Abstract
Lipotoxicity involves pathological alterations to cells and tissues in response to elevated fat levels in blood. Furthermore, this process can disturb both cellular homeostasis and viability. In the current study, the authors show that neural progenitor cells (NPCs) are vulnerable to high levels of palmitic acid (PA) a saturated fatty acid. PA was found to cause cell death associated with elevated reactive oxygen species (ROS) levels, and to reduce NPCs proliferation. To evaluate the lipotoxicity of PA in adult NPCs in the hippocampus, male C57BL/6 mice were divided into two groups and maintained on either a normal diet (ND) or PA-rich high fat diet (HFD) for 2 weeks. Interestingly, short-term PA-rich HFD feeding reduced the survival of newly generated cells in the hippocampal dentate gyrus and hippocampal brain-derived neurotrophic factor levels. These findings suggest PA has a potent lipotoxicity in NPCs and that a PA-rich HFD disrupts hippocampal neurogenesis.
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Abbreviations
- ND:
-
normal diet
- HFD:
-
high fat diet
- MDA:
-
malondialdehyde
- BDNF:
-
brain-derived neurotrophic factor
- NPCs:
-
neural progenitor cells
References
Almaguel, F.G., Liu, J.W., Pacheco, F.J., Casiano, C.A. and De Leon, M. (2009). Activation and reversal of lipotoxicity in PC12 and rat cortical cells following exposure to palmitic acid. J. Neurosci. Res., 87, 1207–1218.
Amtul, Z., Uhrig, M., Rozmahel, R.F. and Beyreuther, K. (2010). Structural basis for the differential effects of omega-3 and omega-6 fatty acids on Abeta production and amyloid plaques. J. Biol. Chem., 286, 6100–6107.
Anderson, M.F., Aberg, M.A., Nilsson, M. and Eriksson, P.S. (2002). Insulin-like growth factor-I and neurogenesis in the adult mammalian brain. Brain Res. Dev. Brain Res., 134, 115–122.
Araki, H., Nishihara, T., Matsuda, M., Fukuhara, A., Kihara, S., Funahashi, T., Kataoka, T.R., Kamada, Y., Kiyohara, T., Tamura, S., Hayashi, N. and Shimomura, I. (2008). Adiponectin plays a protective role in caerulein-induced acute pancreatitis in mice fed a high-fat diet. Gut., 57, 1431–1440.
Bueno, A.A., Oyama, L.M., de Macedo Motoyama, C.S., da Silva Biz, C.R., Silveira, V.L., Ribeiro, E.B. and Oller do Nascimento, C.M. (2010). Long chain saturated fatty acids increase haptoglobin gene expression in C57BL/6J mice adipose tissue and 3T3-L1 cells. Eur. J. Nutr., 49, 235–241.
Cameron, H.A. and McKay, R.D. (1999). Restoring production of hippocampal neurons in old age. Nat. Neurosci., 2, 894–897.
Cao, L., Jiao, X., Zuzga, D.S., Liu, Y., Fong, D.M., Young, D. and During, M.J. (2004). VEGF links hippocampal activity with neurogenesis, learning and memory. Nat. Genet., 36, 827–835.
Chess, D.J. and Stanley, W.C. (2008). Role of diet and fuel overabundance in the development and progression of heart failure. Cardiovasc. Res., 79, 269–278.
Cnop, M. (2008). Fatty acids and glucolipotoxicity in the pathogenesis of Type 2 diabetes. Biochem. Soc. Trans., 36, 348–352.
Comhair, T.M., Garcia Caraballo, S.C., Dejong, C.H., Lamers, W.H. and Koehler, S.E. (2011). Dietary cholesterol, female gender and n-3 fatty acid deficiency are more important factors in the development of non-alcoholic fatty liver disease than the saturation index of the fat. Nutr. Metab. (Lond), 8, 4.
Einstein, O. and Ben-Hur, T. (2008). The changing face of neural stem cell therapy in neurologic diseases. Arch. Neurol., 65, 452–456.
Fraser, T., Tayler, H. and Love, S. (2010). Fatty acid composition of frontal, temporal and parietal neocortex in the normal human brain and in Alzheimer’s disease. Neurochem. Res., 35, 503–513.
