Downregulation of Lactoferrin by PPARalpha Ligands: Role in Perturbation of Hepatocyte Proliferation and Apoptosis

Abstract

PPARalpha (peroxisome proliferator activated receptor alpha) is a transcription factor that mediates the rodent liver tumorigenic responses to peroxisome proliferators via regulation of genes that remain to be identified. Using microarray gene expression profiling of mRNA from wild type versus PPARalpha null mice, we detected a 3- to 7-fold downregulation of hepatic lactoferrin (LF) in response to the PP, diethylhexylphthalate (DEHP; 1150 mg/kg). Northern blot analyses confirmed a significant downregulation of LF mRNA by DEHP in wild type mouse liver. Since LF has been reported to repress tumor necrosis factor-alpha (TNF-alpha), LF downregulation by PPs may permit TNF-alpha levels to rise, enhancing hepatocyte survival and proliferation. To test this hypothesis, we asked if exogenous LF could prevent the perturbation of hepatocyte growth by PPs but not by TNF-alpha. In vitro, the PPs monoethylhexylphthalate (MEHP; 500 microM, the active metabolite of DEHP) and another PP, nafenopin (50 microM) or exogenous TNF-alpha (5000 U/ml) induced hepatocyte proliferation and suppressed apoptosis. LF (200 microM) blocked the growth but not the peroxisome proliferation response to PPs but could not block the growth response to TNF-alpha. Immunocytochemistry using specific antibodies to LF but also to transferrin (TF), a related gene previously shown to contain a PP response element (PPRE), demonstrated that both LF and TF are expressed in murine liver. Furthermore, both were downregulated by DEHP in both wild type and PPARalpha null mouse liver. These data suggest that the regulation of iron binding proteins by PPARalpha ligands plays a role in PP-mediated liver growth, but not in peroxisome proliferation.

Pooling samples within microarray studies: a comparative analysis of rat liver transcription response to prototypical toxicants

“…The implications of elevated proteasomal transcripts are not clear; however, regulation by all compounds of a family of transcripts indicates a treatmentrelated effect. DEHP toxicity has been shown to involve apoptosis (20), while VPA has been shown to induce oxidative stress in rats (41). Clearly, additional insight into these toxicants' mechanisms of action was gained utilizing the individual approach.…”

The miR-214-5p/Lactoferrin/miR-224-5p/ADAM17 Axis Is Involved in Goat Mammary Epithelial Cells’ Immune Regulation

“…The tissue sections were cut into cubes of about 1 mm 3 and cultured in a petri dish at 37 °C in 5% CO 2 . The medium was configured according to the formula of our laboratory [ 16 ]. The culture medium was changed every 2 days until epithelial cells separated from the tissue block.…”

Key Issues in the Role of Peroxisome Proliferator–Activated Receptor Agonism and Cell Signaling in Trichloroethylene Toxicity

“…Proteins identified as being regulated by PPARα were known to be involved not only in lipid metabolism pathways but also in amino acid and carbohydrate metabolism, mitochondrial bioenergetics, and stress responses, including several genes not previously reported to be regulated by PPARα. Hasmall et al (2002) reported a 3- to 7-fold down-regulation of lactoferrin mRNA in response to DEHP in wild-type versus PPAR α knockout mice. The authors suggested that the regulation of iron-binding proteins by PPARα ligands plays a role in peroxisome proliferator–mediated liver growth but not in PP.…”