title: Peroxisome deficiency-induced ER stress and SREBP-2 pathway activation in the liver of newborn PEX2 knock-out mice.
abstract: Disruption of the Pex2 gene leads to peroxisome deficiency and widespread metabolic dysfunction. We previously demonstrated that peroxisomes are critical for maintaining cholesterol homeostasis, using peroxisome-deficient Pex2(-/-) mice on a hybrid Swiss Webster×129S6/SvEv (SW/129) genetic background. Peroxisome deficiency activates hepatic endoplasmic reticulum (ER) stress pathways, leading to dysregulation of the endogenous sterol response mechanism. Herein, we demonstrate a more profound dysregulation of cholesterol homeostasis in newborn Pex2(-/-) mice congenic on a 129S6/SvEv (129) genetic background, and substantial differences between newborn versus postnatal Pex2(-/-) mice in factors that activate ER stress. These differences extend to relationships between activation of genes regulated by SREBP-2 versus PPARα. The SREBP-2 pathway is induced in neonatal Pex2(-/-) livers from 129 and SW/129 strains, despite normal hepatic cholesterol levels. ER stress markers are increased in newborn 129 Pex2(-/-) livers, which occurs in the absence of hepatic steatosis or accumulation of peroxins in the ER. Moreover, the induction of SREBP-2 and ER stress pathways is independent of PPARα activation in livers of newborn 129 and SW/129 Pex2(-/-) mice. Two-week-old wild-type mice treated with the peroxisome proliferator WY-14,643 show strong induction of PPARα-regulated genes and decreased expression of SREBP-2 and its target genes, further demonstrating that SREBP-2 pathway induction is not dependent on PPARα activation. Lastly, there is no activation of either SREBP-2 or ER stress pathways in kidney and lung of newborn Pex2(-/-) mice, suggesting a parallel induction of these pathways in peroxisome-deficient mice. These findings establish novel associations between SREBP-2, ER stress and PPARα pathway inductions.
authors.affiliation: Institute of Cell Biology, ETH Zuerich, CH-8093 Zuerich, Switzerland. werner.kovacs@cell.biol.ethz.ch
authors.forename: Werner J
authors.initials: WJ
authors.lastname: Kovacs
authors.forename: Khanichi N
authors.initials: KN
authors.lastname: Charles
authors.forename: Katharina M
authors.initials: KM
authors.lastname: Walter
authors.forename: Janis E
authors.initials: JE
authors.lastname: Shackelford
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Wikander
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Richards
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Fliesler
authors.forename: Skaidrite K
authors.initials: SK
authors.lastname: Krisans
authors.forename: Phyllis L
authors.initials: PL
authors.lastname: Faust
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D005260:Female; D015870:Gene Expression; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D008055:Lipids / Q000032:analysis / Q000097:blood; D008099:Liver / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D000074428:Peroxisomal Biogenesis Factor 2; D020675:Peroxisomes / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D008055:Lipids; D008565:Membrane Proteins; C000614231:PEX2 protein, mouse; D047493:PPAR alpha; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; D000074428:Peroxisomal Biogenesis Factor 2; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D006904:Hydroxymethylglutaryl-CoA Synthase