Neurochemical Research

, Volume 44, Issue 7, pp 1745–1754 | Cite as

Palmitic Acid-Induced NAD+ Depletion is Associated with the Reduced Function of SIRT1 and Increased Expression of BACE1 in Hippocampal Neurons

  • Manuel Flores-León
  • Martha Pérez-Domínguez
  • Rodrigo González-Barrios
  • Clorinda AriasEmail author
Original Paper


Increased levels of circulating fatty acids, such as palmitic acid (PA), are associated with the development of obesity, insulin resistance, type-2 diabetes and metabolic syndrome. Furthermore, these diseases are linked to an increased risk of cancer, cardiovascular diseases, mild cognitive impairment and even Alzheimer’s disease (AD). However, the precise actions of elevated PA levels on neurons and their association with neuronal metabolic disruption that leads to the expression of pathological markers of AD, such as the overproduction and accumulation of the amyloid-β peptide, represent an area of intense investigation. A possible molecular mechanism involved in the effects of PA may be through dysfunction of the NAD+ sensor enzyme, SIRT1. Therefore, the aim of the present study was to analyze the relationship between the effects of PA metabolism on the function of SIRT1 and the upregulation of BACE1 in cultured hippocampal neurons. PA reduced the total amount of NAD+ in neurons that caused an increase in p65 K310 acetylation due to inhibition of SIRT1 activity and low protein content. Furthermore, BACE1 protein and its activity were increased, and BACE1 was relocated in neurites after PA exposure.


Palmitic acid SIRT1 BACE1 expression Neuronal NAD+ Hippocampal neurons 



This work was supported by Universidad Nacional Autónoma de México (UNAM) (PAPIIT IN202615). The authors thank Patricia Ferrera for technical assistance and Miguel Tapia-Rodriguez for confocal microscopy assistance. M Flores-León is a doctoral student from Programa de Doctorado en Ciencias Bioquímicas, Universidad Nacional Autónoma de México (UNAM) and received a fellowship from CONACYT (449712).

Compliance with ethical standards

Conflict of interest

The authors declare that there is no conflict of interest.

Ethical approval

All procedures involving animals in this studied were performance in accordance with the Regulations for Research in Health Matters (México) and with the approval of the local Animal Care Committee.


