Peroxisome deficiency-induced ER stress and SREBP-2 pathway activation in the liver of newborn PEX2 knock-out mice
- 作者：Werner J. Kovacs
- 关键词：VLCFA ; very long-chain fatty acid ; SREBP ; sterol regulatory element-binding protein ; SCAP ; SREBP cleavage-activating protein ; HMGCR ; 3-hydroxy-3-methylglutaryl-CoA reductase ; CoA ; coenzyme A ; ER ; endoplasmic reticulum ; Pex ; peroxin ; HDL ; high-density lipo
- 刊名：Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids
- 出版年：2012
- 期刊代码：18_13881981
- 类别：bio
- 出版时间：June, 2012
- 卷：1821
- 期：6
- 页码：895-907
- 文件大小：1441 K
摘要
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 Pex2p>鈭?鈭?/em> p> mice on a hybrid Swiss Webster 脳 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 Pex2p>鈭?鈭?/em> p> mice congenic on a 129S6/SvEv (129) genetic background, and substantial differences between newborn versus postnatal Pex2p>鈭?鈭?/em> p> mice in factors that activate ER stress. These differences extend to relationships between activation of genes regulated by SREBP-2 versus PPAR伪. The SREBP-2 pathway is induced in neonatal Pex2p>鈭?鈭?/em> p> livers from 129 and SW/129 strains, despite normal hepatic cholesterol levels. ER stress markers are increased in newborn 129 Pex2p>鈭?鈭?/em> p> 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 PPAR伪 activation in livers of newborn 129 and SW/129 Pex2p>鈭?鈭?/em> p> mice. Two-week-old wild-type mice treated with the peroxisome proliferator WY-14,643 show strong induction of PPAR伪-regulated genes and decreased expression of SREBP-2 and its target genes, further demonstrating that SREBP-2 pathway induction is not dependent on PPAR伪 activation. Lastly, there is no activation of either SREBP-2 or ER stress pathways in kidney and lung of newborn Pex2p>鈭?鈭?/em> p> mice, suggesting a parallel induction of these pathways in peroxisome-deficient mice. These findings establish novel associations between SREBP-2, ER stress and PPAR伪 pathway inductions.