Semin Liver Dis 2023; 43(01): 077-088
DOI: 10.1055/s-0043-1762585
Review Article

Emerging Links between Nonalcoholic Fatty Liver Disease and Neurodegeneration

Taylor J. Kelty
1   Department of Biomedical Sciences, University of Missouri - Columbia, Columbia, Missouri
2   Department of Nutrition and Exercise Physiology, University of Missouri - Columbia, Columbia, Missouri
3   NextGen Precision Health, University of Missouri - Columbia, Columbia, Missouri
Ryan J. Dashek
1   Department of Biomedical Sciences, University of Missouri - Columbia, Columbia, Missouri
3   NextGen Precision Health, University of Missouri - Columbia, Columbia, Missouri
4   Comparative Medicine Program, University of Missouri - Columbia, Columbia, Missouri
W. David Arnold
3   NextGen Precision Health, University of Missouri - Columbia, Columbia, Missouri
5   Physical Medicine and Rehabilitation, University of Missouri - Columbia, Columbia, Missouri
R. Scott Rector
2   Department of Nutrition and Exercise Physiology, University of Missouri - Columbia, Columbia, Missouri
3   NextGen Precision Health, University of Missouri - Columbia, Columbia, Missouri
6   Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, Missouri
7   Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri - Columbia, Columbia, Missouri
› Author Affiliations
Funding This study received funding from the U.S. Department of Health and Human Services, National Institutes of Health: R01 AG070928, R01 DK113701, R01 DK130243, R01 DK130340.


The association between liver and brain health has gained attention as biomarkers of liver function have been revealed to predict neurodegeneration. The liver is a central regulator in metabolic homeostasis. However, in nonalcoholic fatty liver disease (NAFLD), homeostasis is disrupted which can result in extrahepatic organ pathologies. Emerging literature provides insight into the mechanisms behind the liver–brain health axis. These include the increased production of liver-derived factors that promote insulin resistance and loss of neuroprotective factors under conditions of NAFLD that increase insulin resistance in the central nervous system. In addition, elevated proinflammatory cytokines linked to NAFLD negatively impact the blood–brain barrier and increase neuroinflammation. Furthermore, exacerbated dyslipidemia associated with NAFLD and hepatic dysfunction can promote altered brain bioenergetics and oxidative stress. In this review, we summarize the current knowledge of the crosstalk between liver and brain as it relates to the pathophysiology between NAFLD and neurodegeneration, with an emphasis on Alzheimer's disease. We also highlight knowledge gaps and future areas for investigation to strengthen the potential link between NAFLD and neurodegeneration.

Publication History

Article published online:
10 February 2023

© 2023. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

  • References

  • 1 Hou Y, Dan X, Babbar M. et al. Ageing as a risk factor for neurodegenerative disease. Nat Rev Neurol 2019; 15 (10) 565-581
  • 2 Ghareeb DA, Hafez HS, Hussien HM, Kabapy NF. Non-alcoholic fatty liver induces insulin resistance and metabolic disorders with development of brain damage and dysfunction. Metab Brain Dis 2011; 26 (04) 253-267
  • 3 Weinstein G, Davis-Plourde K, Himali JJ, Zelber-Sagi S, Beiser AS, Seshadri S. Non-alcoholic fatty liver disease, liver fibrosis score and cognitive function in middle-aged adults: the Framingham Study. Liver Int 2019; 39 (09) 1713-1721
  • 4 Gholizadeh E, Khaleghian A, Najafgholi Seyfi D, Karbalaei R. Showing NAFLD, as a key connector disease between Alzheimer's disease and diabetes via analysis of systems biology. Gastroenterol Hepatol Bed Bench 2020; 13 (Suppl (Suppl. 01) S89-S97