Hansen, D., Dendale, P., Beelen, M., Jonkers, R.A., Mullens, A., Corluy, L., Meeusen, R. and van Loon, L.J. (2010). Plasma adipokine and inflammatory marker concentrations are altered in obese, as opposed to non-obese, type 2 diabetes patients. Eur. J. Appl. Physiol., 109, 397–404.
Hariri, N., Gougeon, R. and Thibault, L. (2010). A highly saturated fat-rich diet is more obesogenic than diets with lower saturated fat content. Nutr. Res., 30, 632–643.
Ilieva, E.V., Ayala, V., Jove, M., Dalfo, E., Cacabelos, D., Povedano, M., Bellmunt, M.J., Ferrer, I., Pamplona, R. and Portero-Otin, M. (2007). Oxidative and endoplasmic reticulum stress interplay in sporadic amyotrophic lateral sclerosis. Brain., 130, 3111–3123.
Kempermann, G., Kuhn, H.G. and Gage, F.H. (1997). More hippocampal neurons in adult mice living in an enriched environment. Nature., 386, 493–495.
Kernie, S.G., Liebl, D.J. and Parada, L.F. (2000). BDNF regulates eating behavior and locomotor activity in mice. Embo J., 19, 1290–1300.
Kuhn, H.G., Dickinson-Anson, H. and Gage, F.H. (1996). Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J. Neurosci., 16, 2027–2033.
Lee, J., Duan, W., Long, J.M., Ingram, D.K. and Mattson, M.P. (2000). Dietary restriction increases the number of newly generated neural cells, and induces BDNF expression, in the dentate gyrus of rats. J. Mol. Neurosci., 15, 99–108.
Lee, J., Duan, W. and Mattson, M.P. (2002a). Evidence that brainderived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice. J. Neurochem., 82, 1367–1375.
Lee, J., Seroogy, K.B. and Mattson, M.P. (2002b). Dietary restriction enhances neurotrophin expression and neurogenesis in the hippocampus of adult mice. J. Neurochem., 80, 539–547.
Martinez de Morentin, P.B., Varela, L., Ferno, J., Nogueiras, R., Dieguez, C. and Lopez, M. (2010). Hypothalamic lipotoxicity and the metabolic syndrome. Biochim. Biophys. Acta., 1801, 350–361.
Mattson, M.P. (1998). Modification of ion homeostasis by lipid peroxidation: roles in neuronal degeneration and adaptive plasticity. Trends Neurosci., 21, 53–57.
Mayer, C.M. and Belsham, D.D. (2010). Palmitate attenuates insulin signaling and induces endoplasmic reticulum stress and apoptosis in hypothalamic neurons: rescue of resistance and apoptosis through adenosine 5’ monophosphate-activated protein kinase activation. Endocrinology, 151, 576–585.
Olson, A.K., Eadie, B.D., Ernst, C. and Christie, B.R. (2006). Environmental enrichment and voluntary exercise massively increase neurogenesis in the adult hippocampus via dissociable pathways. Hippocampus., 16, 250–260.
Park, H.R., Park, M., Choi, J., Park, K.Y., Chung, H.Y. and Lee, J. (2010). A high-fat diet impairs neurogenesis: involvement of lipid peroxidation and brain-derived neurotrophic factor. Neurosci. Lett., 482, 235–239.
Patil, S., Melrose, J. and Chan, C. (2007). Involvement of astroglial ceramide in palmitic acid-induced Alzheimer-like changes in primary neurons. Eur. J. Neurosci., 26, 2131–2141.
Patil, S., Sheng, L., Masserang, A. and Chan, C. (2006). Palmitic acid-treated astrocytes induce BACE1 upregulation and accumulation of C-terminal fragment of APP in primary cortical neurons. Neurosci. Lett., 406, 55–59.
Pelleymounter, M.A., Cullen, M.J. and Wellman, C.L. (1995). Characteristics of BDNF-induced weight loss. Exp. Neurol., 131, 229–238.
