Functional Peroxisomes Are Essential for Efficient Cholesterol Sensing and Synthesis

Abstract

Cholesterol biosynthesis is a multi-step process involving several subcellular compartments, including peroxisomes. Cells adjust their sterol content by both transcriptional and post-transcriptional feedback regulation, for which sterol regulatory element-binding proteins (SREBPs) are essential; such homeostasis is dysregulated in peroxisome-deficient Pex2 knockout mice. Here, we compared the regulation of cholesterol biosynthesis in Chinese hamster ovary (CHO-K1) cells and in three isogenic peroxisome-deficient CHO cell lines harboring Pex2 gene mutations. Peroxisome deficiency activated expression of cholesterogenic genes, however, cholesterol levels were unchanged. 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) protein levels were increased in mutant cells, whereas HMGCR activity was significantly decreased, resulting in reduced cholesterol synthesis. U18666A, an inhibitor of lysosomal cholesterol export, induced cholesterol biosynthetic enzymes; yet, cholesterol synthesis was still reduced. Interestingly, peroxisome deficiency promoted ER-to-Golgi SREBP cleavage-activating protein (SCAP) trafficking even when cells were cholesterol-loaded. Restoration of functional peroxisomes normalized regulation of cholesterol synthesis and SCAP trafficking. These results highlight the importance of functional peroxisomes for maintaining cholesterol homeostasis and efficient cholesterol synthesis.

Murine deficiency of peroxisomal L-bifunctional protein (EHHADH) causes medium-chain 3-hydroxydicarboxylic aciduria and perturbs hepatic cholesterol homeostasis

“…We did, however, obtain evidence that peroxisomal DCA β-oxidation provides acetyl-CoA units for other biochemical pathways such as ketogenesis. (Charles et al 2020;Fidaleo et al 2011;Kovacs et al 2004Kovacs et al , 2009Martens et al 2008;Nicolas-Francès et al 2014), in line with our findings in the liver of Ehhadh KO mice. Our observations are consistent with previous reports of reduced cholesterol synthesis rates in skin fibroblasts from patients with peroxisomal disorders (Hodge et al 1991).…”

“…The role of peroxisomes in cholesterol metabolism remains a debated issue. In vitro and in vivo studies done in different models of peroxisomal deficiency have reported disturbances of cholesterol homeostasis and activation of the SREBP2 pathway (Charles et al 2020; Fidaleo et al 2011; Kovacs et al 2004, 2009; Martens et al 2008; Nicolas-Francès et al 2014), in line with our findings in the liver of Ehhadh KO mice. Our observations are consistent with previous reports of reduced cholesterol synthesis rates in skin fibroblasts from patients with peroxisomal disorders (Hodge et al 1991).…”

Defining upstream enhancing and inhibiting sequence patterns for plant peroxisome targeting signal type 1 using large‐scale in silico and in vivo analyses

“…The peroxisome is amazingly versatile in its metabolic function, as reflected by the existence of many taxa‐specific proteins and pathways (Charles et al., 2020; Pan et al., 2020; Parsons, 2004). This versatility makes prediction of peroxisomal proteins highly valuable because it may lead to the discovery of new metabolic pathways in different species (Pan et al., 2020; Reumann & Chowdhary, 2018).…”

Peroxisomes in intracellular cholesterol transport: from basic physiology to brain pathology

“…The role of peroxisomes in cholesterol biosynthesis has been a matter of controversy for years [12][13][14]. In fact, convincing evidence supporting a direct involvement of peroxisomes in cholesterol biosynthesis is still lacking, even in a latest study in favor of the viewpoint [15]. It is more likely that peroxisomes contribute to cholesterol homeostasis by transporting the molecule between different organelles and the plasma membrane (PM), which will be discussed in the later sections of this review.…”