  • 5 Kjærgaard K, Mikkelsen ACD, Wernberg CW. et al. Cognitive dysfunction in non-alcoholic fatty liver disease-current knowledge, mechanisms and perspectives. J Clin Med 2021; 10 (04) 10
  • 6 Estes C, Anstee QM, Arias-Loste MT. et al. Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016-2030. J Hepatol 2018; 69 (04) 896-904
  • 7 Carr RM, Oranu A, Khungar V. Nonalcoholic fatty liver disease: pathophysiology and management. Gastroenterol Clin North Am 2016; 45 (04) 639-652
  • 8 Loomba R, Adams LA. The 20% rule of NASH progression: the natural history of advanced fibrosis and cirrhosis caused by NASH. Hepatology 2019; 70 (06) 1885-1888
  • 9 Dyson JK, Anstee QM, McPherson S. Non-alcoholic fatty liver disease: a practical approach to diagnosis and staging. Frontline Gastroenterol 2014; 5 (03) 211-218
  • 10 Pierantonelli I, Svegliati-Baroni G. Nonalcoholic fatty liver disease: basic pathogenetic mechanisms in the progression from NAFLD to NASH. Transplantation 2019; 103 (01) e1-e13
  • 11 Schuster S, Cabrera D, Arrese M, Feldstein AE. Triggering and resolution of inflammation in NASH. Nat Rev Gastroenterol Hepatol 2018; 15 (06) 349-364
  • 12 Tsuchida T, Friedman SL. Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol 2017; 14 (07) 397-411
  • 13 Mederacke I, Hsu CC, Troeger JS. et al. Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat Commun 2013; 4: 2823
  • 14 Gale SA, Acar D, Daffner KR. Dementia. Am J Med 2018; 131 (10) 1161-1169
  • 15 Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol 1956; 11 (03) 298-300
  • 16 Leuner K, Schütt T, Kurz C. et al. Mitochondrion-derived reactive oxygen species lead to enhanced amyloid beta formation. Antioxid Redox Signal 2012; 16 (12) 1421-1433
  • 17 Golpich M, Amini E, Mohamed Z, Azman Ali R, Mohamed Ibrahim N, Ahmadiani A. Mitochondrial dysfunction and biogenesis in neurodegenerative diseases: pathogenesis and treatment. CNS Neurosci Ther 2017; 23 (01) 5-22
  • 18 Troutwine BR, Strope TA, Franczak E. et al. Mitochondrial function and Aβ in Alzheimer's disease postmortem brain. Neurobiol Dis 2022; 171: 105781
  • 19 Cardoso SM, Santana I, Swerdlow RH, Oliveira CR. Mitochondria dysfunction of Alzheimer's disease cybrids enhances Abeta toxicity. J Neurochem 2004; 89 (06) 1417-1426
  • 20 Khan SM, Cassarino DS, Abramova NN. et al. Alzheimer's disease cybrids replicate beta-amyloid abnormalities through cell death pathways. Ann Neurol 2000; 48 (02) 148-155
  • 21 Swerdlow RH, Koppel S, Weidling I, Hayley C, Ji Y, Wilkins HM. Mitochondria, cybrids, aging, and Alzheimer's DISEASE. Prog Mol Biol Transl Sci 2017; 146: 259-302
  • 22 Khansari N, Shakiba Y, Mahmoudi M. Chronic inflammation and oxidative stress as a major cause of age-related diseases and cancer. Recent Pat Inflamm Allergy Drug Discov 2009; 3 (01) 73-80
  • 23 Okello A, Edison P, Archer HA. et al. Microglial activation and amyloid deposition in mild cognitive impairment: a PET study. Neurology 2009; 72 (01) 56-62
  • 24 Bradburn S, Murgatroyd C, Ray N. Neuroinflammation in mild cognitive impairment and Alzheimer's disease: a meta-analysis. Ageing Res Rev 2019; 50: 1-8
  • 25 Steen E, Terry BM, Rivera EJ. et al. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease -- Is this type 3 diabetes?. J Alzheimers Dis 2005; 7 (01) 63-80
  • 26 Moloney AM, Griffin RJ, Timmons S, O'Connor R, Ravid R, O'Neill C. Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer's disease indicate possible resistance to IGF-1 and insulin signalling. Neurobiol Aging 2010; 31 (02) 224-243
  • 27 de la Monte SM, Tong M. Brain metabolic dysfunction at the core of Alzheimer's disease. Biochem Pharmacol 2014; 88 (04) 548-559
  • 28 Meex RCR, Watt MJ. Hepatokines: linking nonalcoholic fatty liver disease and insulin resistance. Nat Rev Endocrinol 2017; 13 (09) 509-520
