Cholesterol biosynthesis and ER stress in peroxisome deficiency

Cholesterol biosynthesis is a multi-step process involving more than 20 enzymes in several subcellular compartments. The pre-squalene segment of the cholesterol/isoprenoid biosynthetic pathway is localized in peroxisomes. This review intends to highlight recent findings illustrating the important role peroxisomes play in cholesterol biosynthesis and maintenance of cholesterol homeostasis. Disruption of the Pex2 gene leads to peroxisome deficiency and widespread metabolic dysfunction. The Pex2−/− mouse model for Zellweger syndrome enabled us to evaluate the role of peroxisomes in cholesterol biosynthesis. These studies have shown that Pex2−/− mice exhibit low levels of cholesterol in plasma and liver. Pex2−/− mice were unable to maintain normal cholesterol homeostasis despite activation of SREBP-2, the master transcriptional regulator of cholesterol biosynthesis, and increased protein levels and activities of cholesterol biosynthetic enzymes. The SREBP-2 pathway remained activated even after normalization of hepatic cholesterol levels in response to bile acid feeding as well as in extrahepatic tissues and the liver of neonatal and longer surviving Pex2 mutants, where cholesterol levels were normal. Several studies have shown that endoplasmic reticulum (ER) stress can dysregulate lipid metabolism via SREBP activation independently of intracellular cholesterol concentration. We demonstrated that peroxisome deficiency activates endoplasmic reticulum stress pathways in Pex2−/− mice, especially the integrated stress response mediated by PERK and ATF4 signaling, and thereby leads to dysregulation of the SREBP-2 pathway. Our findings suggest that functional peroxisomes are necessary to prevent chronic ER stress and dysregulation of the endogenous sterol response pathway. The constitutive activation of ER stress pathways might contribute to organ pathology and metabolic dysfunction in peroxisomal disorder patients.