  1. 1.
    Boden G, Shulman GI (2002) Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and beta-cell dysfunction. Eur J Clin Invest 32:14–23. CrossRefGoogle Scholar
  2. 2.
    Umegaki H (2010) Pathophysiology of cognitive dysfunction in older people with type 2 diabetes: vascular changes or neurodegeneration? Age Ageing 39:8–10. CrossRefGoogle Scholar
  3. 3.
    Schrijvers EMC, Witteman JCM, Sijbrands EJG et al (2010) Insulin metabolism and the risk of Alzheimer disease: the Rotterdam study. Neurology 75:1982–1987. CrossRefGoogle Scholar
  4. 4.
    Sima AAF (2010) Encephalopathies: the emerging diabetic complications. Acta Diabetol 47:279–293. CrossRefGoogle Scholar
  5. 5.
    Matsuzaki T, Sasaki K, Tanizaki Y et al (2010) Insulin resistance is associated with the pathology of Alzheimer disease: the Hisayama study. Neurology 75:764–770. CrossRefGoogle Scholar
  6. 6.
    Viscogliosi G, Andreozzi P, Chiriac IM et al (2012) Screening cognition in the elderly with metabolic syndrome. Metab Syndr Relat Disord 10:358–362. CrossRefGoogle Scholar
  7. 7.
    Gudala K, Bansal D, Schifano F, Bhansali A (2013) Diabetes mellitus and risk of dementia: a meta-analysis of prospective observational studies. J Diabetes Investig 4:640–650. CrossRefGoogle Scholar
  8. 8.
    Hoscheidt SM, Starks EJ, Oh JM et al (2016) Insulin resistance is associated with increased levels of cerebrospinal fluid biomarkers of Alzheimer’s disease and reduced memory function in at-risk healthy middle-aged adults. J Alzheimer’s Dis 52:1373–1383. CrossRefGoogle Scholar
  9. 9.
    Kwon B, Lee HK, Querfurth HW (2014) Oleate prevents palmitate-induced mitochondrial dysfunction, insulin resistance and inflammatory signaling in neuronal cells. Biochim Biophys Acta 1843:1402–1413. CrossRefGoogle Scholar
  10. 10.
    Calvo-Ochoa E, Sánchez-Alegría K, Gómez-Inclán C et al (2017) Palmitic acid stimulates energy metabolism and inhibits insulin/PI3 K/AKT signaling in differentiated human neuroblastoma cells: the role of mTOR activation and mitochondrial ROS production. Neurochem Int 110:75–83. CrossRefGoogle Scholar
  11. 11.
    Hsiao YH, Lin CI, Liao H et al (2014) Palmitic acid-induced neuron cell cycle G2/M arrest and endoplasmic reticular stress through protein palmitoylation in SH-SY5Y human neuroblastoma cells. Int J Mol Sci 15:20876–20899. CrossRefGoogle Scholar
  12. 12.
    Díaz-Ruiz A, Guzmán-Ruiz R, Moreno NR et al (2015) Proteasome dysfunction associated to oxidative stress and proteotoxicity in adipocytes compromises insulin sensitivity in human obesity. Antioxid Redox Signal 23:597–612. CrossRefGoogle Scholar
  13. 13.
    Marwarha G, Claycombe K, Schommer J et al (2016) Palmitate-induced endoplasmic reticulum stress and subsequent C/EBPα homologous protein activation attenuates leptin and insulin-like growth factor 1 expression in the brain. Cell Signal 28:1789–1805. CrossRefGoogle Scholar
  14. 14.
    Marwarha G, Schommer J, Lund J et al (2018) Palmitate-induced C/EBP homologous protein activation leads to NF-κB-mediated increase in BACE1 activity and amyloid beta genesis. J Neurochem 144:761–779. CrossRefGoogle Scholar
  15. 15.
    Little JP, Madeira JM, Klegeris A (2012) The saturated fatty acid palmitate induces human monocytic cell toxicity toward neuronal cells: exploring a possible link between obesity-related metabolic impairments and neuroinflammation. J Alzheimer’s Dis 30:S179–S183. CrossRefGoogle Scholar
  16. 16.
    Yaku K, Okabe K, Nakagawa T (2018) NAD metabolism: implications in aging and longevity. Ageing Res Rev 47:1–17. CrossRefGoogle Scholar
  17. 17.
    Smith JJ, Kenney RD, Gagne DJ et al (2009) Small molecule activators of SIRT1 replicate signaling pathways triggered by calorie restriction in vivo. BMC Syst Biol 3:31. CrossRefGoogle Scholar
  18. 18.
    Hubbard BP, Sinclair DA (2013) Measurement of sirtuin enzyme activity using a substrate-agnostic fluorometric nicotinamide assay. Methods Mol Biol. Google Scholar
  19. 19.
    Hubbard BP, Sinclair DA (2014) Small molecule SIRT1 activators for the treatment of aging and age-related diseases. Trends Pharmacol Sci 35:146–154. CrossRefGoogle Scholar
  20. 20.
    Imai SI, Guarente L (2014) NAD + and sirtuins in aging and disease. Trends Cell Biol 24:464–471. CrossRefGoogle Scholar