  • 29 Kacířová M, Železná B, Blažková M. et al. Aging and high-fat diet feeding lead to peripheral insulin resistance and sex-dependent changes in brain of mouse model of tau pathology THY-Tau22. J Neuroinflammation 2021; 18 (01) 141
  • 30 Rusli F, Deelen J, Andriyani E. et al. Fibroblast growth factor 21 reflects liver fat accumulation and dysregulation of signalling pathways in the liver of C57BL/6J mice. Sci Rep 2016; 6: 30484
  • 31 Gad RA, Abdel-Reheim ES, Shehab GMG, Hafez HS, Abuelsaad ASA. Evaluation of insulin resistance induced brain tissue dysfunction in obese dams and their neonates: role of ipriflavone amelioration. Comb Chem High Throughput Screen 2021; 24 (06) 767-780
  • 32 Watt MJ, Miotto PM, De Nardo W, Montgomery MK. The liver as an endocrine organ-linking NAFLD and insulin resistance. Endocr Rev 2019; 40 (05) 1367-1393
  • 33 Rebelos E, Iozzo P, Guzzardi MA, Brunetto MR, Bonino F. Brain-gut-liver interactions across the spectrum of insulin resistance in metabolic fatty liver disease. World J Gastroenterol 2021; 27 (30) 4999-5018
  • 34 Tricò D, Galderisi A, Mari A. et al. Intrahepatic fat, irrespective of ethnicity, is associated with reduced endogenous insulin clearance and hepatic insulin resistance in obese youths: a cross-sectional and longitudinal study from the Yale Pediatric NAFLD cohort. Diabetes Obes Metab 2020; 22 (09) 1628-1638
  • 35 Williams CD, Stengel J, Asike MI. et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology 2011; 140 (01) 124-131
  • 36 Heni M, Schöpfer P, Peter A. et al. Evidence for altered transport of insulin across the blood-brain barrier in insulin-resistant humans. Acta Diabetol 2014; 51 (04) 679-681
  • 37 Schwartz MW, Figlewicz DF, Kahn SE, Baskin DG, Greenwood MR, Porte Jr D. Insulin binding to brain capillaries is reduced in genetically obese, hyperinsulinemic Zucker rats. Peptides 1990; 11 (03) 467-472
  • 38 Schubert M, Brazil DP, Burks DJ. et al. Insulin receptor substrate-2 deficiency impairs brain growth and promotes tau phosphorylation. J Neurosci 2003; 23 (18) 7084-7092
  • 39 Martín ED, Sánchez-Perez A, Trejo JL. et al. IRS-2 deficiency impairs NMDA receptor-dependent long-term potentiation. Cereb Cortex 2012; 22 (08) 1717-1727
  • 40 Dichtel LE, Corey KE, Misdraji J. et al. The association between IGF-1 levels and the histologic severity of nonalcoholic fatty liver disease. Clin Transl Gastroenterol 2017; 8 (01) e217
  • 41 Logan S, Pharaoh GA, Marlin MC. et al. Insulin-like growth factor receptor signaling regulates working memory, mitochondrial metabolism, and amyloid-β uptake in astrocytes. Mol Metab 2018; 9: 141-155
  • 42 Baumeier C, Schlüter L, Saussenthaler S. et al. Elevated hepatic DPP4 activity promotes insulin resistance and non-alcoholic fatty liver disease. Mol Metab 2017; 6 (10) 1254-1263
  • 43 Cai H, Lu S, Chen Y. et al. Serum retinol binding protein 4 and galectin-3 binding protein as novel markers for postmenopausal nonalcoholic fatty liver disease. Clin Biochem 2018; 56: 95-101
  • 44 Wu H, Jia W, Bao Y. et al. Serum retinol binding protein 4 and nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus. Diabetes Res Clin Pract 2008; 79 (02) 185-190
  • 45 Firneisz G, Varga T, Lengyel G. et al. Serum dipeptidyl peptidase-4 activity in insulin resistant patients with non-alcoholic fatty liver disease: a novel liver disease biomarker. PLoS One 2010; 5 (08) e12226
  • 46 Chen X, Shen T, Li Q. et al. Retinol binding protein-4 levels and non-alcoholic fatty liver disease: a community-based cross-sectional study. Sci Rep 2017; 7: 45100
  • 47 Siddiqui N, Ali J, Parvez S, Zameer S, Najmi AK, Akhtar M. Linagliptin, a DPP-4 inhibitor, ameliorates Aβ (1-42) peptides induced neurodegeneration and brain insulin resistance (BIR) via insulin receptor substrate-1 (IRS-1) in rat model of Alzheimer's disease. Neuropharmacology 2021; 195: 108662
