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Caloric Restriction-Mediated Induction of Lipid Metabolism Gene Expression in Liver is Enhanced by Keap1-Knockdown

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Abstract

Purpose

CR increases fatty acid oxidation to decrease tissue lipid content. The Nuclear factor E2-related factor 2 (Nrf2)-Kelch like ECH associated Protein 1 (Keap1) pathway is an antioxidant gene regulatory pathway that has been previously investigated in weight gain. However, limited interaction of Nrf2/Keap1 and CR exists. The purpose of this study was to determine how Keap1 knockdown (Keap1-KD), which is known to increase Nrf2 activity, affects the CR response, such as weight loss, hepatic lipid decrease, and induction of fatty acid oxidation gene expression.

Methods

C57BL/6 and Keap1-KD mice were maintained on 40% CR or fed ad libitum for 6 weeks. Hepatic lipid content, lipid metabolic gene, and miRNA expression was quantified.

Results

CR lowered hepatic lipid content, and induced fatty acid oxidation gene expression to a greater degree in Keap1-KD compared to C57BL/6 mice. CR differentially altered miRNA 34a, 370, let-7b* in livers of Keap1-KD compared to C57BL/6 mice.

Conclusions

CR induced induction of fatty acid oxidation gene expression was augmented with Keap1 knockdown, which was associated with differential expression of several miRNAs implicated in fatty acid oxidation and lipid accumulation.

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Abbreviations

Acc1:

Acetyl-CoA carboxylase

Acot1:

Acyl-CoA thioesterase 1

AL:

Ad libitum

Cpt1a:

Carnitine palmitoyltransferase 1A

CR:

Caloric Restriction

Fabp4:

Fatty acid binding protein 4

Fas:

Fatty acid synthase

FXR:

Farnesoid X receptor

GCLC:

Glutamate cysteine ligase catalytic subunit, and

GST:

Glutathione S-Transferase

InsR:

insulin receptor

Keap1:

Kelch like ECH-associated Protein 1

Lxr:

Liver x receptor

NAFLD:

Non-alcoholic fatty liver disease

NQO1:

NAD(P) H:quinone oxidoreductase

Nrf2:

Nuclear factor E2-Related factor 2

Pgc-1α:

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha

Pparα:

Peroxisome Proliferator activated receptor α

RISC:

RNA induced silencing complex

Scd1:

Stearoyl-CoA desaturase

Sirt1:

Sirtuin1

Srebp1c:

Sterol regulatory element binding protein 1c

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Authors and Affiliations

  1. Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, 7 Greenhouse Road, Kingston, Rhode Island, 02881, USA

    Supriya R. Kulkarni, Laura E. Armstrong & Angela L. Slitt

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  1. Supriya R. Kulkarni
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  2. Laura E. Armstrong
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  3. Angela L. Slitt
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Correspondence to Angela L. Slitt.

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Kulkarni, S.R., Armstrong, L.E. & Slitt, A.L. Caloric Restriction-Mediated Induction of Lipid Metabolism Gene Expression in Liver is Enhanced by Keap1-Knockdown. Pharm Res 30, 2221–2231 (2013). https://doi.org/10.1007/s11095-013-1138-9

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  • DOI: https://doi.org/10.1007/s11095-013-1138-9

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