Divergence between human and murine peroxisome proliferator-activated receptor alpha ligand specificities

Oswal, Dhawal Pravin; Balanarasimha, Madhumitha; Loyer, Jeannette K.; Bedi, Shimpi; Soman, Frances L.; Rider, S. Dean; Hostetler, Heather A.

doi:10.1194/jlr.m035436

Cited by 30 publications

(66 citation statements)

References 36 publications

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“…The nuclear receptors have a DNA binding domain and a ligand binding domain. Species differences in nuclear receptor ligand specificity have been observed (Oswal et al, 2013). In particular, mouse PXR is not activated by rifampicin (RIF), a strong ligand of human PXR.…”

Section: Introductionmentioning

confidence: 98%

Expression of hepatic cytochrome P450s and UDP-glucuronosyltransferases in PXR and CAR double humanized mice treated with rifampicin

Lee

Kim³

et al. 2015

Toxicology Letters

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Section: Introductionmentioning

confidence: 98%

Expression of hepatic cytochrome P450s and UDP-glucuronosyltransferases in PXR and CAR double humanized mice treated with rifampicin

Lee

Kim³

et al. 2015

Toxicology Letters

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“…Recently, we have demonstrated that LCFA and their thioesters (long-chain fatty acyl-CoA; LCFA-CoA) constitute high-affinity endogenous ligands of human PPARα (hPPARα) and mouse PPARα (mPPARα). Such ligand binding induces PPARα conformational changes and increases transactivation, consistent with expectations for an endogenous ligand of a ligand-activated nuclear receptor [7]. Thus, PPARα in conjunction with LCFA and their metabolites could serve to regulate metabolic pathways governing fuel utilization, storage, transport and mobilization.…”

Section: Introductionmentioning

confidence: 55%

“…Thus, PPARα in conjunction with LCFA and their metabolites could serve to regulate metabolic pathways governing fuel utilization, storage, transport and mobilization. However, we also reported differences in binding affinities and the extent of ligand-induced transactivation between mPPARα and hPPARα in response to saturated LCFA [7]. …”

Section: Introductionmentioning

confidence: 99%

“…For example, a single amino acid change in the mouse PPARα-LBD (E282) results in altered activity of the protein [19], and a valine to methionine substitution in human PPARα (V444M) produced PPARδ ligand binding characteristics, resulting in loss of fibrate responsiveness [20]. While we have reported differences in mPPARα and hPPARα in response to saturated LCFA [7], the goal of this study was to explore the mechanisms underlying such divergence. We have used methods including: molecular modeling and in silico docking, mutagenesis, spectrofluorometry, circular dichroism spectroscopy and transactivation studies to identify a single amino acid change at position 272 that is largely responsible for the altered saturated LCFA binding.…”

Section: Introductionmentioning

confidence: 99%

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A single amino acid change humanizes long-chain fatty acid binding and activation of mouse peroxisome proliferator-activated receptor α

Oswal

Alter

Rider

et al. 2014

Journal of Molecular Graphics and Modelling

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Peroxisome proliferator-activated receptor α (PPARα) is an important regulator of hepatic lipid metabolism which functions through ligand binding. Despite high amino acid sequence identity (>90%), marked differences in PPARα ligand binding, activation and gene regulation have been noted across species. Similar to previous observations with synthetic agonists, we have recently reported differences in ligand affinities and extent of activation between human PPARα (hPPARα) and mouse PPARα (mPPARα) in response to long chain fatty acids (LCFA). The present study was aimed to determine if structural alterations could account for these differences. The binding of PPARα to LCFA was examined through in silico molecular modeling and docking simulations. Modeling suggested that variances at amino acid position 272 are likely to be responsible for differences in saturated LCFA binding to hPPARα and mPPARα. To confirm these results experimentally, LCFA binding, circular dichroism, and transactivation studies were performed using a F272I mutant form of mPPARα. Experimental data correlated with in silico docking simulations, further confirming the importance of amino acid 272 in LCFA binding. Although the driving force for evolution of species differences at this position are yet unidentified, this study enhances our understanding of ligand-induced regulation by PPARα and demonstrates the efficacy of molecular modeling and docking simulations.

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“…The molecular mechanism responsible for differential effects is unknown, but is most likely related to D2-dependent peroxisomal metabolism of fatty acids. LCFAs, VLCFAs, and their coenzyme A thioesters are putative endogenous PPARa ligands with varying affinity for human and mouse PPARs (Lin et al, 1999;Hostetler et al, 2005Hostetler et al, , 2006Oswal et al, 2013). We previously demonstrated that the absence of D2 altered endogenous LCFA and VLCFA contents in mouse brain and adipose tissues (Fourcade et al, 2009;Liu et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

ABCD2 Alters Peroxisome Proliferator-Activated ReceptorαSignaling In Vitro, but Does Not Impair Responses to Fenofibrate Therapy in a Mouse Model of Diet-Induced Obesity

Liu

Liang

et al. 2014

Mol Pharmacol

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Fenofibrate is a peroxisome proliferator-activated receptor (PPAR) a ligand that has been widely used as a lipid-lowering agent in the treatment of hypertriglyceridemia. ABCD2 (D2) is a peroxisomal long-chain acyl-CoA transporter that is highly induced by fenofibrate in the livers of mice. To determine whether D2 is a modifier of fibrate responses, wild-type and D2-deficient mice were treated with fenofibrate for 14 days. The absence of D2 altered expression of gene clusters associated with lipid metabolism, including PPARa signaling. Using 3T3-L1 adipocytes, which express high levels of D2, we confirmed that knockdown of D2 modified genomic responses to fibrate treatment. We next evaluated the impact of D2 on effects of fibrates in a mouse model of diet-induced obesity. Fenofibrate treatment opposed the development of obesity, hypertriglyceridemia, and insulin resistance. However, these effects were unaffected by D2 genotype. We concluded that D2 can modulate genomic responses to fibrates, but that these effects are not sufficiently robust to alter the effects of fibrates on diet-induced obesity phenotypes.

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Divergence between human and murine peroxisome proliferator-activated receptor alpha ligand specificities

Cited by 30 publications

References 36 publications

Expression of hepatic cytochrome P450s and UDP-glucuronosyltransferases in PXR and CAR double humanized mice treated with rifampicin

Expression of hepatic cytochrome P450s and UDP-glucuronosyltransferases in PXR and CAR double humanized mice treated with rifampicin

A single amino acid change humanizes long-chain fatty acid binding and activation of mouse peroxisome proliferator-activated receptor α

ABCD2 Alters Peroxisome Proliferator-Activated ReceptorαSignaling In Vitro, but Does Not Impair Responses to Fenofibrate Therapy in a Mouse Model of Diet-Induced Obesity

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