Localization of the pre-squalene segment of the isoprenoid biosynthetic pathway in mammalian peroxisomes

Abstract

Previous studies have indicated that the early steps in the isoprenoid/cholesterol biosynthetic pathway occur in peroxisomes. However, the role of peroxisomes in cholesterol biosynthesis has recently been questioned in several reports concluding that three of the peroxisomal cholesterol biosynthetic enzymes, namely mevalonate kinase, phosphomevalonate kinase, and mevalonate diphosphate decarboxylase, do not localize to peroxisomes in human cells even though they contain consensus peroxisomal targeting signals. We re-investigated the subcellular localization of the cholesterol biosynthetic enzymes of the pre-squalene segment in human cells by using new stable isotopic techniques and data computations with isotopomer spectral analysis, in combination with immunoXuorescence and cell permeabilization techniques. Our present Wndings clearly show and conWrm previous studies that the pre-squalene segment of the cholesterol biosynthetic pathway is localized to peroxisomes. In addition, our data are consistent with the hypothesis that acetyl-CoA derived from peroxisomal -oxidation of very long-chain fatty acids and medium-chain dicarboxylic acids is preferentially channeled to cholesterol synthesis inside the peroxisomes without mixing with the cytosolic acetyl-CoA pool.

Peroxisomes and peroxisomal disorders: The main facts

“…Further conversion of HMG-CoA to mevalonate might take place both in the ER and peroxisomes, although recent studies show contradictory results (Kovacs et al, 2007). However, the following conversion of mevalonate to farnesyl diphosphate (FPP) occurs predominantly in the peroxisomes.…”

“…Although HMG-CoA reductase is lacking of peroxisomal targeting information, a number of studies indicate that it is located not only in the ER but also in peroxisomes (Keller et al, 1985;Keller, 1986;Engfelt et al, 1997; reviewed by Olivier et al, 2000 andKovacs et al, 2007).…”

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

“…The pre-squalene segment of the cholesterol biosynthetic pathway is localized to peroxisomes, and acetyl-CoA derived from peroxisomal ␤-oxidation of very long-chain fatty acids and medium-chain dicarboxylic acids is channeled preferentially to cholesterol synthesis inside the peroxisomes (11).…”

Synthesis and Biosynthetic Trafficking of Membrane Lipids

“…Sterol synthesis by microsomal enzymes is highly efficient to the extent that organization via multienzyme complex(es) have been suggested (Gaylor and Delwiche 1973). However, several of the cholesterol biosynthetic enzymes are also found in other compartments, such as peroxisomes (presqualene steps [Kovacs et al 2007]), nucleus (Wu et al 2004), or nuclear envelope (Zwerger et al 2010) (sterol 24-reductase and lamin B receptor, respectively), lipid droplets (NAD(P)H steroid dehydrogenase like protein) (Ohashi et al 2003), and the Golgi complex (Cotman et al 2004) (lanosterol 14 a-demethylase). What functions this compartmentalization of the enzymes might serve, is not known.…”