  21. 21.
    Morris BJ (2013) Seven sirtuins for seven deadly diseases ofaging. Free Radic Biol Med 56:133–171. CrossRefGoogle Scholar
  22. 22.
    Kumar R, Chaterjee P, Sharma PK et al (2013) Sirtuin1: a promising serum protein marker for early detection of Alzheimer’s disease. PLoS ONE. Google Scholar
  23. 23.
    Lutz MI, Milenkovic I, Regelsberger G, Kovacs GG (2014) Distinct patterns of sirtuin expression during progression of Alzheimer’s disease. NeuroMolecular Med. Google Scholar
  24. 24.
    Braidy N, Jayasena T, Poljak A, Sachdev PS (2012) Sirtuins in cognitive ageing and Alzheimerʼs disease. Curr Opin Psychiatry 25:226–230. CrossRefGoogle Scholar
  25. 25.
    Vassar R (1999) Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286:735–741. CrossRefGoogle Scholar
  26. 26.
    De Strooper B, Annaert W (2000) Proteolytic processing and cell biological functions of the amyloid precursor protein. J Cell Sci 113:1857–1870Google Scholar
  27. 27.
    Donmez G, Wang D, Cohen DE, Guarente L (2010) SIRT1 suppresses β-amyloid production by activating the α-secretase gene ADAM10. Cell 142:320–332. CrossRefGoogle Scholar
  28. 28.
    Bonda DJ, Lee H, Camins A et al (2011) The sirtuin pathway in ageing and Alzheimer disease: mechanistic and therapeutic considerations. Lancet Neurol 10:275–279. CrossRefGoogle Scholar
  29. 29.
    Hernández-Fonseca K, Massieu L (2005) Disruption of endoplasmic reticulum calcium stores is involved in neuronal death induced by glycolysis inhibition in cultured hippocampal neurons. J Neurosci Res 82:196–205. CrossRefGoogle Scholar
  30. 30.
    Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63. CrossRefGoogle Scholar
  31. 31.
    Clore JN, Allred J, White D et al (2002) The role of plasma fatty acid composition in endogenous glucose production in patients with type 2 diabetes mellitus. Metabolism 51:1471–1477. CrossRefGoogle Scholar
  32. 32.
    Schönfeld P, Reiser G (2013) Why does brain metabolism not favor burning of fatty acids to provide energy? Reflections on disadvantages of the use of free fatty acids as fuel for brain. J Cereb Blood Flow Metab 33:1493–1499. CrossRefGoogle Scholar
  33. 33.
    Panov A, Orynbayeva Z, Vavilin V, Lyakhovich V (2014) Fatty acids in energy metabolism of the central nervous system. Biomed Res Int 2014:1–22. CrossRefGoogle Scholar
  34. 34.
    Yeung F, Hoberg JE, Ramsey CS et al (2004) Modulation of NF-κB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J 23:2369–2380. CrossRefGoogle Scholar
  35. 35.
    Marwarha G, Raza S, Meiers C, Ghribi O (2014) Leptin attenuates BACE1 expression and amyloid-β genesis via the activation of SIRT1 signaling pathway. Biochim Biophys Acta 1842:1587–1595. CrossRefGoogle Scholar
  36. 36.
    Huse JT, Pijak DS, Leslie GJ et al (2000) Maturation and endosomal targeting of β-site amyloid precursor protein-cleaving enzyme. J Biol Chem 275:33729–33737. CrossRefGoogle Scholar
  37. 37.
    Deng M, He W, Tan Y et al (2013) Increased expression of reticulon 3 in neurons leads to reduced axonal transport of β site amyloid precursor protein-cleaving enzyme. J Biol Chem. Google Scholar
  38. 38.
    Kandalepas PC, Sadleir KR, Eimer WA et al (2013) The Alzheimer’s β-secretase BACE1 localizes to normal presynaptic terminals and to dystrophic presynaptic terminals surrounding amyloid plaques. Acta Neuropathol. Google Scholar
  39. 39.
    Shi Y, Sun Y, Sun X et al (2018) Up-regulation of HO-1 by Nrf2 activation protects against palmitic acid-induced ROS increase in human neuroblastoma BE(2)-M17 cells. Nutr Res. Google Scholar
  40. 40.
    Sergi D, Morris AC, Kahn DE et al (2018) Palmitic acid triggers inflammatory responses in N42 cultured hypothalamic cells partially via ceramide synthesis but not via TLR4. Nutr Neurosci. Google Scholar
  41. 41.
    Dhopeshwarkar GA, Subramanian C, McConnell DH, Mead JF (1972) Fatty acid transport into the brain. BBA. Google Scholar
  42. 42.
    Fraser T, Tayler H, Love S (2010) Fatty acid composition of frontal, temporal and parietal neocortex in the normal human brain and in Alzheimer’s disease. Neurochem Res. Google Scholar
  43. 43.
    Wanders RJA, Waterham HR (2006) Biochemistry of mammalian peroxisomes revisited. Annu Rev Biochem 75:295–332. CrossRefGoogle Scholar
