Interactions of a very long chain fatty acid with model membranes and serum albumin. Implications for the pathogenesis of adrenoleukodystrophy.
Open accessAbstract
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 13C-enriched HA with model membranes (phospholipid bilayer vesicles) and bovine serum albumin (BSA) by 13C 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 pKa (7.4) similar to other fatty acids; the acyl chain must then penetrate very deeply into the membrane. Desorption of HA from vesicles (t1+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 albumin.
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VLCFAs influence membrane properties such as curvature and permeability.
“VLCFAs are thought to influence membrane properties such as curvature and permeability46,47.”
From Peroxisomal very long-chain fatty acid transport is targeted by herpesviruses and the antiviral host response (2022) · cites this paper as [47]
The Discussion reports that excess VLCFAs can profoundly affect membrane structure and describes altered phospholipid packing in model membranes. It does not establish effects on membrane curvature or permeability, the specific properties named in the citing sentence. (LLM, conf=0.85)
Experimental — accuracy not yet measuredElevated levels of VLCFA have been shown to be detrimental to adrenocortical cells in culture and to model membranes.
“although elevated levels of VLCFA have been shown to be detrimental to adrenocortical cells in culture (34,42) and to model membranes (43).”
From Functional overlap between ABCD1 (ALD) and ABCD2 (ALDR) transporters: a therapeutic target for X-adrenoleukodystrophy (2004) · cites this paper as [43]
The desorption of C26:0 from a phospholipid bilayer model membrane is 10,000 times slower than that of C16:0 and C18:0 fatty acids.
“The desorption of C26:0 from a phospholipid bilayer model membrane is 10,000 times slower than that of C16:0 and C18:0 fatty acids [35].”
From X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects (2012) · cites this paper as [35]
Inclusion of C26:0 in a model membrane disrupts membrane structure.
“Microcalorimetric studies have shown that inclusion of C26:0 in a model membrane disrupts membrane structure [35].”
From X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects (2012) · cites this paper as [35]
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“Such perturbations may result in alterations of membrane structure, stability and function [19–21], oxidative stress [22,23], energy metabolism [24,25] and increased expression of inducible nitric oxide synthase [26,27].”
BackgroundDiffusion tensor–based imaging reveals occult abnormalities in adrenomyeloneuropathy
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- Authors
- Ho, J. K., Moser, H., Kishimoto, Y., & Hamilton, J. A.
- Affiliations
- Boston University (US)
- Corresponding author
- Hamilton, J A
- ORCID
- Hamilton, J A
- Venue
- Journal of Clinical Investigation
- Published
- 1995-09-01
- Volume
- 96
- Issue
- 3
- Pages
- 1455-1463
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC185769
- OpenAlex
- W2018016330
- Cited by
- 199
- References
- 40
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 12 · 2023: 2 · 2022: 3 · 2021: 5 · 2020: 8 · 2019: 5 · 2018: 3 · 2017: 8 · 2016: 8 · 2015: 7 · 2014: 7 · 2013: 11 · 2012: 9
- FWCI
- 1.61
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ns013559-20)
- National Heart, Lung, and Blood Institute (P01HL026335, HL26335)
- National Institute of Neurological Disorders and Stroke (NS-13559)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
- Keywords
- adrenoleukodystrophy, very long chain fatty acids, hexacosanoic acid, 13C NMR, model membranes, phospholipid bilayers, bovine serum albumin, fatty acid binding, membrane structure, pathogenesis, neurological symptoms
- MeSH terms
- Adrenoleukodystrophy, Animals, Cattle, Fatty Acids, Nonesterified, Fatty Acids, Unsaturated, Humans, Lipid Bilayers, Models, Structural, Models, Theoretical, Magnetic Resonance Spectroscopy, Serum Albumin, Bovine
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