Peroxisome Deficiency Causes a Complex Phenotype because of Hepatic SREBP/Insig Dysregulation Associated with Endoplasmic Reticulum Stress

Abstract

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.

Hepatic dysfunction in peroxisomal disorders

“…Similar to the few observations in patients with PBD, generalized and conditional mouse models lacking PEX5 or PEX2 in hepatocytes exhibit mitochondrial and ER alterations and lipid accumulations [16,21,80]. These changes closely follow the loss of functional peroxisomes in time, illustrating the dependence of other cellular compartments on intact peroxisomes [81,82].…”

“…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].…”

Plasmalogens the neglected regulatory and scavenging lipid species

“…If the cell cannot achieve these goals autophagy and apoptosis are induced (Schroder and Kaufman, 2005). ER stress has been experimentally observed in a Pex2−/− mouse model for peroxisomal biogenesis disorders (PBD) supporting the protective function of plasmalogens in oxidative stress (Kovacs et al, 2009). Furthermore high levels of lysoplasmalogens inhibit NaK-ATPase (Schonefeld et al, 1996) and lack of plasmalogens may result in impaired Ca 2+ release, intracellular Ca 2+ overload and ER stress (Hale et al, 1998).…”

The peroxisome: an update on mysteries

“…As a consequence, Pex5 knockout mice lose body weight despite increased food intake. Disruption of peroxisome function, however, seems to compromise not only carbohydrate but also cholesterol metabolism, which is regulated by the sterol regulatory element-binding protein (SREBP) family of transcription factors (Kovacs et al 2004(Kovacs et al , 2009). Hepatocytes of peroxisome-deficient Pex2 -/-mice have been reported to experience ER stress, which in turn disturbs the expression of SREBP-2, SREBP-1c and Insig-2a, leading to further deregulation of endogenous sterol response pathways.…”