Peroxisome deficiency causes a complex phenotype because of hepatic SREBP/Insig dysregulation associated with endoplasmic reticulum stress.
Regulation of hepatic cholesterol biosynthesis, lipogenesis, and insulin signaling intersect at the transcriptional level by control of SREBP and Insig genes. We previously demonstrated that peroxisome-deficient PEX2-/- mice activate SREBP-2 pathways but are unable to maintain normal cholesterol homeostasis. In this study, we demonstrate that oral bile acid treatment normalized hepatic and plasma cholesterol levels and hepatic cholesterol synthesis in early postnatal PEX2 mutants, but SREBP-2 and its target gene expressions remained increased. SREBP-2 pathway induction was also observed in neonatal and longer surviving PEX2 mutants, where hepatic cholesterol levels were normal. Abnormal expression patterns for SREBP-1c and Insig-2a, and novel regulation of Insig-2b, further demonstrate that peroxisome deficiency widely affects the regulation of related metabolic pathways. We have provided the first demonstration that peroxisome deficiency activates hepatic endoplasmic reticulum (ER) stress pathways, especially the integrated stress response mediated by PERK and ATF4 signaling. Our studies suggest a mechanism whereby ER stress leads to dysregulation of the endogenous sterol response mechanism and concordantly activates oxidative stress pathways. Several metabolic derangements in peroxisome-deficient PEX2-/- liver are likely to trigger ER stress, including perturbed flux of mevalonate metabolites, altered bile acid homeostasis, changes in fatty acid levels and composition, and oxidative stress.
Kovacs
Werner J
WJ
Institute of Cell Biology, ETH Zürich, CH-8093 Zürich, Switzerland. werner.kovacs@cell.biol.ethz.ch
Tape
Khanichi N
KN
Shackelford
Janis E
JE
Wikander
Thomas M
TM
Richards
Michael J
MJ
Fliesler
Steven J
SJ
Krisans
Skaidrite K
SK
Faust
Phyllis L
PL
D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D000074428:Peroxisomal Biogenesis Factor 2; D020675:Peroxisomes / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D015398:Signal Transduction / Q000235:genetics; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological
C081452:Atf4 protein, mouse; C506120:Insig2 protein, mouse; D008565:Membrane Proteins; C000614231:PEX2 protein, mouse; C497388:Srebf1 protein, mouse; C497391:Srebf2 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D000074428:Peroxisomal Biogenesis Factor 2; D051701:Activating Transcription Factor 4; D002784:Cholesterol