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. 2010 Sep 8;5(9):e12538.
doi: 10.1371/journal.pone.0012538.

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

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

Giuseppe Astarita et al. PLoS One. .
Free PMC article


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.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.


Figure 1
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 2
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.

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