Alteration of Hepatic but Not Renal Transporter Expression in Diet-Induced Obese Mice

More, Vijay R.; Slitt, Angela L.

doi:10.1124/dmd.110.037507

Cited by 38 publications

(22 citation statements)

References 45 publications

(47 reference statements)

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“…The up-regulation of Slco10a1 could increase hepatobiliary clearance and normalise serum bile acid level. Likewise, More & Slitt (33) reported an increase in the hepatic expression levels of Abcc2 as well as Slco1a4 in a diet-induced murine model of obesity. In addition, Martin et al (13) reported an increase in the mRNA levels of Abcc2, Abcb11 and FXR in an ob/ob mouse model.…”

Section: Discussionmentioning

confidence: 99%

Effect of a high-fat diet on the hepatic expression of nuclear receptors and their target genes: relevance to drug disposition

et al. 2015

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More than 1·4 billion individuals are overweight or obese worldwide. While complications often require therapeutic intervention, data regarding the impact of obesity on drug disposition are scarce. As the influence of diet-induced obesity on drug transport and metabolic pathways is currently unclear, the objective of the present study was to investigate the effect of high fat feeding for 13 weeks in female Sprague -Dawley rats on the hepatic expression of the nuclear receptors pregnane X receptor (PXR), constitutive androstane receptor (CAR), liver X receptor (LXR) and farnesoid X receptor (FXR) and several of their target genes. We hypothesised that high fat feeding would alter the gene expression of major hepatic transporters through a dysregulation of the expression of the nuclear receptors. The results demonstrated that, along with a significant increase in body fat and weight, a high-fat diet (HFD) induced a significant 2-fold increase in the expression of PXR as well as a 2-, 5-and 2·5-fold increase in the hepatic expression of the PXR target genes Abcc2, Abcb1a and Cyp3a2, respectively (P,0·05). The expression levels of FXR were significantly increased in rats fed a HFD in addition to the increase in the expression levels of FXR target genes Abcb11 and Abcb4. The expression levels of both LXRa and LXRb were slightly but significantly increased in rats fed a HFD, and the expression levels of their target genes Abca1 and Abcg5, but not Abcg8, were significantly increased. The expression of the nuclear receptor CAR was not significantly altered between the groups. This suggests that a HFD may induce changes in the hepatobiliary transport and metabolism of endogenous and exogenous compounds.

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Section: Discussionmentioning

confidence: 99%

Effect of a high-fat diet on the hepatic expression of nuclear receptors and their target genes: relevance to drug disposition

et al. 2015

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“…Oatp1a4 and 2b1 western blots were attempted, but not successful. Details of the antibodies used are as previously published (25). …”

Section: Methodsmentioning

confidence: 99%

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

Kulkarni

Donepudi

et al. 2013

Pharm Res

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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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“…Regulation of hepatic and renal transporters has been investigated in rodent models of diabetes and obesity (Cheng et al, 2008; More and Slitt, 2011). In a study of obese mice with Type II diabetes (ob/ob strain), mRNA and protein expression of uptake transporters were decreased in the liver (Cheng et al, 2008).…”

Section: 1 Introductionmentioning

confidence: 99%

Renal efflux transporter expression in pregnant mice with Type I diabetes

Yacovino

Aleksunes

2012

Toxicology Letters

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Prior research suggests that sex hormones and metabolic changes, such as obesity and hyperglycemia, can alter renal transporter expression in rodents. The purpose of this study was to characterize the expression of kidney efflux transporters and regulatory transcription factors in response to Type I diabetes and pregnancy. Female C57BL/6 mice were treated with multiple low doses of streptozotocin (STZ) to induce hyperglycemia and then mated with normoglycemic male mice. Transporter mRNA and protein expression were quantified in kidneys from vehicle- and STZ-treated non-pregnant and pregnant mice on gestation day 14. Pregnancy decreased the expression of Mdr1b, Mrp4, and 5 proteins and increased the mRNA and protein expression of Mrp3 by 50 to 60%. STZ treatment elevated Mrp1, 2, 4, and 5 and reduced Mrp3, 6, and Mdr1b mRNA and/or protein in non-pregnant mice. Pregnancy had little effect on STZ-mediated changes in renal efflux transporter expression. Transcriptional profiles of Hnf1α, PXR, AhR, and Nrf2 were altered in patterns similar to some efflux transporters suggesting potential involvement in their regulation. Taken together, these results suggest that renal drug efflux transporters and regulatory signaling pathways are altered by endocrine and metabolic changes that occur during pregnancy and Type I diabetes.

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Alteration of Hepatic but Not Renal Transporter Expression in Diet-Induced Obese Mice

Cited by 38 publications

References 45 publications

Effect of a high-fat diet on the hepatic expression of nuclear receptors and their target genes: relevance to drug disposition

Effect of a high-fat diet on the hepatic expression of nuclear receptors and their target genes: relevance to drug disposition

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

Renal efflux transporter expression in pregnant mice with Type I diabetes

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