Lignoceric acid is oxidized in the peroxisome: implications for the Zellweger cerebro-hepato-renal syndrome and adrenoleukodystrophy.

Abstract

The deficient oxidation and accumulation of very-long-chain fatty acids in the Zellweger cerebro-hepatorenal syndrome (CHRS) and X chromosome-linked adrenoleukodystrophy (ALD), coupled with the observation that peroxisomes are lacking in CHRS, prompted us to investigate the subcellular localization of the catabolism of lignoceric acid (C24:0). Peroxisomal and mitochondrial-rich fractions were separated from rat liver crude mitochondria by sucrose density gradient centrifugation. Enzyme activity for the oxidation of l1-4C]palmitic acid to water-soluble acetate was 2-to 3-fold higher in the mitochondrial than in the peroxisomal-rich fraction whereas [1-I4C~lignoceric acid was oxidized at a 2-to 3-fold higher rate in the peroxisomal than in the mitochondrial fraction. Moreover, unlike palmitic acid oxidation, lignoceric acid oxidation was not inhibited by potassium cyanide in either rat liver fractions or human skin cultured fibroblasts, showing that lignoceric acid is mainly and possibly exclusively oxidized in peroxisomes. We also conducted studies to clarify the striking phenotypic differences between CHRS and the childhood form of ALD. In contrast to CHRS, we found normal hepatocellular peroxisomes in the liver biopsy of a childhood ALD patient. In addition, in the presence of potassium cyanide, the oxidation of palmitic acid in cultured skin fibroblasts was inhibited by 62% in control and X chromosome-linked ALD patients compared with 88% in CHRS and neonatal ALD. This differential effect may be related to differences in peroxisomal morphology in those disorders.Peroxisomes are now known to have a variety of physiological functions in addition to their previously recognized role in the formation and reduction of hydrogen peroxide. More than 40 enzymes have now been localized to this organelle (1). These include those playing a major role in the ,B oxidation of fatty acids, particularly long-chain-length fatty acids (2, 3). It has been estimated that 30% of palmitate (2) and 50-67% of erucic acid (C22:1) (3) oxidation takes place in the peroxisomes. Among other peroxisomal enzymes are those involved in certain steps in the biosynthesis of glycerolipids and glycerol/ether lipids (4) and of bile acids (5), D-amino acid oxidases, the enzymes of the glyoxylate cycle, and those concerned with ethanoxanthine and urate (6) metabolism. Recently, 3-hydroxy-3-methylglutaryl-Co A reductase has also been localized in the peroxisome (7). The recognition that peroxisomes have a wide range of physiological functions, coupled with the demonstration that they are absent or diminished in certain disease states, has led to the concept of a newly recognized category of diseases, namely, disorders of the peroxisome (8, 9 The present studies of lignoceric acid (n-tetracosanoic acid, C24:0) metabolism were prompted by our observation that striking elevation of plasma and tissue levels of verylong-chain (>22) fatty acids-particularly hexacosanoic acid-are present in all patients with CHRS (19). These acids are normal constitue...

The peroxisomal ABC transporter family

“…Recent results by Kemp et al [42] have shown the same with deuterated C24:0 as substrate. These results, first reported by Singh et al [81], suggested that the accumulation of VLCFAs in X-ALD patients is directly explained by the depressed oxidation of C26:0 in peroxisomes in X-ALD cells. Studies, notably by McGuinness and co-workers [55] have challenged this conclusion.…”

Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism

“…S4C). To confirm changes to peroxisomal function, we measured oxidation of lignoceric acid (C24:0), which requires peroxisomes to be catabolized (29). Results show that both total and partial lignoceric acid oxidation is increased in Cpt1b m−/− homogenates (Fig.…”

Therapy of X-linked adrenoleukodystrophy

“…3 For reasons that are not yet understood this defect leads to the accumulation of saturated very long chain fatty acids (VLCFA) such as hexacosanoic acid (C26:0) in the adrenal gland and nervous system white matter 4 and other tissues and in plasma. 5 The VLCFA excess appears to be due to their impaired degradation, 5,6 a reaction that normally takes place in the peroxisome, 7 although recent studies indicate that the defects in fatty acid metabolism are complex and not yet fully understood. 8 Demonstration of excess of VLCFA in plasma is the most commonly used diagnostic assay.…”