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Effect of Caloric Restriction and AMPK Activation on Hepatic Nuclear Receptor, Biotransformation Enzyme, and Transporter Expression in Lean and Obese Mice

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Abstract

Purpose

Fatty liver alters liver transporter expression. Caloric restriction (CR), the recommended therapy to reverse fatty liver, increases Sirtuin1 deacetylase activity in liver. This study evaluated whether CR and CR mimetics reversed obesity-induced transporter expression in liver and hepatocytes.

Methods

mRNA and protein expression was determined in adult lean (lean) and leptin-deficient obese (OB) mice fed ad libitum or placed on 40% (kCal) reduced diet. Hepatocytes were isolated from lean and OB mice, treated with AMP Kinase activators, and gene expression was determined.

Results

CR decreased Oatp1a1, Oatp1b2, and Abcb11 mRNA expression in lean, but not OB mice. CR increased Abcc2 mRNA OB livers, whereas protein expression increased in both genotypes. CR increased Abcc3 protein expression increased in OB livers. CR did not alter Abcc1, 4 and 5 mRNA expression in lean mice but decreased expression in livers of OB mice. CR increased Abcc4 protein in lean, but not OB mice.

Conclusions

CR restriction reversed the expression of some, but not all transporters in livers of OB mice. Overall, these data indicate a potential for CR to restore some hepatic transporter changes in OB mice, but suggest a functional leptin axis is needed for reversal of expression for some transporters.

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Abbreviations

Abcc:

ATP-Binding Cassette, sub-family C

Ahr:

Aryl hydrocarbon receptor

AL:

ad libitum

AMPK:

AMP Kinase

Car:

Constitutive androstane receptor

CR:

caloric restriction

Creb:

cAMP response element binding protein

Cyp:

Cytochrome P450

Fxr:

Farnesoid x receptor

Gclc:

Glutamate-cysteine ligase, catalytic subunit

Gsta1:

Glutathione S-transferase a1

Ho-1:

Heme oxygenase 1

Nqo1:

NADPH:quinone oxidoreductase

NR:

nuclear receptor

Nrf2:

Nuclear factor (erythroid-derived 2)-like 2

Oatp:

Organic anion transporting polypeptide (Oatp)

Pepck:

Phosphoenolpyruvate carboxykinase

PGC1α:

Peroxisome proliferator-activated receptor-γ coactivator-1α

PPAR:

Peroxisome proliferator-activated receptor

PXR:

Pregnane X receptor

RXR:

Retinoid X receptor

Sod1:

Superoxide dismutase 1

Srebp-1c:

Sterol regulatory element binding protein 1c

TF:

transcription factor

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Acknowledgments

This work was presented, in part, at the annual Society of Toxicology (SOT) meeting, March 7-11, 2010, Salt Lake City, Utah

This work was supported by grants to from the National Institute of Health [4R01ES016042 and 5K22ES013782 to ALS], and also supported, in part, by Rhode Island IDeA Network of Biomedical Research Excellence [Award # P20RR016457] from the National Center for Research Resources, National Institute of Health.

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

    Supriya R. Kulkarni, Jialin Xu, Ajay C. Donepudi, Wei Wei & Angela L. Slitt

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  1. Supriya R. Kulkarni
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Correspondence to Angela L. Slitt.

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Kulkarni, S.R., Xu, J., Donepudi, A.C. et al. Effect of Caloric Restriction and AMPK Activation on Hepatic Nuclear Receptor, Biotransformation Enzyme, and Transporter Expression in Lean and Obese Mice. Pharm Res 30, 2232–2247 (2013). https://doi.org/10.1007/s11095-013-1140-2

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