Peroxisomes cholesterol synthesis

Where does cholesterol synthesis take place All of the enzymes that convert acetyl-CoA to famesyl-PP have classically been thought of as cytosolic enzymes, with the exception of HMG-CoA reductase, which is typically depicted as an ER enzyme with the catalytic site facing the cytosol. Enzymes that convert famesyl-PP to cholesterol are classically described as microsomal. However, there is evidence that many of the enzymes in this pathway are also, or exclusively, peroxisomal [4]. 

Evidence in favor of peroxisomal involvement in cholesterol biosynthesis is the following. The molecular cloning of cDNAs encoding many of these enzymes revealed peroxisomal targeting sequences (W.J. Kovacs, 2003). The availability of specific antibodies allowed immunocytochemical localization to peroxisomes [4] (W.J. Kovacs, 2006). Fibroblasts from individuals with peroxisome biogenesis disorders showed reduced enzymatic activities of cholesterol biosynthetic enzymes, reduced rates of cholesterol synthesis, and lower cholesterol content [4]. Together these data suggest that peroxisomes may play a role in all steps in the cholesterol biosynthetic pathway, except the conversion of famesyl-PP to squalene. The latter reaction is catalyzed by squalene synthase, which is found. solely in the ER. 

It is not clear why cholesterol synthesis might be compartmentalized such that intermediates cycle between peroxisomes and the cytosol. One possibility is to permit the shunting of acetyl-CoA derived from peroxisomal p-oxidation of long-chain fatty acids preferentially into the cholesterol biosynthetic pathway rather than allowing it to be released into the cytosol for incorporation into cellular fatty acids (W.J. Kovacs, 2006). 

Cholesterol is formed biosynthetically from isopentenyl pyrophosphate (active isoprene). The majority of cholesterol in the body derives from de novo biosynthesis in the liver [1,2]. Cholesterol synthetic pathway has been assumed to occur primarily in the cytoplasm and endoplasmic reticulum (ER). However, more recent evidences have suggested that the enzymes, except squalene synthase, squalene epoxidase and oxidosqualene cyclase, are partly localized in the peroxisomes, which are essential for normal cholesterol synthesis [11]. 

In disorders which affect cholesterol synthesis (e.g, mevalonic aciduria, 7-dehydrocholesterol reductase deficiency [Smith-Lemli-Opitz syndrome]) there may be markedly reduced bile acid synthesis - these disorders are beyond the scope of his chapter. As indicated in section 3, the synthesis of bile acids involves conversion of C27 bile acids (cholestanoic acids) to their C24 analogues (cholanic acids) and this occurs by a process of )5-oxidation in the peroxisomes. Thus defective bile acid synthesis occurs in disorders of peroxisomal yff-oxidation and in disorders of peroxisome biogenesis. These disorders affect pathways other than the bile acid synthesis pathway and are discussed in Chap. 23. 

The enzymes in peroxisomes do not attack shorter-chain fatty acids the P-oxidation sequence ends at oc-tanoyl-CoA. Octanoyl and acetyl groups are both further oxidized in mitochondria. Another role of peroxisomal P-oxidation is to shorten the side chain of cholesterol in bile acid formation (Chapter 26). Peroxisomes also take part in the synthesis of ether glycerolipids (Chapter 24), cholesterol, and dolichol (Figure 26-2). 

Peroxisomes are small granules arranged in clusters around the smooth ER and glycogen stores. They contain about 50 enzymes, some of which are used in respiration, purine catabolism and alcohol metabolism. They are responsible for about 20% of the oxygen consumption in the liver via a respiratory pathway that produces heat rather than ATP as its product. They differ from lysosomes in that they are not formed from outgrowths of the Golgi apparatus but are self-replicating, rather like mitochondria. They also play an important role in the metabolism of fatty acids as well as cholesterol and bile acid synthesis. 

Cholesterol and phospholipids. Most lipids found in myelin are common to other cellular membranes. Cholesterol content is high and cholesterol esters are not present in normal myelin. Phospholipids are also common to other cellular membranes, except for the great quantity of ethanolamine phosphoglycerides in the plasmalogen form. The synthesis of plasmalogens is modified in Zellweger syndrome which is a peroxisomal syndrome that also increases VLCFA. This syndrome and other peroxisomal diseases may cause demyelination (Powers, 2005). 

Another forefront technique to improve the function of the stratum corneum and enhance barrier repair in dry skin is the use of epidermal differentiation. A number of hormone receptors for epidermal differentiation have been identified. This family of receptors includes retinoic acid receptors, the steroid receptors, the thyroid receptors, the Vitamin D receptors, the peroxisome proliferator-activated receptors, the farnesol-activated receptors, and the liver-activated receptors. It is reported that these transcription factors bind their respective ligands and regulate many of the aspects of cellular proliferation and differentiation. Examples of ligands for the last three transcription factors are fatty acids for the peroxisome proliferator-activated receptor, famesol for the farnesol-activated receptor, and hydroxylated cholesterol derivatives for the liver-activated receptor. The stimulation of epidermal differentiation stimulated the synthesis of involucrin, filaggrin, and the enzymes of the ceramide synthesis pathway (74). 