Rios, M., Fan, G., Fekete, C., Kelly, J., Bates, B., Kuehn, R., Lechan, R.M. and Jaenisch, R. (2001). Conditional deletion of brain-derived neurotrophic factor in the postnatal brain leads to obesity and hyperactivity.Mol. Endocrinol., 15, 1748–1757.
Ruiperez, V., Darios, F. and Davletov, B. (2010). Alpha-synuclein, lipids and Parkinson’s disease. Prog. Lipid Res., 49, 420–428.
Snyder, E.Y., Deitcher, D.L., Walsh, C., Arnold-Aldea, S., Hartwieg, E.A. and Cepko, C.L. (1992). Multipotent neural cell lines can engraft and participate in development of mouse cerebellum. Cell., 68, 33–51.
Spector, A.A. (1975). Fatty acid binding to plasma albumin. J. Lipid Res., 16, 165–179.
Taepavarapruk, P. and Song, C. (2010). Reductions of acetylcholine release and nerve growth factor expression are correlated with memory impairment induced by interleukin-1beta administrations: effects of omega-3 fatty acid EPA treatment. J. Neurochem., 112, 1054–1064.
Ulloth, J.E., Casiano, C.A. and De Leon, M. (2003). Palmitic and stearic fatty acids induce caspase-dependent and -independent cell death in nerve growth factor differentiated PC12 cells. J. Neurochem., 84, 655–668.
van Praag, H., Kempermann, G. and Gage, F.H. (1999). Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat. Neurosci., 2, 266–270.
van Praag, H., Schinder, A.F., Christie, B.R., Toni, N., Palmer, T.D. and Gage, F.H. (2002). Functional neurogenesis in the adult hippocampus. Nature., 415, 1030–1034.
Walter, J., Keiner, S., Witte, O.W. and Redecker, C. (2009). Agerelated effects on hippocampal precursor cell subpopulations and neurogenesis. Neurobiol. Aging.
Warner-Schmidt, J.L. and Duman, R.S. (2006). Hippocampal neurogenesis: opposing effects of stress and antidepressant treatment. Hippocampus., 16, 239–249.
White, B.C., Sullivan, J.M., DeGracia, D.J., O’Neil, B.J., Neumar, R.W., Grossman, L.I., Rafols, J.A. and Krause, G.S. (2000). Brain ischemia and reperfusion: molecular mechanisms of neuronal injury. J. Neurol. Sci., 179, 1–33.
Wrede, C.E., Dickson, L.M., Lingohr, M.K., Briaud, I. and Rhodes, C.J. (2002). Protein kinase B/Akt prevents fatty acidinduced apoptosis in pancreatic beta-cells (INS-1). J. Biol. Chem., 277, 49676–49684.
Yamato, M., Shiba, T., Yoshida, M., Ide, T., Seri, N., Kudou, W., Kinugawa, S. and Tsutsui, H. (2007). Fatty acids increase the circulating levels of oxidative stress factors in mice with dietinduced obesity via redox changes of albumin. Febs J., 274, 3855–3863.
Yu, H., Bi, Y., Ma, W., He, L., Yuan, L., Feng, J. and Xiao, R. (2010). Long-term effects of high lipid and high energy diet on serum lipid, brain fatty acid composition, and memory and learning ability in mice. Int. J. Dev. Neurosci., 28, 271–276.
Yun, J.W., Lee, B.S., Kim, C.W. and Kim, B.H. (2007). Comparison with 3 high-fat diet for studying obesity in C57BL/6 mouse. Lab. Anim. Res., 23, 245–250.
Zhang, W., Hu, X., Yang, W., Gao, Y. and Chen, J. (2010). Omega-3 polyunsaturated fatty acid supplementation confers long-term neuroprotection against neonatal hypoxic-ischemic brain injury through anti-inflammatory actions. Stroke., 41, 2341–2347.
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Park, H.R., Kim, JY., Park, KY. et al. Lipotoxicity of Palmitic Acid on Neural Progenitor Cells and Hippocampal Neurogenesis. Toxicol Res. 27, 103–110 (2011). https://doi.org/10.5487/TR.2011.27.2.103
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DOI: https://doi.org/10.5487/TR.2011.27.2.103