitamins, chemical treatment by injection: D-glucose	Days 45-89	liver	RTPCR	Fig. 3
fbp1a	WT	chemical treatment by injection: D-glucose	Days 45-89	liver	RTPCR	Fig. 4
fbp1a	WT	control	Days 45-89	liver	RTPCR	Fig. 4
g6pc1a.1	cyp2r1^{ihb153/ihb153}	chemical treatment by injection: D-glucose	Days 45-89	liver	RTPCR	Fig. 4
g6pc1a.1	cyp2r1^{ihb153/ihb153}	control	Days 45-89	liver	RTPCR	Fig. 4

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
WT	chemical treatment by injection: D-glucose	Days 45-89	blood glucose normal amount, normal	Fig. 2
WT	chemical treatment by injection: D-glucose	Days 45-89	blood insulin normal amount, normal	Fig. 2
WT	chemical treatment by injection: D-glucose	Days 45-89	liver glycogen normal amount, normal	Fig. 3
WT	chemical treatment by environment: glucose	Prim-5	whole organism glucose increased amount, abnormal	Fig. 6
WT	chemical treatment by environment: glucose	Long-pec	whole organism glucose increased amount, abnormal	Fig. 6
WT	chemical treatment by environment: glucose	Protruding-mouth	whole organism glucose increased amount, abnormal	Fig. 6
WT	chemical treatment by environment: glucose	Day 4	whole organism insra expression increased amount, abnormal	Fig. 6
WT	chemical treatment by environment: glucose	Day 4	whole organism insrb expression increased amount, abnormal	Fig. 6
WT	chemical treatment by environment: glucose	Day 4	whole organism glucose increased amount, abnormal	Fig. 6
WT	chemical treatment by environment: glucose, chemical treatment by environment: calcitriol	Prim-5	whole organism glucose amount, ameliorated	Fig. 6

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Mutations / Transgenics

Allele	Type	Affected Genomic Region
ihb153	Small Deletion	cyp2r1
ihb357	Indel	insra
ihb358	Small Deletion	insrb

Human Disease / Model

Sequence Targeting Reagents

Fish

Antibodies

Orthology

Engineered Foreign Genes

Mapping

Shao et al., 2022 ZDB-PUB-220428-3 PMID:35474468

Vitamin D regulates insulin pathway and glucose metabolism in zebrafish (Danio rerio)

Shao et al., 2022

ZDB-PUB-220428-3
PMID:35474468