Peroxisomes: a nexus for lipid metabolism and cellular signaling

Abstract

Peroxisomes are often dismissed as the cellular hoi polloi, relegated to cleaning up reactive oxygen chemical debris discarded by other organelles. However, their functions extend far beyond hydrogen peroxide metabolism. Peroxisomes are intimately associated with lipid droplets and mitochondria, and their ability to carry out fatty acid oxidation and lipid synthesis, especially the production of ether lipids, may be critical for generating cellular signals required for normal physiology. Here, we review the biology of peroxisomes and their potential relevance to human disorders including cancer, obesity-related diabetes, and degenerative neurologic disease.

Figure 1. Structure and functions of peroxisomes

The peroxisome is a single membrane-enclosed organelle that plays an important role in metabolism. The main metabolic functions of peroxisomes in mammalian cells include β-oxidation of very long chain fatty acids, α-oxidation of branched chain fatty acids, synthesis of bile acids and ether-linked phospholipids and removal of reactive oxygen species. Peroxisomes in many, but not all, cell types contain a dense crystalline core of oxidative enzymes.

Figure 2

A. Potential pathways to peroxisomal biogenesis. Peroxisomes are generated autonomously through division of pre-existing organelles (top) or through a de novo process involving budding from the ER followed by import of matrix proteins (bottom). B. Peroxisomal membrane protein import. Peroxisomal membrane proteins (PMPs) are imported post-translationally to the peroxisomal membrane. Pex19 is a soluble chaperone that binds to PMPs and transports them to the peroxisomal membrane, where it docks with a complex containing Pex16 and Pex3. Following insertion of the PMP, Pex19 is recycled back to the cytosol.

Figure 3. Chemical structures of diacyl- and ether-linked phospholipids

In conventional diacyl phospholipids, fatty acyl side chains are linked to the sn-1 and sn-2 positions of the glycerol backbone by ester bonds. Ether-linked phospholipids are a special class of glycerophospholipids that have an alkyl chain attached to the sn-1 position by an ether bond. The sn-2 substituent of ether lipids is generally an ester-linked acyl chain as in diacylphospholipids. The headgroup of ether phospholipids is usually choline or ethanolamine. Some of the ether linked phospholipids have a cis double bond adjacent to the ether bond, and are referred to as alkenyl-acylphospholipids or more commonly as plasmalogens. According to convention, plasmalogen form of phospholipids have the prefix “plasmenyl”, as in plasmenylcholine. Alkyl-acylphospholipids have the prefix “plasmanyl”.

Figure 4. Acyl DHAP pathway of phospholipid synthesis

This pathway is obligatory for synthesis of ether-linked phospholipids and is also an alternative route for synthesis of diacylphospholipids. Phospholipid synthesis begins in peroxisomes and is completed in the ER. The pathway uses dihydroxacetone phosphate (DHAP), generated by glycerol 3-phosphate dehydrogenase (G3PDH)-mediated dehydrogenation of G3P, as a building block for the synthesis of phospholipids. Fatty acyl CoA produced by de novo lipogenesis is used by DHAPAT (DHAP acyltransferase) to acylate DHAP, or is reduced to a fatty alcohol by a peroxisomal membrane-associated fatty acyl CoA reductase in an NADPH-dependent reaction. The fatty alcohol is used by alkyl DHAP synthase (ADHAPS) to convert acyl DHAP to alkyl DHAP. Acyl DHAP or alkyl DHAP can be reduced to 1-acyl G3P (lysophosphatidic acid) or its ether lipid equivalent, 1-O-alkyl G3P (AGP), respectively, by acyl/alkyl DHAP reductase (also called PexRAP). The subsequent steps of phospholipid synthesis, including acylation at the sn-2 position, occur in the ER.

Figure 5. Relationship between peroxisomes and PPARγ

PPARγ is a key regulator of adipocyte differentiation as well as function and is activated by multiple endogenous ligands, including alkyl ether phospholipids, which are synthesized in peroxisomes. PPARγ exists as a heterodimer with RXR and regulates expression of a large number of genes harboring PPAR response elements (PPRE), including genes involved in adipogenesis, lipid metabolism, and glucose homeostasis. Emerging studies indicate that PPARγ also regulates the expression of genes involved in peroxisomal biogenesis, suggesting a feed-forward mechanism of PPARγ activation.