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.

Hif-2α Promotes Degradation of Mammalian Peroxisomes by Selective Autophagy

“…Changes in the fatty acid profile of Vhl À/À /Hif1a À/À livers were similar as in Vhl À/À livers ( Figure 2G; Table S2). Importantly, fatty acid profiles from Vhl À/À and Vhl À/À /Hif1a À/À livers were comparable to P13 peroxisomedeficient Pex2 À/À livers that also displayed steatosis ( Figure S4A) (Keane et al, 2007;Kovacs et al, 2012).…”

Hepatic dysfunction in peroxisomal disorders

“…These changes closely follow the loss of functional peroxisomes in time, illustrating the dependence of other cellular compartments on intact peroxisomes [81,82]. Mitochondria are affected at several levels, including the mtDNA, the activity of the respiratory complexes and the structure of the inner membrane whereas matrix function is preserved or even increased [21,83].…”

“…It was also shown that the ER compartment is enlarged in peroxisome deficient hepatocytes and mediators of ER stress signaling pathways (PERK, ATF4) are upregulated [80][81][82]. It was suggested that these ER perturbations deregulate SREBP signaling and cholesterol homeostasis [82].…”

“…It was suggested that these ER perturbations deregulate SREBP signaling and cholesterol homeostasis [82].…”

Molecular Mechanisms and Physiological Significance of Organelle Interactions and Cooperation

“…Indirect consequences of reduced peroxisomal metabolism like activation of ER stress pathways and mitochondrial dysfunction might also contribute to alterations in lipid metabolism Kovacs et al, 2009Kovacs et al, , 2012. Toxic effects of accumulation of peroxisomal β-oxidation substrates might damage the mitochondrial compartment by altering the lipid composition of mitochondrial membranes.…”