Statins, used predominantly in the treatment of hypercholesterolemia, act by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which regulates the synthesis of cholesterol. Statins are also agonists of peroxisome proliferator activated receptors (PPARs), which are part of the nuclear receptor superfamily and when activated, can suppress transcription of pro-inflammatory genes (Chinetti et al., 2000). In vitro and in vivo studies have shown that a decrease in serum cholesterol inhibits the production of beta amyloid and plaque (Simons et al., 1998 Fassbender et al.,... 

Although the mitochondria are the primary site of oxidation for dietary and storage fats, the peroxisomal oxidation pathway is responsible for the oxidation of very long-chain fatty acids, jS-methyl branched fatty acids, and bile acid precursors. The peroxisomal pathway also plays a role in the oxidation of dicarboxylic acids. In addition, it plays a role in isoprenoid biosynthesis and amino acid metabolism. Peroxisomes are also involved in bile acid biosynthesis, a part of plasmalogen synthesis and glyoxylate transamination. Furthermore, the literature indicates that peroxisomes participate in cholesterol biosynthesis, hydrogen peroxide-based cellular respiration, purine, fatty acid, long-chain... 

As already noted, the final steps In the synthesis of cholesterol and phospholipids take place primarily In the ER, although some of these membrane lipids are produced In mitochondria and peroxisomes (plasmalogens). Thus the plasma membrane and the membranes bounding other organelles (e.g., Golgi, lysosomes) must obtain these lipids by means of one or more Intracellular transport processes. For example. In one Important pathway, phosphatidylserine made In the ER Is transported to the Inner mitochondrial membrane where It Is decarboxylated to phosphatidylethanolamlne, some of which either returns to the ER for conversion Into phosphatidylcholine or moves to other organelles. 

Peroxisomes are present in greater number in the liver than in other tissues. Liver peroxisomes contain the enzymes for the oxidation of very-long-chain fatty acids such as C24 0 and phytanic acid, for the cleavage of the cholesterol side chain necessary for the synthesis of bile salts, for a step in the biosynthesis of ether lipids, and for several steps in arachidonic acid metabohsm. Peroxisomes also contain catalase and are capable of detoxifying hydrogen peroxide. 

TTA is a fatty acid analogue in which a sulfur atom replaces the P-mehylene groups in the alkyl-chain (a 3-thia fatty acid). TTA, therefore, cannot be P-oxidized. Paradoxically, TTA is both mitochondrial and peroxisomal proliferator and the hepatic mitochondrial and peroxisomal fatty acid oxidation capacities are increased (Table 2). In addition to its biochemical and morphological effects, TTA decrease serum TG (Table 1) very low density lipoprotein (VLDL)-TG, cholesterol and free fatty acid (NEFA) levels in rats. Thus, the observed reduction in plasma TG levels during TTA administration could be accomplished by retarded synthesis, reduced hepatic output, enhanced clearance or a combination of these factors. 3-Thia fatty acid resulted in a slight inhibition in the activities of ATP-citrate lyase and fatty acid synthase. However, the impact of... 

Very-long-chain fatty acids as erucic acid (A -docosenoic acid, C22 l), polyunsaturated fatty acids, methyl-branched fatty acids, dicarboxylic fatty acids, prostaglandins, and the cholesterol side chain in bile acid synthesis are preferentially or exclusively oxidised in peroxisomes. Peroxisomal P-oxidation starts with introduction of a A2,3-double bond catalysed by acyl-CoA oxidase, which consumes O2 and produces H2O2 (Foerster et al. 1981). 

Fig. 32.1. The classical ( neutral ) pathway for the synthesis of bile acids from cholesterol, where the modification of the steroid nucleus occurs prior to side-chain modification. Also illustrated are the inborn errors of bile acid synthesis and the resulting abnormal metabolites. 32.1, 3) -hydroxy-A -C27-steroid dehydrogenase (3) -HSDH) deficiency 32.2, A -3-oxosteroid 5 -reductase deficiency 32.3, sterol 27-hydroxylase deficiency (cerebrotendinous xanthomatosis, CTX) PD, peroxisomal disorders (defects of peroxisome biogenesis and peroxisomal j -oxidation). The abnormal metabolites that are readily detected by analysis of urine by LSI-MS are shown in boxes. Cholic acid can also be synthesised from 5 -cholestane-3a,7a,12a,25-tetrol this is the so-called microsomal or 25-hydroxylase pathway of cholic acid synthesis, which provides an alternative route for side-chain modification other than peroxisomal j -oxidation...

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