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Cited by 218Fatty Acid Research and HealthAlzheimer's disease research and treatmentsDementia and Cognitive Impairment Research

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Deficient Liver Biosynthesis of Docosahexaenoic Acid Correlates with Cognitive Impairment in Alzheimer's Disease

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Astarita, Giuseppe, Jung, Kwang-Mook, Berchtold, Nicole C., Nguyen, Vinh Q., Gillen, Daniel L., Head, Elizabeth, Cotman, Carl W., Piomelli, Daniele·2010·PLoS ONE
DOI 10.1371/journal.pone.0012538PMC PMC2935886
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Abstract

Reduced brain levels of docosahexaenoic acid (C22:6n-3), a neurotrophic and neuroprotective fatty acid, may contribute to cognitive decline in Alzheimer's disease. Here, we investigated whether the liver enzyme system that provides docosahexaenoic acid to the brain is dysfunctional in this disease. Docosahexaenoic acid levels were reduced in temporal cortex, mid-frontal cortex and cerebellum of subjects with Alzheimer's disease, compared to control subjects (P = 0.007). Mini Mental State Examination (MMSE) scores positively correlated with docosahexaenoic/α-linolenic ratios in temporal cortex (P = 0.005) and mid-frontal cortex (P = 0.018), but not cerebellum. Similarly, liver docosahexaenoic acid content was lower in Alzheimer's disease patients than control subjects (P = 0.011). Liver docosahexaenoic/α-linolenic ratios correlated positively with MMSE scores (r = 0.78; P<0.0001), and negatively with global deterioration scale grades (P = 0.013). Docosahexaenoic acid precursors, including tetracosahexaenoic acid (C24:6n-3), were elevated in liver of Alzheimer's disease patients (P = 0.041), whereas expression of peroxisomal d-bifunctional protein, which catalyzes the conversion of tetracosahexaenoic acid into docosahexaenoic acid, was reduced (P = 0.048). Other genes involved in docosahexaenoic acid metabolism were not affected. The results indicate that a deficit in d-bifunctional protein activity impairs docosahexaenoic acid biosynthesis in liver of Alzheimer's disease patients, lessening the flux of this neuroprotective fatty acid to the brain.

