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Altered cellular redox status, sirtuin abundance and clock gene expression in a mouse model of developmentally primed NASH

Altered cellular redox status, sirtuin abundance and clock gene expression in a mouse model of developmentally primed NASH
Altered cellular redox status, sirtuin abundance and clock gene expression in a mouse model of developmentally primed NASH
Background: We have previously shown that high fat (HF) feeding during pregnancy primes the development of non-alcoholic steatohepatits (NASH) in the adult offspring. However, the underlying mechanisms are unclear.

Aims: Since the endogenous molecular clock can regulate hepatic lipid metabolism, we investigated whether exposure to a HF diet during development could alter hepatic clock gene expression and contribute to NASH onset in later life.

Methods: Female mice were fed either a control (C, 7% kcal fat) or HF (45% kcal fat) diet. Offspring were fed either a C or HF diet resulting in four offspring groups: C/C, C/HF, HF/C and HF/HF. NAFLD progression, cellular redox status, Sirtuin expression (Sirt1, Sirt3), and
39 the expression of core clock genes (Clock, Bmal1, Per2, Cry2) and clock-controlled genes involved in lipid metabolism (Rev-Erb?, Rev-Erb?, ROR?, and Srebp1c) were measured in offspring livers.

Results: Offspring fed a HF diet developed NAFLD. However HF fed offspring of mothers fed a HF diet developed NASH, coupled with significantly reduced NAD+/NADH (p<0.05, HF/HF vs C/C), Sirt1 (p<0.001, HF/HF vs C/C), Sirt3 (p<0.01, HF/HF vs C/C), perturbed
45 clock gene expression, and elevated expression of genes involved lipid metabolism, such as Srebp1c (p<0.05, C/HF and HF/HF vs C/C).

Conclusion: Our results suggest that exposure to excess dietary fat during early and postnatal life increases the susceptibility to develop NASH in adulthood, involving altered cellular redox status, reduced Sirtuin abundance, and desynchronised clock gene expression.
1388-1981
584-593
Bruce, K.D.
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Szczepankiewicz, D
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Sihota, K.K.
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Ravindraanandan, M.
3a78352b-ca3e-465c-80e1-b6ff6c37482c
Thomas, H.
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Lillycrop, K.A.
eeaaa78d-0c4d-4033-a178-60ce7345a2cc
Burdge, G.C.
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Hanson, M.A.
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Byrne, C.D.
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Cagampang, F.R.
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Bruce, K.D.
1ded890b-addf-45bd-ba59-dbaedaeee931
Szczepankiewicz, D
80f47241-92ae-4ef5-a375-50d5706a003d
Sihota, K.K.
9d7490ea-9203-4bc6-9a70-fc6cf9b0b9eb
Ravindraanandan, M.
3a78352b-ca3e-465c-80e1-b6ff6c37482c
Thomas, H.
a5cd108c-a73e-47fc-8832-0c2c3f313199
Lillycrop, K.A.
eeaaa78d-0c4d-4033-a178-60ce7345a2cc
Burdge, G.C.
09d60a07-8ca1-4351-9bf1-de6ffcfb2159
Hanson, M.A.
1952fad1-abc7-4284-a0bc-a7eb31f70a3f
Byrne, C.D.
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Cagampang, F.R.
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Bruce, K.D., Szczepankiewicz, D, Sihota, K.K., Ravindraanandan, M., Thomas, H., Lillycrop, K.A., Burdge, G.C., Hanson, M.A., Byrne, C.D. and Cagampang, F.R. (2016) Altered cellular redox status, sirtuin abundance and clock gene expression in a mouse model of developmentally primed NASH. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 1861 (7), 584-593. (doi:10.1016/j.bbalip.2016.03.026). (PMID:27040510)

Record type: Article

Abstract

Background: We have previously shown that high fat (HF) feeding during pregnancy primes the development of non-alcoholic steatohepatits (NASH) in the adult offspring. However, the underlying mechanisms are unclear.

Aims: Since the endogenous molecular clock can regulate hepatic lipid metabolism, we investigated whether exposure to a HF diet during development could alter hepatic clock gene expression and contribute to NASH onset in later life.

Methods: Female mice were fed either a control (C, 7% kcal fat) or HF (45% kcal fat) diet. Offspring were fed either a C or HF diet resulting in four offspring groups: C/C, C/HF, HF/C and HF/HF. NAFLD progression, cellular redox status, Sirtuin expression (Sirt1, Sirt3), and
39 the expression of core clock genes (Clock, Bmal1, Per2, Cry2) and clock-controlled genes involved in lipid metabolism (Rev-Erb?, Rev-Erb?, ROR?, and Srebp1c) were measured in offspring livers.

Results: Offspring fed a HF diet developed NAFLD. However HF fed offspring of mothers fed a HF diet developed NASH, coupled with significantly reduced NAD+/NADH (p<0.05, HF/HF vs C/C), Sirt1 (p<0.001, HF/HF vs C/C), Sirt3 (p<0.01, HF/HF vs C/C), perturbed
45 clock gene expression, and elevated expression of genes involved lipid metabolism, such as Srebp1c (p<0.05, C/HF and HF/HF vs C/C).

Conclusion: Our results suggest that exposure to excess dietary fat during early and postnatal life increases the susceptibility to develop NASH in adulthood, involving altered cellular redox status, reduced Sirtuin abundance, and desynchronised clock gene expression.

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More information

Accepted/In Press date: 25 March 2016
e-pub ahead of print date: 31 March 2016
Published date: July 2016
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 390661
URI: http://eprints.soton.ac.uk/id/eprint/390661
ISSN: 1388-1981
PURE UUID: a5e5946e-a714-4fe8-85ea-1703d3e36994
ORCID for K.A. Lillycrop: ORCID iD orcid.org/0000-0001-7350-5489
ORCID for G.C. Burdge: ORCID iD orcid.org/0000-0002-7665-2967
ORCID for M.A. Hanson: ORCID iD orcid.org/0000-0002-6907-613X
ORCID for C.D. Byrne: ORCID iD orcid.org/0000-0001-6322-7753
ORCID for F.R. Cagampang: ORCID iD orcid.org/0000-0003-4404-9853

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Date deposited: 06 Apr 2016 10:25
Last modified: 10 Dec 2019 06:35

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