Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

PNAS 102 (31): 10858-10863

Copyright © 2005 by the National Academy of Sciences.


Docosahexaenoic acid: A positive modulator of Akt signaling in neuronal survival

Mohammed Akbar, Frances Calderon, Zhiming Wen, and Hee-Yong Kim *

Section of Mass Spectrometry, Laboratory of Membrane Biochemistry and Biophysics, National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20952-8115

Edited by Thomas C. Südhof, University of Texas Southwestern Medical Center, Dallas, TX

Accepted for publication June 8, 2005.

Received for publication April 7, 2005.

Abstract: Phosphatidylinositol 3-kinase [PI (3)K]/Akt signaling is a critical pathway in cell survival. Here, we demonstrate a mechanism where membrane alteration by the n-3 fatty acid status affects Akt signaling, impacting neuronal survival. Docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid highly enriched in neuronal membranes, promotes neuronal survival by facilitating membrane translocation/activation of Akt through its capacity to increase phosphatidylserine (PS), the major acidic phospholipid in cell membranes. The activation of PI (3)K and phosphatidylsinositol triphosphate formation were not affected by DHA, indicating that membrane interaction of Akt is the event responsible for the DHA effect. Docosapentaenoic acid, which replaces DHA during n-3 fatty acid deficiency, was less effective in accumulating PS and translocating Akt and thus less effective in preventing apoptosis. Consistently, in vivo reduction of DHA by dietary depletion of n-3 fatty acids decreased hippocampal PS and increased neuronal susceptibility to apoptosis in cultures. This mechanism may contribute to neurological deficits associated with n-3 fatty acid deficiency and support protective effects of DHA in pathological models such as brain ischemia or Alzheimer's disease.

Key Words: apoptosis • phosphatidylserine • hippocampus • docosapentaenoic acid • n-3 fatty acid deficiency

Author contributions: H.-Y.K. designed research; M.A., F.C., and Z.W. performed research; M.A., F.C., Z.W., and H.-Y.K. analyzed data; and M.A., F.C., and H.-Y.K. wrote the paper.

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: DHA, docosahexaenoic acid; DPA, docosapentaenoic acid; PS, phosphatidylserine; PI, phosphatidylinositol; PIP, phosphatidylsinositol phosphate; PIP3, phosphatidylinositol triphosphate; PI (3)K, phosphatidylinositol 3-kinase; IGF, insulin growth factor; PH domain, pleckstrin homology domain.

