PUBLICATION

Elevated 4-hydroxynonenal induces hyperglycaemia via Aldh3a1 loss in zebrafish and associates with diabetes progression in humans

Authors

Lou, B., Boger, M., Bennewitz, K., Sticht, C., Kopf, S., Morgenstern, J., Fleming, T., Hell, R., Yuan, Z., Nawroth, P.P., Kroll, J.

ID

ZDB-PUB-201002-181

Date

2020

Source

Redox Biology 37: 101723 (Journal)

Registered Authors

Kroll, Jens

Keywords

4-hydroxynonenal, Aldh3a1, Diabetes, Glucose homeostasis, Reactive carbonyl species

Datasets

GEO:GSE151770

MeSH Terms

Aldehyde Dehydrogenase*/genetics
Humans
Hyperglycemia*/genetics
Aldehydes
Animals
Diabetes Mellitus*
Zebrafish*/genetics
Gene Knockout Techniques

(all 8)

PubMed

32980661 Full text @ Redox Biol.

Abstract

Increased methylglyoxal (MG) formation is associated with diabetes and its complications. In zebrafish, knockout of the main MG detoxifying system Glyoxalase 1, led to limited MG elevation but significantly elevated aldehyde dehydrogenases (ALDH) activity and aldh3a1 expression, suggesting the compensatory role of Aldh3a1 in diabetes. To evaluate the function of Aldh3a1 in glucose homeostasis and diabetes, aldh3a1^-/- zebrafish mutants were generated using CRISPR-Cas9. Vasculature and pancreas morphology were analysed by zebrafish transgenic reporter lines. Corresponding reactive carbonyl species (RCS), glucose, transcriptome and metabolomics screenings were performed and ALDH activity was measured for further verification. Aldh3a1^-/- zebrafish larvae displayed retinal vasodilatory alterations, impaired glucose homeostasis, which can be aggravated via pdx1 silencing induced hyperglycaemia. Unexpectedly, MG was not altered, but 4-hydroxynonenal (4-HNE), another prominent lipid peroxidation RCS exhibited high affinity with Aldh3a1, was increased in aldh3a1 mutants. 4-HNE was responsible for the retinal phenotype via pancreas disruption induced hyperglycaemia and can be rescued via l-Carnosine treatment. Furthermore, in type 2 diabetic patients, serum 4-HNE was increased and correlated with disease progression. Thus, our data suggest impaired 4-HNE detoxification and elevated 4-HNE concentration as biomarkers but also the possible inducers for diabetes, from genetic susceptibility to the pathological progression.

Genes / Markers

Figures

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Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
aldh1a3	WT	control	Long-pec	whole organism	RTPCR	Fig. S6
aldh1a3	WT + MO1-pdx1	standard conditions	Long-pec	whole organism	RTPCR	Fig. S6
aldh1l2	WT	control	Long-pec	whole organism	RTPCR	Fig. S6
aldh1l2	WT + MO1-pdx1	standard conditions	Long-pec	whole organism	RTPCR	Fig. S6
aldh3a1	WT	standard conditions	Adult	brain	RTPCR	Fig. 1
aldh3a1	WT	standard conditions	Adult	eye	RTPCR	Fig. 1
aldh3a1	WT	standard conditions	Prim-5	whole organism	RTPCR	Fig. 1
aldh3a1	WT	standard conditions	Day 4	whole organism	RTPCR	Fig. 1
aldh3a1	WT	standard conditions	Long-pec	whole organism	RTPCR	Fig. 1
aldh3a1	WT	standard conditions	Protruding-mouth	whole organism	RTPCR	Fig. 1

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
WT	chemical treatment by environment: 4-hydroxynon-2-enal	Long-pec	whole organism ins expression decreased amount, abnormal	Fig. 8
WT	chemical treatment by environment: 4-hydroxynon-2-enal	Long-pec	whole organism pdx1 expression decreased amount, abnormal	Fig. 8
WT	chemical treatment by environment: 4-hydroxynon-2-enal	Day 5	whole organism glucose increased amount, abnormal	Fig. 8
WT + MO1-aldh3a1	standard conditions	Long-pec	whole organism ins expression decreased amount, abnormal	Fig. 5
WT + MO1-aldh3a1	standard conditions	Long-pec	whole organism pdx1 expression decreased amount, abnormal	Fig. 5
WT + MO1-pdx1	standard conditions	Long-pec	whole organism aldh1a3 expression increased amount, abnormal	Fig. S6
WT + MO1-pdx1	standard conditions	Long-pec	whole organism aldh1l2 expression increased amount, abnormal	Fig. S6
WT + MO1-pdx1	standard conditions	Long-pec	whole organism aldh3a1 expression increased amount, abnormal	Fig. S6
WT + MO1-pdx1	standard conditions	Long-pec	whole organism aldh3b1 expression increased amount, abnormal	Fig. S6
WT + MO1-pdx1	standard conditions	Long-pec	whole organism aldh7a1 expression decreased amount, abnormal	Fig. S6

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
jh4Tg	Tg(ins:NTR-mCherry)	Transgenic Insertion
ml2Tg	Tg(mnx1:GFP)	Transgenic Insertion
y1Tg	Tg(fli1:EGFP)	Transgenic Insertion
zf3260		Indel	aldh3a1

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Human Disease / Model

Human Disease	Fish	Conditions	Evidence
type 2 diabetes mellitus			TAS

Sequence Targeting Reagents

Target	Reagent	Reagent Type
aldh3a1	CRISPR1-aldh3a1	CRISPR
aldh3a1	MO1-aldh3a1	MRPHLNO
aldh3a1	MO2-aldh3a1	MRPHLNO
pdx1	MO1-pdx1	MRPHLNO

Fish

Fish
aldh3a1^{zf3260/zf3260}
aldh3a1^{zf3260/zf3260} + MO1-pdx1
aldh3a1^{zf3260/zf3260}; y1Tg
aldh3a1^{zf3260/zf3260}; y1Tg + MO1-pdx1
jh4Tg
jh4Tg + MO1-aldh3a1
jh4Tg + MO1-pdx1
jh4Tg + MO2-aldh3a1
ml2Tg
ml2Tg + MO1-aldh3a1

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Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
EGFP	EFG	EGFP
GFP	EFG	GFP
mCherry	EFG	mCherry
NTR	EFG	NTR

Mapping

Lou et al., 2020 ZDB-PUB-201002-181 PMID:32980661

Elevated 4-hydroxynonenal induces hyperglycaemia via Aldh3a1 loss in zebrafish and associates with diabetes progression in humans

Lou et al., 2020

ZDB-PUB-201002-181
PMID:32980661