Regulation of cell proliferation and cell death by peroxisome proliferators

Abstract

Peroxisome proliferators cause increases in liver mass in rodents, linked to changes in cell proliferation and cell death of hepatocytes. These effects are reversible upon cessation of treatment. The underlying mechanism of the response in rodent liver is complex, but clearly dependent on activation of the nuclear receptor PPARalpha. Other signaling pathways have been implicated in this response, but evidence is mixed. Differing sensitivity among various species to effects of peroxisome proliferators has been associated with differences in PPARalpha expression and function. Changes in cell proliferation and cell death in neoplastic hepatocytes also have been found in liver tumors caused by long-term treatment with peroxisome proliferators.

Eicosapentaenoic acid lowers plasma and liver cholesterol levels in the presence of peroxisome proliferators-activated receptor alpha

“…PPARs play pleiotropic roles in lipid and carbohydrate metabolism (Bocher et al, 2002;Lefebvre et al, 2006), cell proliferation and differentiation (Michalik et al, 2002;Cattley, 2003), and inflammation (Duez et al, 2001;Clark, 2002). We studied physiological and pathophysiological functions of PPARα using PPARα-null mice, and clarified hepatic and cardiac transcriptional regulation for mitochondrial fatty acid β-oxidation (Aoyama et al, 1998;Watanabe et al, 2000), and lipid consumption in the kidney (Kamijo et al, 2002).…”

Long-term administration of DHEA prevents fat deposition in rats fed a high-fat diet

“…The present study also showed that the PPARα mRNA level was decreased in 50 and 100 mg/kg DHEA treatment groups, this was accompanied by the decreased expression of ACO and LCPT-1. PPARα is a member of the nuclear hormone receptor family of transcription factors (Cattley 2003), which regulates the transcription of genes that encode peroxisomal and certain mitochondrial enzymes for fatty acid oxidation (Bremer 2001). Rocchi and Auwerx (2000) have demonstrated that PPARα can increase the rate of fatty acid β-oxidation by increasing the expression of several PPARα target genes, such as CPT-I and ACO.…”

Mechanism of action of liver growth induced by peroxisome proliferators

“…However, peroxisome proliferation involves several other changes that are not strictly 'peroxi-somal', and these changes involve metabolic functions in the cell, as well as shifts the rate of entry of hepatocytes into cell proliferation (mitosis) and cell death (apoptosis) (Cattley, 2003).…”

“…Among the hypolipidemic drugs studied, clofibrate (ester), clofibric acid, and ciprofibrate are in clinical use (Cattley, 2003). Other hypolipidemic drugs include WY-14,643, BR-931, methylclofenapate, and nafenopin, compounds that were discovered in the search for more potent drug candidates, but were not entered into clinical use.…”

“…Among the non drug compounds used in research is the phthalate ester plasticizer di-(2-ethylhexyl) phthalate (DEHP), which is often used because it is cheap, available with high purity, and easy to dose (Cattley, 2003).…”