  • 48 Nakaoku Y, Saito S, Yamamoto Y, Maki T, Takahashi R, Ihara M. The dipeptidyl peptidase-4 inhibitor linagliptin ameliorates high-fat induced cognitive decline in tauopathy model mice. Int J Mol Sci 2019; 20 (10) 20
  • 49 Sa-Nguanmoo P, Tanajak P, Kerdphoo S. et al. SGLT2-inhibitor and DPP-4 inhibitor improve brain function via attenuating mitochondrial dysfunction, insulin resistance, inflammation, and apoptosis in HFD-induced obese rats. Toxicol Appl Pharmacol 2017; 333: 43-50
  • 50 Pipatpiboon N, Pintana H, Pratchayasakul W, Chattipakorn N, Chattipakorn SC. DPP4-inhibitor improves neuronal insulin receptor function, brain mitochondrial function and cognitive function in rats with insulin resistance induced by high-fat diet consumption. Eur J Neurosci 2013; 37 (05) 839-849
  • 51 Mody N, Agouni A, McIlroy GD, Platt B, Delibegovic M. Susceptibility to diet-induced obesity and glucose intolerance in the APP (SWE)/PSEN1 (A246E) mouse model of Alzheimer's disease is associated with increased brain levels of protein tyrosine phosphatase 1B (PTP1B) and retinol-binding protein 4 (RBP4), and basal phosphorylation of S6 ribosomal protein. Diabetologia 2011; 54 (08) 2143-2151
  • 52 Nielsen JE, Honoré B, Vestergård K. et al. Shotgun-based proteomics of extracellular vesicles in Alzheimer's disease reveals biomarkers involved in immunological and coagulation pathways. Sci Rep 2021; 11 (01) 18518
  • 53 Kakazu E, Mauer AS, Yin M, Malhi H. Hepatocytes release ceramide-enriched pro-inflammatory extracellular vesicles in an IRE1α-dependent manner. J Lipid Res 2016; 57 (02) 233-245
  • 54 Cruciani-Guglielmacci C, López M, Campana M, le Stunff H. Brain ceramide metabolism in the control of energy balance. Front Physiol 2017; 8: 787
  • 55 Promrat K, Longato L, Wands JR, de la Monte SM. Weight loss amelioration of non-alcoholic steatohepatitis linked to shifts in hepatic ceramide expression and serum ceramide levels. Hepatol Res 2011; 41 (08) 754-762
  • 56 Luukkonen PK, Zhou Y, Sädevirta S. et al. Hepatic ceramides dissociate steatosis and insulin resistance in patients with non-alcoholic fatty liver disease. J Hepatol 2016; 64 (05) 1167-1175
  • 57 de la Monte SM, Tong M, Nguyen V, Setshedi M, Longato L, Wands JR. Ceramide-mediated insulin resistance and impairment of cognitive-motor functions. J Alzheimers Dis 2010; 21 (03) 967-984
  • 58 Summers SA. Ceramides in insulin resistance and lipotoxicity. Prog Lipid Res 2006; 45 (01) 42-72
  • 59 Katsel P, Li C, Haroutunian V. Gene expression alterations in the sphingolipid metabolism pathways during progression of dementia and Alzheimer's disease: a shift toward ceramide accumulation at the earliest recognizable stages of Alzheimer's disease?. Neurochem Res 2007; 32 (4-5): 845-856
  • 60 Lyn-Cook Jr LE, Lawton M, Tong M. et al. Hepatic ceramide may mediate brain insulin resistance and neurodegeneration in type 2 diabetes and non-alcoholic steatohepatitis. J Alzheimers Dis 2009; 16 (04) 715-729
  • 61 Jager J, Grémeaux T, Cormont M, Le Marchand-Brustel Y, Tanti JF. Interleukin-1beta-induced insulin resistance in adipocytes through down-regulation of insulin receptor substrate-1 expression. Endocrinology 2007; 148 (01) 241-251
  • 62 Clemenzi MN, Wellhauser L, Aljghami ME, Belsham DD. Tumour necrosis factor α induces neuroinflammation and insulin resistance in immortalised hypothalamic neurones through independent pathways. J Neuroendocrinol 2019; 31 (01) e12678
  • 63 Komleva YK, Potapenko IV, Lopatina OL. et al. NLRP3 inflammasome blocking as a potential treatment of central insulin resistance in early-stage Alzheimer's disease. Int J Mol Sci 2021; 22 (21) 22
  • 64 Dixon LJ, Barnes M, Tang H, Pritchard MT, Nagy LE. Kupffer cells in the liver. Compr Physiol 2013; 3 (02) 785-797