* To whom correspondence should be addressed. E-mail: hykim{at}

Omega-3 Fatty Acids Protect the Brain against Ischemic Injury by Activating Nrf2 and Upregulating Heme Oxygenase 1.
M. Zhang, S. Wang, L. Mao, R. K. Leak, Y. Shi, W. Zhang, X. Hu, B. Sun, G. Cao, Y. Gao, et al. (2014)
J. Neurosci. 34, 1903-1915
   Abstract »    Full Text »    PDF »
Polyunsaturated fatty acids affect the localization and signaling of PIP3/AKT in prostate cancer cells.
Z. Gu, J. Wu, S. Wang, J. Suburu, H. Chen, M. J. Thomas, L. Shi, I. J. Edwards, I. M. Berquin, and Y. Q. Chen (2013)
Carcinogenesis 34, 1968-1975
   Abstract »    Full Text »    PDF »
Retinoid X receptor activation is essential for docosahexaenoic acid protection of retina photoreceptors.
O. L. German, S. Monaco, D. L. Agnolazza, N. P. Rotstein, and L. E. Politi (2013)
J. Lipid Res. 54, 2236-2246
   Abstract »    Full Text »    PDF »
The Systems Theory of Autistogenesis: Putting the Pieces Together.
J. P. Malone (2012)
SAGE Open 2, 2158244012444281
   Abstract »    Full Text »    PDF »
Accumulation of Dietary Docosahexaenoic Acid in the Brain Attenuates Acute Immune Response and Development of Postischemic Neuronal Damage.
M. Lalancette-Hebert, C. Julien, P. Cordeau, I. Bohacek, Y.-C. Weng, F. Calon, and J. Kriz (2011)
Stroke 42, 2903-2909
   Abstract »    Full Text »    PDF »
Phosphatidylserine is a critical modulator for Akt activation.
B. X. Huang, M. Akbar, K. Kevala, and H.-Y. Kim (2011)
J. Cell Biol. 192, 979-992
   Abstract »    Full Text »    PDF »
Blood Eicosapentaenoic and Docosahexaenoic Acids Predict All-Cause Mortality in Patients With Stable Coronary Heart Disease: The Heart and Soul Study.
J. V. Pottala, S. Garg, B. E. Cohen, M. A. Whooley, and W. S. Harris (2010)
Circ Cardiovasc Qual Outcomes 3, 406-412
   Abstract »    Full Text »    PDF »
Docosahexaenoic Acid-Enriched Fish Oil Attenuates Kidney Disease and Prolongs Median and Maximal Life Span of Autoimmune Lupus-Prone Mice.
G. V. Halade, M. M. Rahman, A. Bhattacharya, J. L. Barnes, B. Chandrasekar, and G. Fernandes (2010)
J. Immunol. 184, 5280-5286
   Abstract »    Full Text »    PDF »
DHA May Prevent Age-Related Dementia.
G. M. Cole and S. A. Frautschy (2010)
J. Nutr. 140, 869-874
   Abstract »    Full Text »    PDF »
Dietary Docosahexaenoic Acid Supplementation Modulates Hippocampal Development in the Pemt-/- Mouse.
K.-A. da Costa, K. S. Rai, C. N. Craciunescu, K. Parikh, M. G. Mehedint, L. M. Sanders, A. McLean-Pottinger, and S. H. Zeisel (2010)
J. Biol. Chem. 285, 1008-1015
   Abstract »    Full Text »    PDF »
Disruption of FADS2 gene in mice impairs male reproduction and causes dermal and intestinal ulceration.
C. K. Stroud, T. Y. Nara, M. Roqueta-Rivera, E. C. Radlowski, P. Lawrence, Y. Zhang, B. H. Cho, M. Segre, R. A. Hess, J. T. Brenna, et al. (2009)
J. Lipid Res. 50, 1870-1880
   Abstract »    Full Text »    PDF »
Starving Neurons Show Sex Difference in Autophagy.
L. Du, R. W. Hickey, H. Bayir, S. C. Watkins, V. A. Tyurin, F. Guo, P. M. Kochanek, L. W. Jenkins, J. Ren, G. Gibson, et al. (2009)
J. Biol. Chem. 284, 2383-2396
   Abstract »    Full Text »    PDF »
The emerging role of group VI calcium-independent phospholipase A2 in releasing docosahexaenoic acid from brain phospholipids.
J. T. Green, S. K. Orr, and R. P. Bazinet (2008)
J. Lipid Res. 49, 939-944
   Abstract »    Full Text »    PDF »
Polyunsaturated fatty acids block platelet-activating factor-induced phosphatidylinositol 3 kinase/Akt-mediated apoptosis in intestinal epithelial cells.
J. Lu, M. S. Caplan, D. Li, and T. Jilling (2008)
Am J Physiol Gastrointest Liver Physiol 294, G1181-G1190
   Abstract »    Full Text »    PDF »
Beneficial effects of dietary omega-3 polyunsaturated fatty acid on toxin-induced neuronal degeneration in an animal model of Parkinson's disease.
M. Bousquet, M. Saint-Pierre, C. Julien, N. Salem Jr., F. Cicchetti, and F. Calon (2008)
FASEB J 22, 1213-1225
   Abstract »    Full Text »    PDF »
The low density lipoprotein receptor is not necessary for maintaining mouse brain polyunsaturated fatty acid concentrations.
C. T. Chen, D. W. L. Ma, J. H. Kim, H. T. J. Mount, and R. P. Bazinet (2008)
J. Lipid Res. 49, 147-152
   Abstract »    Full Text »    PDF »
Omega-3 Fatty Acid Docosahexaenoic Acid Increases SorLA/LR11, a Sorting Protein with Reduced Expression in Sporadic Alzheimer's Disease (AD): Relevance to AD Prevention.
Q.-L. Ma, B. Teter, O. J. Ubeda, T. Morihara, D. Dhoot, M. D. Nyby, M. L. Tuck, S. A. Frautschy, and G. M. Cole (2007)
J. Neurosci. 27, 14299-14307
   Abstract »    Full Text »    PDF »
Oxidative and endoplasmic reticulum stress interplay in sporadic amyotrophic lateral sclerosis.
E. V. Ilieva, V. Ayala, M. Jove, E. Dalfo, D. Cacabelos, M. Povedano, M. J. Bellmunt, I. Ferrer, R. Pamplona, and M. Portero-Otin (2007)
Brain 130, 3111-3123
   Abstract »    Full Text »    PDF »
Homeostatic Regulation of Photoreceptor Cell Integrity: Significance of the Potent Mediator Neuroprotectin D1 Biosynthesized from Docosahexaenoic Acid The Proctor Lecture.
N. G. Bazan (2007)
Invest. Ophthalmol. Vis. Sci. 48, 4866-4881
   Full Text »    PDF »
Photoreceptor outer segment phagocytosis attenuates oxidative stress-induced apoptosis with concomitant neuroprotectin D1 synthesis.
P. K. Mukherjee, V. L. Marcheselli, J. C. de Rivero Vaccari, W. C. Gordon, F. E. Jackson, and N. G. Bazan (2007)
PNAS 104, 13158-13163
   Abstract »    Full Text »    PDF »
Novel Metabolism of Docosahexaenoic Acid in Neural Cells.
H.-Y. Kim (2007)
J. Biol. Chem. 282, 18661-18665
   Full Text »    PDF »
Long-chain n-3 polyunsaturated fatty acids dissociate phosphorylation of Akt from phosphatidylinositol 3'-kinase activity in rats.
C. Le Foll, C. Corporeau, V. Le Guen, J.-P. Gouygou, J.-P. Berge, and J. Delarue (2007)
Am J Physiol Endocrinol Metab 292, E1223-E1230
   Abstract »    Full Text »    PDF »
A Novel Phosphatidylcholine Which Contains Pentadecanoic Acid at sn-1 and Docosahexaenoic Acid at sn-2 in Schizochytrium sp. F26-b.
E. Abe, Y. Hayashi, Y. Hama, M. Hayashi, M. Inagaki, and M. Ito (2006)
J. Biochem. 140, 247-253
   Abstract »    Full Text »    PDF »
Docosahexaenoic Acid Protects from Amyloid and Dendritic Pathology in an Alzheimer's Disease Mouse Model.
G. M. Cole and S. A. Frautschy (2006)
Nutrition and Health 18, 249-259
   Abstract »    PDF »
Role of Docosahexaenoic Acid in Neuronal Plasma Membranes.
J. A. Glomset (2006)
Sci. STKE 2006, pe6
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882