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Figure 1 Overview of docosahexaenoic acid biosynthesis in liver. Diet-derived α-linolenic acid (C18:3n-3) is transformed into tetracosahexaenoic acid (C24:6n-3) by the sequential action of Δ6 and Δ5 desaturases (encoded by the FADS2 and FADS1 genes, respectively) and elongases (such as that encoded by the HELO1 gene) present in the endoplasmatic reticulum. Tetracosahexaenoic acid is transported into peroxisomes (shaded area), presumably by proteins encoded by the ABCD1 or ABCD2 genes, and then converted into docosahexaenoic acid (C22:6n-3) by sequential action of acyl coenzyme-A oxidase (encoded by the ACOX1 gene), d-bifunctional protein (encoded by the HSD17B4 gene), and various peroxisomal thiolases (not shown). The figure shows chemical structures of fatty acids quantified in our analyses.
Figure 1 Overview of docosahexaenoic acid biosynthesis in liver. Diet-derived α-linolenic acid (C18:3n-3) is transformed into tetracosahexaenoic acid (C24:6n-3) by the sequential action of Δ6 and Δ5 desaturases (encoded by the FADS2 and FADS1 genes, respectively) and elongases (such as that encoded by the HELO1 gene) present in the endoplasmatic reticulum. Tetracosahexaenoic acid is transported into peroxisomes (shaded area), presumably by proteins encoded by the ABCD1 or ABCD2 genes, and then converted into docosahexaenoic acid (C22:6n-3) by sequential action of acyl coenzyme-A oxidase (encoded by the ACOX1 gene), d-bifunctional protein (encoded by the HSD17B4 gene), and various peroxisomal thiolases (not shown). The figure shows chemical structures of fatty acids quantified in our analyses.CC BY · PubMed Central
Figure 2 Liver metabolism in Alzheimer's disease patients. Levels of free docosahexaenoic acid (Panel A) and 1-O-1′-(Z)-octadecenyl, 2-docosahexaenoyl-sn-glycero-3-phosphoethanolamine (Panel B) in liver tissue from control subjects (open squares) and Alzheimer's disease patients (closed circles). Correlation between individual docosahexaenoic/α-linolenic ratios in liver and most recent Mini-Mental State Examination scores (Panel C) or global deterioration scale grades (Panel D). HSD17B4 mRNA, encoding for d-bifunctional protein (Panel E) and pristanic acid levels (Panel F) in liver from control subjects (open squares) and subjects with Alzheimer's disease (closed circles). Lipid content is expressed in nanomoles per gram of wet tissue and mRNA levels are expressed in arbitrary units. There were statistically detectable differences between control subjects and Alzheimer's disease patients in the levels of docosahexaenoic acid (P = 0.0077) and 1-O-1′-(Z)-octadecenyl, 2-docosahexaenoyl-sn-glycero-3-phosphoethanolamine (P = 0.003) by two-tailed Welch's t-test. There was a significant correlation between docosahexaenoic/α-linolenic ratios in liver and Mini-Mental State Examination scores with use of the partial correlation analysis after adjustment for age, gender and post mortem interval. Global deterioration scale grades correlate significantly (P = 0.013) with the docosahexaenoic/α-linolenic ratios using a linear regression analysis adjusting for age, gender and post mortem interval. There were statistically detectable differences between control subjects and patients in the levels of HSD17B4 mRNA (P = 0.048) and pristanic acid (P = 0.0009) by two-tailed Welch's t-test.
Figure 2 Liver metabolism in Alzheimer's disease patients. Levels of free docosahexaenoic acid (Panel A) and 1-O-1′-(Z)-octadecenyl, 2-docosahexaenoyl-sn-glycero-3-phosphoethanolamine (Panel B) in liver tissue from control subjects (open squares) and Alzheimer's disease patients (closed circles). Correlation between individual docosahexaenoic/α-linolenic ratios in liver and most recent Mini-Mental State Examination scores (Panel C) or global deterioration scale grades (Panel D). HSD17B4 mRNA, encoding for d-bifunctional protein (Panel E) and pristanic acid levels (Panel F) in liver from control subjects (open squares) and subjects with Alzheimer's disease (closed circles). Lipid content is expressed in nanomoles per gram of wet tissue and mRNA levels are expressed in arbitrary units. There were statistically detectable differences between control subjects and Alzheimer's disease patients in the levels of docosahexaenoic acid (P = 0.0077) and 1-O-1′-(Z)-octadecenyl, 2-docosahexaenoyl-sn-glycero-3-phosphoethanolamine (P = 0.003) by two-tailed Welch's t-test. There was a significant correlation between docosahexaenoic/α-linolenic ratios in liver and Mini-Mental State Examination scores with use of the partial correlation analysis after adjustment for age, gender and post mortem interval. Global deterioration scale grades correlate significantly (P = 0.013) with the docosahexaenoic/α-linolenic ratios using a linear regression analysis adjusting for age, gender and post mortem interval. There were statistically detectable differences between control subjects and patients in the levels of HSD17B4 mRNA (P = 0.048) and pristanic acid (P = 0.0009) by two-tailed Welch's t-test.CC BY · PubMed Central

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Authors
Astarita, G., Jung, K.-M., Berchtold, N. C., Nguyen, V. Q., Gillen, D. L., Head, E., Cotman, C. W., & Piomelli, D.
Affiliations
  • University of Rome Tor Vergata (IT)
  • University of California, Irvine (US)
  • University of Kentucky (US)
Corresponding author
Piomelli, Daniele
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2010-09-08
Volume
5
Issue
9
Pages
e12538
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0012538
PMC
PMC2935886
OpenAlex
W1993630867
Cited by
218
References
42
Citations by year
2026: 3 · 2025: 6 · 2024: 17 · 2023: 9 · 2022: 15 · 2021: 19 · 2020: 16 · 2019: 15 · 2018: 9 · 2017: 18 · 2016: 19 · 2015: 21 · 2014: 14 · 2013: 14 · 2012: 11
FWCI
11.23
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UKnowledge (University of Kentucky) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • Figshare (submittedVersion, cc-by)
Funders
  • Michael J. Fox Foundation for Parkinson's Research (05-901, 211002, P30 AG19610)
  • Agilent Foundation
  • Arizona Department of Health Services (P30 AG19610, P50 AG016573, 05-901, 211002, Contract 211002)
  • Arizona Biomedical Research Commission (P30 AG19610, 05–901, 211002)
  • University of California, Irvine (P50AG016573)
  • National Institute on Aging (211002, P01AG000538, P30-AG-19610, AG-016573, P01 AG00538, AG-19610, AG 00538, P50AG016573, P30AG019610, 05-901)
  • National Institute on Drug Abuse (R01DA012447)
Topics
  • Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
docosahexaenoic acid, Alzheimer's disease, cognitive impairment, omega-3 fatty acids, temporal cortex, cerebellum
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Brain, Cognition, Docosahexaenoic Acids, Female, Humans, Liver, Male, Neuropsychological Tests, Case-Control Studies

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