  • 65 Micu ES, Amzolini AM, Barău Abu-Alhija A. et al. Systemic and adipose tissue inflammation in NASH: correlations with histopathological aspects. Rom J Morphol Embryol 2021; 62 (02) 509-515
  • 66 Luci C, Bourinet M, Leclère PS, Anty R, Gual P. Chronic inflammation in non-alcoholic steatohepatitis: molecular mechanisms and therapeutic strategies. Front Endocrinol (Lausanne) 2020; 11: 597648
  • 67 Bennett H, Troutman TD, Sakai M, Glass CK. Epigenetic regulation of Kupffer cell function in health and disease. Front Immunol 2021; 11: 609618
  • 68 Lesmana CR, Hasan I, Budihusodo U. et al. Diagnostic value of a group of biochemical markers of liver fibrosis in patients with non-alcoholic steatohepatitis. J Dig Dis 2009; 10 (03) 201-206
  • 69 Gutierrez EG, Banks WA, Kastin AJ. Murine tumor necrosis factor alpha is transported from blood to brain in the mouse. J Neuroimmunol 1993; 47 (02) 169-176
  • 70 Biesmans S, Bouwknecht JA, Ver Donck L. et al. Peripheral administration of tumor necrosis factor-alpha induces neuroinflammation and sickness but not depressive-like behavior in mice. BioMed Res Int 2015; 2015: 716920
  • 71 D'Mello C, Le T, Swain MG. Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factor alpha signaling during peripheral organ inflammation. J Neurosci 2009; 29 (07) 2089-2102
  • 72 Trepanowski JF, Mey J, Varady KA. Fetuin-A: a novel link between obesity and related complications. Int J Obes 2015; 39 (05) 734-741
  • 73 Goustin AS, Derar N, Abou-Samra AB. Ahsg-fetuin blocks the metabolic arm of insulin action through its interaction with the 95-kD β-subunit of the insulin receptor. Cell Signal 2013; 25 (04) 981-988
  • 74 Peter A, Kovarova M, Staiger H. et al. The hepatokines fetuin-A and fetuin-B are upregulated in the state of hepatic steatosis and may differently impact on glucose homeostasis in humans. Am J Physiol Endocrinol Metab 2018; 314 (03) E266-E273
  • 75 Sardana O, Goyal R, Bedi O. Molecular and pathobiological involvement of fetuin-A in the pathogenesis of NAFLD. Inflammopharmacology 2021; 29 (04) 1061-1074
  • 76 Mukhuty A, Fouzder C, Mukherjee S. et al. Palmitate induced fetuin-A secretion from pancreatic β-cells adversely affects its function and elicits inflammation. Biochem Biophys Res Commun 2017; 491 (04) 1118-1124
  • 77 Altamimi M. Could autism be associated with nutritional status in the Palestinian population? The outcomes of the Palestinian micronutrient survey. Nutr Metab Insights 2018; 11: 1178638818773078
  • 78 Mondal A, Bose D, Saha P. et al. Lipocalin 2 induces neuroinflammation and blood-brain barrier dysfunction through liver-brain axis in murine model of nonalcoholic steatohepatitis. J Neuroinflammation 2020; 17 (01) 201
  • 79 Wree A, McGeough MD, Peña CA. et al. NLRP3 inflammasome activation is required for fibrosis development in NAFLD. J Mol Med (Berl) 2014; 92 (10) 1069-1082
  • 80 Csak T, Ganz M, Pespisa J, Kodys K, Dolganiuc A, Szabo G. Fatty acid and endotoxin activate inflammasomes in mouse hepatocytes that release danger signals to stimulate immune cells. Hepatology 2011; 54 (01) 133-144
  • 81 Qiao C, Zhang Q, Jiang Q. et al. Inhibition of the hepatic Nlrp3 protects dopaminergic neurons via attenuating systemic inflammation in a MPTP/p mouse model of Parkinson's disease. J Neuroinflammation 2018; 15 (01) 193
  • 82 Lee SH, Yang EJ. Relationship between liver pathology and disease progression in a murine model of amyotrophic lateral sclerosis. Neurodegener Dis 2018; 18 (04) 200-207
  • 83 Masui Y, Mozai T, Kakehi K. Functional and morphometric study of the liver in motor neuron disease. J Neurol 1985; 232 (01) 15-19
  • 84 Ban LA, Shackel NA, McLennan SV. Extracellular vesicles: a new frontier in biomarker discovery for non-alcoholic fatty liver disease. Int J Mol Sci 2016; 17 (03) 376
