The Effects of Peroxisome Proliferators on Global Lipid Homeostasis and the Possible Significance of These Effects to Other Responses to These Xenobiotics

Abstract

Peroxisome proliferators (PPs) have been shown to regulate hepatic lipid metabolism via activation of the peroxisome proliferator-activated receptor alpha (PPAR-alpha). Recent studies have revealed that PPs also exert considerable influence on certain extrahepatic tissues, including adipose tissue and lymphoid organs, in an indirect fashion. Inhibition of the proliferation of thymocytes and splenocytes and alteration of fatty acid uptake into and release from adipose tissue might be consequences of the hypolipidemic effect of PPs involving both PPARalpha-dependent and -independent pathways. Exposure to PPs reduces the cholesterol content of circulating low-density lipoprotein (LDL), which is the major supply of this steroid to most peripheral tissues. In addition, PPs increase serum levels of high-density lipoprotein (HDL), which extracts cholesterol from peripheral tissues and returns it to the liver, thereby further decreasing the cholesterol content of peripheral tissues. This net flux of cholesterol from extrahepatic tissues to the liver represents a change in global lipid homeostasis. In normal healthy young mice, this hypolipidemic effect could result in loss of cholesterol and other lipids from peripheral tissues (e.g., adipose tissue, thymus, and spleen), especially from plasma membrane caveolae, which might perturb normal cellular signaling and result in tissue atrophy. On the other hand, the increased hepatic cholesterol content in the hepatocyte plasma membrane might actually enhance signaling, playing a role in the liver hypertrophy and hepatocarcinogenecally associated with long-term PP treatment. In conclusion, it is important to consider the systemic effects of PPs, rather than to focus on the liver alone.

Mechanisms underlying the anti-androgenic effects of diethylhexyl phthalate in fetal rat testis

“…PPAR agonists increase the flux of cholesterol from extrahepatic tissues to the liver, as reviewed by Xie et al (2002). Corresponding to this, reduced serum cholesterol was observed in adult male rats dosed with 125-1000 mg/kg bw/day of DEHP for 9 weeks (Dalgaard et al, 2000).…”

“…SF-1 is known to regulate the expression of genes involved in steroidogenesis, and PPARs are nuclear receptors that among many other functions regulate genes involved in cholesterol uptake and transport (Xie et al, 2002). A role for PPARs in the testicular toxicity of phthalates may be speculated, as the most testis toxic phthalates are strong PPAR activators (reviewed by Corton and Lapinskas, 2005).…”

Disruption of Hepatic Lipid Homeostasis in Mice after Amiodarone Treatment Is Associated with Peroxisome Proliferator-Activated Receptor-αTarget Gene Activation

“…However, in addition to the dramatic effects on peroxisomal ␤-oxidation, constitutive levels of mitochondrial ␤-oxidation are also reduced in the PPAR␣(Ϫ/Ϫ) mouse model (Aoyama et al, 1998), demonstrating the importance of this protein in overall fatty acid homeostasis. Furthermore, many of the beneficial actions of fibrates, including hypolipidemia and anti-inflammatory and antiatherosclerotic effects, are common to both humans and rodents (Xie et al, 2002;Francis et al, 2003a). Determination of whether the present findings are relevant to amiodarone-induced hepatotoxicity in humans requires additional study.…”

Adverse Outcome Pathway: Peroxisome Proliferator-Activated Receptor α Activation and Reproductive Toxicity—Development and Application in Assessment of Endocrine Disruptors/Reproductive Toxicants

“…PPARs regulate genes involved in cholesterol uptake and transport. [44][45][46] The indirect link between PPARs and regulation of cholesterol transport in mitochondria derives from studies demonstrating PPARa-dependent control of TSPO. 45,46 PPARa is present in steroidogenic cells, for example, in testes during development as well as in adult testes 31,47 ; and modulation of its activity has been shown to impact on TSPO transcriptional activity.…”