Plasmalogen deficiency in cerebral adrenoleukodystrophy and its modulation by lovastatin

Abstract

In cerebral adrenoleukodystrophy (cALD), an accumulation of very long chain fatty acids stems from a defect of the peroxisomal ALD protein (ALDP) and results in the loss of myelin/ oligodendrocytes, induction of inflammatory disease and mental deterioration. In brain white matter of cALD patients, we observed not only increased levels of very long chain fatty acid but also reduced levels of plasmenylethanolamine (PlsEtn) and increased levels of reactive oxygen species (ROS). The loss of PlsEtn was greatest in the plaque area and lesser but significant at histologically normal-looking areas of the cALD brain. The reduction in PlsEtn was related to oxidative stress, as supported by increased levels of reactive lipid aldehydes (4-hydroxynonenal and acrolein) and deleterious oxidized proteins (protein carbonyl) in all areas of the cALD brain. This inverse relationship between the levels of PlsEtn and reactive oxygen species (ROS) was further supported in an in vitro study using gene-silencing for dihydroxyacetone phosphate-acyl transferase, a key enzyme for PlsEtn biosynthesis. Levels of PlsEtn were also found decreased in vitro following gene-silencing for the ALDP/ALDrelated protein. Furthermore, low levels of PlsEtn were detected in brain white matter of ALDP knock out (KO) mice. A treatment of ALDP KO mice with lovastatin increased PlsEtn levels in the brain. Further, in an in vitro study, lovastatin treatment of rat C6 glial cells increased PlsEtn biosynthesis and reduced the cytokine-induced ROS accumulation. In summary, this study reports that altered metabolism of PlsEtn and ROS in cALD may be corrected by lovastatin treatment.

HDAC inhibitor SAHA normalizes the levels of VLCFAs in human skin fibroblasts from X-ALD patients and downregulates the expression of proinflammatory cytokines in Abcd1/2-silenced mouse astrocytes

“…Studies with phenylacetate (PA) from our laboratory ( 83 ) and with PBA from other laboratories ( 29 ) have shown that these compounds (PBA and PA) have very low potency, insofar as millimolar amounts of these proinfl ammatory cytokines) ( 19 ), which was mediated by the activation of NF-B and 5-LOX and increased levels of ROS ( 13 ). SAHA treatment of Abcd1/2-silenced mouse astrocytes reduced the expressions of iNOS and TNF-␣ (mRNA and protein), suppressed NF-B activation, and reduced ROS production.…”

“…[1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]palmitic acid and 125 I-labeled protein A were obtained from ICN (Cleveland, OH).…”

Blockage of cytosolic phospholipase A2 alpha by monoclonal antibody attenuates focal ischemic brain damage in mice

“…Determination of FFA and LPC FFA and LPC were determined and quantified using HPRLC. The needed lipids samples were extracted from brain tissue using the Folch method (23). FFA was determined and quantified using high-performance thin layer chromatography (HPTLC) plates (24).…”

Extrinsic effectors regulating genes for plasmalogen biosynthetic enzymes in HepG2 cells

“…Monounsaturated long-chain fatty acids such as oleic acid (C18:1) and erucic acid (C22:1), myo-inositol, and Pl precursors, alkylglycerol and HG, have been reported to increase Pl levels in laboratory animals and humans [19][20][21][22][23]. However, they unexpectedly reduced the gene expression of Pl biosynthetic enzymes in HepG2 cells (Table 2).…”

“…Accordingly, we attempted to increase the levels of plasma Pls as a preventative strategy for diseases associated with oxidative stress and aging. This was achieved in laboratory animals as well as humans through administration of the Pl precursor alkylglycerol [19], myoinositol (MI) [20,21], monounsaturated long-chain fatty acids [22], and the hypolipidemic agent, statin [23]. However, their effects on the gene expression of Pl biosynthetic enzymes remain unknown.…”