  44. 44.
    Berger J, Dorninger F, Forss-Petter S, Kunze M (2016) Peroxisomes in brain development and function. Biochim Biophys Acta 5:4. Google Scholar
  45. 45.
    Vanhove G, Van Veldhoven PP, Vanhoutte F et al (1991) Mitochondrial and peroxisomal beta oxidation of the branched chain fatty acid 2-methylpalmitate in rat liver. J Biol Chem 266:24670–24675Google Scholar
  46. 46.
    Liu L, Martin R, Chan C (2013) Palmitate-activated astrocytes via serine palmitoyltransferase increase BACE1 in primary neurons by sphingomyelinases. Neurobiol Aging 34:540–550. CrossRefGoogle Scholar
  47. 47.
    Rahman M, Nirala NK, Singh A et al (2014) Drosophila sirt2/mammalian SIRT3 deacetylates ATP synthase β and regulates complex V activity. J Cell Biol 206:289–305. CrossRefGoogle Scholar
  48. 48.
    Imai SI, Armstrong CM, Kaeberlein M, Guarente L (2000) Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403:795–800. CrossRefGoogle Scholar
  49. 49.
    Bitterman KJ, Anderson RM, Cohen HY et al (2002) Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast Sir2 and human SIRT1. J Biol Chem. Google Scholar
  50. 50.
    Revollo JR, Grimm AA, Imai SI (2004) The NAD biosynthesis pathway mediated by nicotinamide phosphoribosyltransferase regulates Sir2 activity in mammalian cells. J Biol Chem 5:4. Google Scholar
  51. 51.
    Kauppinen A, Suuronen T, Ojala J et al (2013) Antagonistic crosstalk between NF-κB and SIRT1 in the regulation of inflammation and metabolic disorders. Cell Signal 25:1939–1948. CrossRefGoogle Scholar
  52. 52.
    Yuzefovych L, Wilson G, Rachek L (2010) Different effects of oleate vs. palmitate on mitochondrial function, apoptosis, and insulin signaling in L6 skeletal muscle cells: role of oxidative stress. Am J Physiol Metab 299:E1096–E1105. Google Scholar
  53. 53.
    De Kreutzenberg SV, Ceolotto G, Papparella I et al (2010) Downregulation of the longevity-associated protein sirtuin 1 in insulin resistance and metabolic syndrome: potential biochemical mechanisms. Diabetes 59:1006–1015. CrossRefGoogle Scholar
  54. 54.
    Caito S, Rajendrasozhan S, Cook S et al (2010) SIRT1 is a redox-sensitive deacetylase that is post-translationally modified by oxidants and carbonyl stress. FASEB J 24:3145–3159. CrossRefGoogle Scholar
  55. 55.
    Milner J (2009) Cellular regulation of SIRT1. Curr Pharm Des 15:39–44. CrossRefGoogle Scholar
  56. 56.
    Cao L, Liu C, Wang F, Wang H (2013) SIRT1 negatively regulates amyloid-beta-induced inflammation via the NF-κB pathway. Braz J Med Biol Res 46:659–669. CrossRefGoogle Scholar
  57. 57.
    Bourne KZ, Ferrari DC, Lange-Dohna C et al (2007) Differential regulation of BACE1 promoter activity by nuclear factor-κB in neurons and glia upon exposure to β-amyloid peptides. J Neurosci Res 85:1194–1204. CrossRefGoogle Scholar
  58. 58.
    Chen CH, Zhou W, Liu S et al (2012) Increased NF-κB signalling up-regulates BACE1 expression and its therapeutic potential in Alzheimer’s disease. Int J Neuropsychopharmacol 15:77–90. CrossRefGoogle Scholar
  59. 59.
    Chami L, Buggia-Prévot V, Duplan E et al (2012) Nuclear factor-κB regulates βAPP and β- and γ-secretases differently at physiological and supraphysiological Aβ concentrations. J Biol Chem 287:24573–24584. CrossRefGoogle Scholar
  60. 60.
    Wang R, Li JJ, Diao S et al (2013) Metabolic stress modulates Alzheimer’s β-secretase gene transcription via SIRT1-PPARγ-PGC-1 in neurons. Cell Metab 17:685–694. CrossRefGoogle Scholar
  61. 61.
    Ben Halima S, Mishra S, Raja KMP et al (2016) Specific inhibition of β-secretase processing of the Alzheimer disease amyloid precursor protein. Cell Rep 14:2127–2141. CrossRefGoogle Scholar
  62. 62.
    Andrew RJ, Fernandez CG, Stanley M et al (2017) Lack of BACE1 S-palmitoylation reduces amyloid burden and mitigates memory deficits in transgenic mouse models of Alzheimer’s disease. Proc Natl Acad Sci 114:201708568. CrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones BiomédicasUniversidad Nacional Autónoma de MéxicoMéxicoMexico
  2. 2.Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología (INCan)-Instituto de Investigaciones Biomédicas (IIB)Universidad Nacional Autónoma de México (UNAM)MéxicoMexico

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