  • 85 Cai S, Cheng X, Pan X, Li J. Emerging role of exosomes in liver physiology and pathology. Hepatol Res 2017; 47 (02) 194-203
  • 86 Srinivas AN, Suresh D, Santhekadur PK, Suvarna D, Kumar DP. Extracellular vesicles as inflammatory drivers in NAFLD. Front Immunol 2021; 11: 627424
  • 87 Morán L, Cubero FJ. Extracellular vesicles in liver disease and beyond. World J Gastroenterol 2018; 24 (40) 4519-4526
  • 88 Sato K, Meng F, Glaser S, Alpini G. Exosomes in liver pathology. J Hepatol 2016; 65 (01) 213-221
  • 89 Povero D, Eguchi A, Li H. et al. Circulating extracellular vesicles with specific proteome and liver microRNAs are potential biomarkers for liver injury in experimental fatty liver disease. PLoS One 2014; 9 (12) e113651
  • 90 Mann J, Reeves HL, Feldstein AE. Liquid biopsy for liver diseases. Gut 2018; 67 (12) 2204-2212
  • 91 Zhou B, Xu K, Zheng X. et al. Application of exosomes as liquid biopsy in clinical diagnosis. Signal Transduct Target Ther 2020; 5 (01) 144
  • 92 Urban SK, Mocan T, Sänger H, Lukacs-Kornek V, Kornek M. Extracellular vesicles in liver diseases: diagnostic, prognostic, and therapeutic application. Semin Liver Dis 2019; 39 (01) 70-77
  • 93 Hirsova P, Gores GJ. Death receptor-mediated cell death and proinflammatory signaling in nonalcoholic steatohepatitis. Cell Mol Gastroenterol Hepatol 2015; 1 (01) 17-27
  • 94 Hirsova P, Ibrahim SH, Krishnan A. et al. Lipid-induced signaling causes release of inflammatory extracellular vesicles from hepatocytes. Gastroenterology 2016; 150 (04) 956-967
  • 95 Ibrahim SH, Hirsova P, Tomita K. et al. Mixed lineage kinase 3 mediates release of C-X-C motif ligand 10-bearing chemotactic extracellular vesicles from lipotoxic hepatocytes. Hepatology 2016; 63 (03) 731-744
  • 96 Hirsova P, Weng P, Salim W. et al. TRAIL deletion prevents liver, but not adipose tissue, inflammation during murine diet-induced obesity. Hepatol Commun 2017; 1 (07) 648-662
  • 97 Garcia-Martinez I, Santoro N, Chen Y. et al. Hepatocyte mitochondrial DNA drives nonalcoholic steatohepatitis by activation of TLR9. J Clin Invest 2016; 126 (03) 859-864
  • 98 Qin L, Zou J, Barnett A, Vetreno RP, Crews FT, Coleman Jr LG. TRAIL mediates neuronal death in AUD: a link between neuroinflammation and neurodegeneration. Int J Mol Sci 2021; 22 (05) 22
  • 99 Clarner T, Janssen K, Nellessen L. et al. CXCL10 triggers early microglial activation in the cuprizone model. J Immunol 2015; 194 (07) 3400-3413
  • 100 Haruwaka K, Ikegami A, Tachibana Y. et al. Dual microglia effects on blood brain barrier permeability induced by systemic inflammation. Nat Commun 2019; 10 (01) 5816
  • 101 Zamudio F, Loon AR, Smeltzer S. et al. TDP-43 mediated blood-brain barrier permeability and leukocyte infiltration promote neurodegeneration in a low-grade systemic inflammation mouse model. J Neuroinflammation 2020; 17 (01) 283
  • 102 Zhang Y, Gao Z, Wang D. et al. Accumulation of natural killer cells in ischemic brain tissues and the chemotactic effect of IP-10. J Neuroinflammation 2014; 11: 79
  • 103 Tsao N, Hsu HP, Wu CM, Liu CC, Lei HY. Tumour necrosis factor-alpha causes an increase in blood-brain barrier permeability during sepsis. J Med Microbiol 2001; 50 (09) 812-821
  • 104 Palomino-Antolin A, Narros-Fernández P, Farré-Alins V. et al. Time-dependent dual effect of NLRP3 inflammasome in brain ischaemia. Br J Pharmacol 2022; 179 (07) 1395-1410
  • 105 Ding YX, Eerduna GW, Duan SJ. et al. Escin ameliorates the impairments of neurological function and blood brain barrier by inhibiting systemic inflammation in intracerebral hemorrhagic mice. Exp Neurol 2021; 337: 113554
  • 106 Kao YC, Ho PC, Tu YK, Jou IM, Tsai KJ. Lipids and Alzheimer's disease. Int J Mol Sci 2020; 21 (04) 21
