The Pollutant Diethylhexyl Phthalate Regulates Hepatic Energy Metabolism Via Species-Specific PPAR[alpha]-Dependent Mechanisms

By Feige, Jerome N.; Gerber, Alan et al. | Environmental Health Perspectives, February 2010 | Go to article overview

The Pollutant Diethylhexyl Phthalate Regulates Hepatic Energy Metabolism Via Species-Specific PPAR[alpha]-Dependent Mechanisms


Feige, Jerome N., Gerber, Alan, Casals-Casas, Cristina, Yang, Qian, Winkler, Carine, Bedu, Elodie, Bueno, Manuel, Gelman, Laurent, Auwerx, Johan, Gonzalez, Frank J., Desvergne, Beatrice, Environmental Health Perspectives


BACKGROUND: The modulation of energetic homeostasis by pollutants has recently emerged as a potential contributor to the onset of metabolic disorders. Diethylhexyl phthalate (DEHP) is a widely used industrial plasticizer to which humans are widely exposed. Phthalates can activate the three peroxisome proliferator--activated receptor (PPAR) isotypes on cellular models and induce peroxisome proliferation in rodents.

OBJECTIVES: In this study, we aimed to evaluate the systemic and metabolic consequences of DEHP exposure that have remained so far unexplored and to characterize the underlying molecular mechanisms of action.

METHODS: As a proof of concept and mechanism, genetically engineered mouse models of PPARs were exposed to high doses of DEHP, followed by metabolic and molecular analyses.

RESULTS: DEHP-treated mice were protected from diet-induced obesity via PPAR[alpha]-dependent activation of hepatic fatty acid catabolism, whereas the activity of neither PPAR[beta] nor PPAR[gamma] was affected. However, the lean phenotype observed in response to DEHP in wild-type mice was surprisingly abolished in PPAR[alpha]-humanized mice. These species differences are associated with a different pattern of coregulator recruitment.

CONCLUSION: These results demonstrate that DEHP exerts species-specific metabolic actions that rely to a large extent on PPAR[alpha] signaling and highlight the metabolic importance of the species-specific activation of PPAR[alpha] by xenobiotic compounds.

Key WORDS: DEHP, endocrine disruptor, metabolism, PPAR, species specificity. Environ Health Perspect 118:234-241 (2010). doi:10.1289/ehp.0901217 available via http://dx.doi.org/ [Online 8 October 2009]

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The prevalence of obesity and its associated metabolic complications has dramatically increased during the past decades; it has been suggested that this could, to some extent, be linked to the exposure to environmental pollutants, which coincidently increased during the same period (Baillie-Hamilton 2002; Grun and Blumberg 2007; Heindel 2003; Newbold et al. 2007). Endocrine disruptors constitute a wide class of chemicals that can affect human and animal populations by interfering with the synthesis, elimination, and mechanisms of action of hormones (Markey et al. 2002; Waring and Harris 2005). One of their key mechanisms of action is the modulation of gene expression programs by targeting the activity of a family of nuclear receptors that are activated by intracellular lipophilic hormones and mediators. The concept of endocrine disruption, which initially arose because of the interference with reproductive biology, is now gradually being broadened to other receptors implicated in different aspects of homeostasis (Tabb and Blumberg 2006).

Metabolic homeostasis requires a controlled balance between energy storage and use, and several nuclear receptors as well as their coregulators are instrumental in regulating these processes (Desvergne et al. 2006; Feige and Auwerx 2007). Among these, peroxisome proliferator--activated receptors (PPARs) play a prominent role by acting as lipid sensors that cooperate in different organs to adapt gene expression to a given metabolic status (Desvergne et al. 2004; Evans et al. 2004; Feige et al. 2006). PPAR[alpha] (NR1C1) is the founding member of the family and was initially isolated as the receptor inducing the hepatic proliferation of peroxisomes in rodents in response to synthetic chemicals. However, this function represents only a small subset of the physiologic functions regulated by this receptor. PPAR[alpha] and PPAR[beta]/[delta] (NR1C2, referred to here as PPAR[beta]) share partially overlapping functions in the control of catabolic metabolism by promoting fatty acid oxidation in tissues with high metabolic rates such as liver or muscle (Desvergne et al. 2004; Evans et al. 2004; Feige et al. 2006). In contrast, PPAR[gamma] (NR1C3) controls fat storage in adipose tissue by promoting differentiation and survival of adipocytes and also plays major roles in the control of insulin sensitivity (Lehrke and Lazar 2005). …

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