Effects of long-chain, saturated fatty acids on membrane microviscosity and adrenocorticotropin responsiveness of human adrenocortical cells in vitro.

Whitcomb, Randall W.; Linehan, W. Marston; Knazek, Richard A.

doi:10.1172/jci113292

Cited by 157 publications

(76 citation statements)

References 23 publications

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“…Neither human nor mouse AMN spinal cord displays cell death despite accumulation of LPC C26:0 42. For some time, it has been known that excess VLCFA (40 µM and above) affects membrane function and causes toxicity to adrenocortical cells, oligodendrocytes, astrocytes, and neurons 43, 44. For example, excess free VLCFA induces depolarization of mitochondria and deregulation of the intracellular calcium homeostasis,42 and in the brain, this can cause activation and apoptosis of microglia 4.…”

Section: Discussionmentioning

confidence: 99%

Microglial dysfunction as a key pathological change in adrenomyeloneuropathy

Gong

Sasidharan

Laheji

et al. 2017

Annals of Neurology

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ObjectiveMutations in ABCD1 cause the neurodegenerative disease, adrenoleukodystrophy, which manifests as the spinal cord axonopathy adrenomyeloneuropathy (AMN) in nearly all males surviving into adulthood. Microglial dysfunction has long been implicated in pathogenesis of brain disease, but its role in the spinal cord is unclear.MethodsWe assessed spinal cord microglia in humans and mice with AMN and investigated the role of ABCD1 in microglial activity toward neuronal phagocytosis in cell culture. Because mutations in ABCD1 lead to incorporation of very‐long‐chain fatty acids into phospholipids, we separately examined the effects of lysophosphatidylcholine (LPC) upon microglia.ResultsWithin the spinal cord of humans and mice with AMN, upregulation of several phagocytosis‐related markers, such as MFGE8 and TREM2, precedes complement activation and synapse loss. Unexpectedly, this occurs in the absence of overt inflammation. LPC C26:0 added to ABCD1‐deficient microglia in culture further enhances MFGE8 expression, aggravates phagocytosis, and leads to neuronal injury. Furthermore, exposure to a MFGE8‐blocking antibody reduces phagocytic activity.InterpretationSpinal cord microglia lacking ABCD1 are primed for phagocytosis, affecting neurons within an altered metabolic milieu. Blocking phagocytosis or specific phagocytic receptors may alleviate synapse loss and axonal degeneration. Ann Neurol 2017;82:813–827

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Section: Discussionmentioning

confidence: 99%

Microglial dysfunction as a key pathological change in adrenomyeloneuropathy

Gong

Sasidharan

Laheji

et al. 2017

Annals of Neurology

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“…However, a positive result has been obtained in patients in whom therapy was begun before neurological symptoms were present ( 15), suggesting that the fatty acid abnormality is of pathogenic significance. Up to this time the main support for a direct toxic effect of VLCFA is provided by studies that show that red cell membranes of ALD patients have increased microviscosity and VLCFA content ( 16) and that addition of VLCFA to adrenocortical cells in vitro increases their membrane microviscosity and impairs their capacity to respond to ACTH stimulation (17).…”

Section: Introductionmentioning

confidence: 99%

Interactions of a very long chain fatty acid with model membranes and serum albumin. Implications for the pathogenesis of adrenoleukodystrophy.

Moser²,

Kishimoto³

et al. 1995

J. Clin. Invest.

182

109

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Adrenoleukodystrophy (ALD) is an inherited disorder of fatty acid metabolism marked by accumulation of very long chain saturated fatty acids (VLCFA), especially the 26-carbon acid, hexacosanoic acid (HA), in membranes and tissues. We have studied interactions of '3C-enriched HA with model membranes (phospholipid bilayer vesicles) and bovine serum albumin (BSA) by "C NMR spectroscopy to compare properties of HA with those of typical dietary fatty acids. In phospholipid bilayers the carboxyl group of HA is localized in the aqueous interface, with an apparent pK.(7.4) similar to other fatty acids; the acyl chain must then penetrate very deeply into the membrane. Desorption of HA from vesicles (tl/2 = 3 h) is orders of magnitude slower than shorter chain fatty acids. In mixtures of vesicles and BSA, HA partitions much more favorably to phospholipid bilayers than typical fatty acids. BSA binds a maximum of only 1 mole of HA at one binding site. Calorimetric experiments show strong perturbations of acyl chains of phospholipids by HA. We predict that disruptive effects of VLCFA on cell membrane structure and function may explain the neurological manifestations of ALD patients. These effects will be further amplified by slow desorption of VLCFA from membranes and by the ineffective binding to serum albu-

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“…It is well-known that free fatty acids act as potent detergents that can damage cellular membranes (Ho et al, 1995). Membrane properties (e.g., acyl chain order, fluidity, permeability, fusion events, lipid raft microdomains, protein activity) are affected by changes in VLCFAs, VLCPUFAs, DHA, and plasmalogen levels, influencing secretory and vesicular trafficking pathways (Whitcomb et al, 1988;David et al, 1998;Gleissman et al, 2010;Obara et al, 2013). Hypoxia or loss of VHL function has been shown to delay endocytosis and thereby to enhance receptor tyrosine kinasemediated signaling .…”

Section: Metabolic Consequences Of Reduced Peroxisome Abundancementioning

confidence: 99%

Molecular Mechanisms and Physiological Significance of Organelle Interactions and Cooperation

2017

Frontiers Research Topics

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Effects of long-chain, saturated fatty acids on membrane microviscosity and adrenocorticotropin responsiveness of human adrenocortical cells in vitro.

Abstract: It is hypothesized that cells exposed to LCFA have increased membrane microviscosity with a consequent decrease in their ability to respond to ACHI. This decrease in trophic support may contribute to the adrenal insufficiency and atrophy in patients with ALD.

Cited by 157 publications

References 23 publications

Microglial dysfunction as a key pathological change in adrenomyeloneuropathy

Microglial dysfunction as a key pathological change in adrenomyeloneuropathy

Interactions of a very long chain fatty acid with model membranes and serum albumin. Implications for the pathogenesis of adrenoleukodystrophy.

Molecular Mechanisms and Physiological Significance of Organelle Interactions and Cooperation

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