  • 107 Bowman GL, Kaye JA, Quinn JF. Dyslipidemia and blood-brain barrier integrity in Alzheimer's disease. Curr Gerontol Geriatr Res 2012; 2012: 184042
  • 108 de Paula GC, Brunetta HS, Engel DF. et al. Hippocampal function is impaired by a short-term high-fat diet in mice: increased blood-brain barrier permeability and neuroinflammation as triggering events. Front Neurosci 2021; 15: 734158
  • 109 Pinçon A, De Montgolfier O, Akkoyunlu N. et al. Non-alcoholic fatty liver disease, and the underlying altered fatty acid metabolism, reveals brain hypoperfusion and contributes to the cognitive decline in APP/PS1 mice. Metabolites 2019; 9 (05) 9
  • 110 Cohen DE, Fisher EA. Lipoprotein metabolism, dyslipidemia, and nonalcoholic fatty liver disease. Semin Liver Dis 2013; 33 (04) 380-388
  • 111 McCullough A, Previs SF, Dasarathy J. et al. HDL flux is higher in patients with nonalcoholic fatty liver disease. Am J Physiol Endocrinol Metab 2019; 317 (05) E852 –E862
  • 112 Zuliani G, Cavalieri M, Galvani M. et al. Markers of endothelial dysfunction in older subjects with late onset Alzheimer's disease or vascular dementia. J Neurol Sci 2008; 272 (1-2): 164-170
  • 113 Zuliani G, Cavalieri M, Galvani M. et al. Relationship between low levels of high-density lipoprotein cholesterol and dementia in the elderly. The InChianti study. J Gerontol A Biol Sci Med Sci 2010; 65 (05) 559-564
  • 114 Razay G, Vreugdenhil A, Wilcock G. The metabolic syndrome and Alzheimer disease. Arch Neurol 2007; 64 (01) 93-96
  • 115 Nakahara T, Hyogo H, Yoneda M. et al; Japan Study Group of Nonalcoholic Fatty Liver Disease. Type 2 diabetes mellitus is associated with the fibrosis severity in patients with nonalcoholic fatty liver disease in a large retrospective cohort of Japanese patients. J Gastroenterol 2014; 49 (11) 1477-1484
  • 116 Wingo TS, Cutler DJ, Wingo AP. et al. Association of early-onset Alzheimer disease with elevated low-density lipoprotein cholesterol levels and rare genetic coding variants of APOB. JAMA Neurol 2019; 76 (07) 809-817
  • 117 Bereczki E, Bernát G, Csont T, Ferdinandy P, Scheich H, Sántha M. Overexpression of human apolipoprotein B-100 induces severe neurodegeneration in transgenic mice. J Proteome Res 2008; 7 (06) 2246-2252
  • 118 de Oliveira J, Engel DF, de Paula GC. et al. High cholesterol diet exacerbates blood-brain barrier disruption in LDLr-/- mice: impact on cognitive function. J Alzheimers Dis 2020; 78 (01) 97-115
  • 119 Banks WA, Farr SA, Salameh TS. et al. Triglycerides cross the blood-brain barrier and induce central leptin and insulin receptor resistance. Int J Obes 2018; 42 (03) 391-397
  • 120 Lee LL, Aung HH, Wilson DW, Anderson SE, Rutledge JC, Rutkowsky JM. Triglyceride-rich lipoprotein lipolysis products increase blood-brain barrier transfer coefficient and induce astrocyte lipid droplets and cell stress. Am J Physiol Cell Physiol 2017; 312 (04) C500-C516
  • 121 Barrows BR, Timlin MT, Parks EJ. Spillover of dietary fatty acids and use of serum nonesterified fatty acids for the synthesis of VLDL-triacylglycerol under two different feeding regimens. Diabetes 2005; 54 (09) 2668-2673
  • 122 Fabbrini E, Mohammed BS, Magkos F, Korenblat KM, Patterson BW, Klein S. Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease. Gastroenterology 2008; 134 (02) 424-431
  • 123 Jeong S, Oh YH, Choi S. et al. Association of non-alcoholic fatty liver disease with incident dementia later in life among elder adults. Clin Mol Hepatol 2022; 28 (03) 510-521
  • 124 Shirai K, Saito Y, Yoshida S, Matsuoka N. Existence of lipoprotein lipase in rat brain microvessels. Tohoku J Exp Med 1986; 149 (04) 449-450
  • 125 Hamilton LK, Dufresne M, Joppé SE. et al. Aberrant lipid metabolism in the forebrain niche suppresses adult neural stem cell proliferation in an animal model of Alzheimer's disease. Cell Stem Cell 2015; 17 (04) 397-411
  • 126 Hussain G, Schmitt F, Loeffler JP, Gonzalez de Aguilar JL. Fatting the brain: a brief of recent research. Front Cell Neurosci 2013; 7: 144
  • 127 Loera-Valencia R, Goikolea J, Parrado-Fernandez C, Merino-Serrais P, Maioli S. Alterations in cholesterol metabolism as a risk factor for developing Alzheimer's disease: potential novel targets for treatment. J Steroid Biochem Mol Biol 2019; 190: 104-114
  • 128 Zhao XS, Wu Q, Peng J. et al. Hyperlipidemia-induced apoptosis of hippocampal neurons in apoE(-/-) mice may be associated with increased PCSK9 expression. Mol Med Rep 2017; 15 (02) 712-718
  • 129 Rolfe DF, Brown GC. Cellular energy utilization and molecular origin of standard metabolic rate in mammals. Physiol Rev 1997; 77 (03) 731-758
  • 130 Mergenthaler P, Lindauer U, Dienel GA, Meisel A. Sugar for the brain: the role of glucose in physiological and pathological brain function. Trends Neurosci 2013; 36 (10) 587-597
  • 131 Erbsloh F, Bernsmeier A, Hillesheim H. [The glucose consumption of the brain & its dependence on the liver]. Arch Psychiatr Nervenkr Z Gesamte Neurol Psychiatr 1958; 196 (06) 611-626
  • 132 Schönfeld P, Reiser G. Brain energy metabolism spurns fatty acids as fuel due to their inherent mitotoxicity and potential capacity to unleash neurodegeneration. Neurochem Int 2017; 109: 68-77
  • 133 Brand MD. The sites and topology of mitochondrial superoxide production. Exp Gerontol 2010; 45 (7-8): 466-472
  • 134 Ren X, Zou L, Zhang X. et al. Redox signaling mediated by thioredoxin and glutathione systems in the central nervous system. Antioxid Redox Signal 2017; 27 (13) 989-1010
  • 135 Zitka O, Skalickova S, Gumulec J. et al. Redox status expressed as GSH:GSSG ratio as a marker for oxidative stress in paediatric tumour patients. Oncol Lett 2012; 4 (06) 1247-1253
  • 136 Erecińska M, Silver IA. Tissue oxygen tension and brain sensitivity to hypoxia. Respir Physiol 2001; 128 (03) 263-276
  • 137 Seo SW, Gottesman RF, Clark JM. et al. Nonalcoholic fatty liver disease is associated with cognitive function in adults. Neurology 2016; 86 (12) 1136-1142
  • 138 Weinstein G, Zelber-Sagi S, Preis SR. et al. Association of nonalcoholic fatty liver disease with lower brain volume in healthy middle-aged adults in the Framingham study. JAMA Neurol 2018; 75 (01) 97-104
  • 139 Zeltser N, Meyer I, Hernandez GV. et al. Neurodegeneration in juvenile Iberian pigs with diet-induced nonalcoholic fatty liver disease. Am J Physiol Endocrinol Metab 2020; 319 (03) E592-E606
  • 140 Schönfeld P, Schlüter T, Fischer KD, Reiser G. Non-esterified polyunsaturated fatty acids distinctly modulate the mitochondrial and cellular ROS production in normoxia and hypoxia. J Neurochem 2011; 118 (01) 69-78
  • 141 Kim DG, Krenz A, Toussaint LE. et al. Non-alcoholic fatty liver disease induces signs of Alzheimer's disease (AD) in wild-type mice and accelerates pathological signs of AD in an AD model. J Neuroinflammation 2016; 13: 1
  • 142 Zhou Z, Niu X, Cao J, Li H. Non-alcoholic fatty liver disease and the risk of dementia. Liver Int 2022; 42 (08) 1912-1913
  • 143 Balzano T, Forteza J, Borreda I. et al. Histological features of cerebellar neuropathology in patients with alcoholic and nonalcoholic steatohepatitis. J Neuropathol Exp Neurol 2018; 77 (09) 837-845
  • 144 Nho K, Kueider-Paisley A, Ahmad S. et al; Alzheimer's Disease Neuroimaging Initiative and the Alzheimer Disease Metabolomics Consortium. Association of altered liver enzymes with Alzheimer disease diagnosis, cognition, neuroimaging measures, and cerebrospinal fluid biomarkers. JAMA Netw Open 2019; 2 (07) e197978
  • 145 Shang Y, Nasr P, Ekstedt M. et al. Non-alcoholic fatty liver disease does not increase dementia risk although histology data might improve risk prediction. JHEP Rep 2020; 3 (02) 100218