Browse > Article
http://dx.doi.org/10.4162/nrp.2019.13.1.3

Nicotinamide riboside regulates inflammation and mitochondrial markers in AML12 hepatocytes  

Lee, Hee Jae (Department of Food and Nutrition, Seoul Women's University)
Yang, Soo Jin (Department of Food and Nutrition, Seoul Women's University)
Publication Information
Nutrition Research and Practice / v.13, no.1, 2019 , pp. 3-10 More about this Journal
Abstract
BACKGROUND/OBJECTIVES: The $NAD^+$ precursor nicotinamide riboside (NR) is a type of vitamin $B_3$ found in cow's milk and yeast-containing food products such as beer. Recent studies suggested that NR prevents hearing loss, high-fat diet-induced obesity, Alzheimer's disease, and mitochondrial myopathy. The objective of this study was to investigate the effects of NR on inflammation and mitochondrial biogenesis in AML12 mouse hepatocytes. MATERIALS/METHODS: A subset of hepatocytes was treated with palmitic acid (PA; $250{\mu}M$) for 48 h to induce hepatocyte steatosis. The hepatocytes were treated with NR ($10{\mu}M$ and 10 mM) for 24 h with and without PA. The cell viability and the levels of sirtuins, inflammatory markers, and mitochondrial markers were analyzed. RESULTS: Cytotoxicity of NR was examined by PrestoBlue assay. Exposure to NR had no effect on cell viability or morphology. Gene expression of sirtuin 1 (Sirt1) and Sirt3 was significantly upregulated by NR in PA-treated hepatocytes. However, Sirt1 activities were increased in hepatocytes treated with low-dose NR. Hepatic pro-inflammatory markers including tumor necrosis factor-alpha and interleukin-6 were decreased in NR-treated cells. NR upregulated anti-inflammatory molecule adiponectin, and, tended to down-regulate hepatokine fetuin-A in PA-treated hepatocytes, suggesting its inverse regulation on these cytokines. NR increased levels of mitochondrial markers including peroxisome proliferator-activated receptor ${\gamma}$ coactivator-$1{\alpha}$, carnitine palmitoyltransferase 1, uncoupling protein 2, transcription factor A, mitochondrial and mitochondrial DNA in PA-treated hepatocytes. CONCLUSIONS: These data demonstrated that NR attenuated hepatic inflammation and increased levels of mitochondrial markers in hepatocytes.
Keywords
Fatty liver; inflammation; mitochondria; niacin;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Picard F, Kurtev M, Chung N, Topark-Ngarm A, Senawong T, Machado De Oliveira R, Leid M, McBurney MW, Guarente L. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-$\gamma$. Nature 2004;429:771-6.   DOI
2 Kim JE, Chen J, Lou Z. DBC1 is a negative regulator of SIRT1. Nature 2008;451:583-6.   DOI
3 Zhao W, Kruse JP, Tang Y, Jung SY, Qin J, Gu W. Negative regulation of the deacetylase SIRT1 by DBC1. Nature 2008;451:587-90.   DOI
4 Houtkooper RH, Pirinen E, Auwerx J. Sirtuins as regulators of metabolism and healthspan. Nat Rev Mol Cell Biol 2012;13:225-38.   DOI
5 Cohen JC, Horton JD, Hobbs HH. Human fatty liver disease: old questions and new insights. Science 2011;332:1519-23.   DOI
6 Kinoshita T, Imamura R, Kushiyama H, Suda T. NLRP3 mediates NF-${\kappa}B$ activation and cytokine induction in microbially induced and sterile inflammation. PLoS One 2015;10:e0119179.   DOI
7 Tak PP, Firestein GS. NF-${\kappa}B$: a key role in inflammatory diseases. J Clin Invest 2001;107:7-11.   DOI
8 Lin X, Braymer HD, Bray GA, York DA. Differential expression of insulin receptor tyrosine kinase inhibitor (fetuin) gene in a model of diet-induced obesity. Life Sci 1998;63:145-53.   DOI
9 Lee HJ, Lim Y, Yang SJ. Involvement of resveratrol in crosstalk between adipokine adiponectin and hepatokine fetuin-A in vivo and in vitro. J Nutr Biochem 2015;26:1254-60.   DOI
10 Begriche K, Igoudjil A, Pessayre D, Fromenty B. Mitochondrial dysfunction in NASH: causes, consequences and possible means to prevent it. Mitochondrion 2006;6:1-28.
11 Sheng B, Wang X, Su B, Lee HG, Casadesus G, Perry G, Zhu X. Impaired mitochondrial biogenesis contributes to mitochondrial dysfunction in Alzheimer's disease. J Neurochem 2012;120:419-29.   DOI
12 Ren J, Pulakat L, Whaley-Connell A, Sowers JR. Mitochondrial biogenesis in the metabolic syndrome and cardiovascular disease. J Mol Med (Berl) 2010;88:993-1001.   DOI
13 Lopez-Lluch G, Irusta PM, Navas P, de Cabo R. Mitochondrial biogenesis and healthy aging. Exp Gerontol 2008;43:813-9.   DOI
14 Austin S, St-Pierre J. $PGC1{\alpha}$ and mitochondrial metabolism--emerging concepts and relevance in ageing and neurodegenerative disorders. J Cell Sci 2012;125:4963-71.   DOI
15 Goffart S, Wiesner RJ. Regulation and co-ordination of nuclear gene expression during mitochondrial biogenesis. Exp Physiol 2003;88: 33-40.   DOI
16 Handschin C, Spiegelman BM. Peroxisome proliferator-activated receptor gamma coactivator 1 coactivators, energy homeostasis, and metabolism. Endocr Rev 2006;27:728-35.   DOI
17 Canto C, Houtkooper RH, Pirinen E, Youn DY, Oosterveer MH, Cen Y, Fernandez-Marcos PJ, Yamamoto H, Andreux PA, Cettour-Rose P, Gademann K, Rinsch C, Schoonjans K, Sauve AA, Auwerx J. The $NAD^{+}$ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab 2012;15:838-47.   DOI
18 Shima K, Zhu M, Kuwajima M. A role of nicotinamide-induced increase in pancreatic ${\beta}$-cell mass on blood glucose control after discontinuation of the treatment in partially pancreatectomized OLETF rats. Diabetes Res Clin Pract 1998;41:1-8.   DOI
19 Knip M, Douek IF, Moore WP, Gillmor HA, McLean AE, Bingley PJ, Gale EA; European Nicotinamide Diabetes Intervention Trial Group. Safety of high-dose nicotinamide: a review. Diabetologia 2000;43: 1337-45.   DOI
20 Trammell SA, Schmidt MS, Weidemann BJ, Redpath P, Jaksch F, Dellinger RW, Li Z, Abel ED, Migaud ME, Brenner C. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat Commun 2016;7:12948.   DOI
21 Brown KD, Maqsood S, Huang JY, Pan Y, Harkcom W, Li W, Sauve A, Verdin E, Jaffrey SR. Activation of SIRT3 by the $NAD^{+}$ precursor nicotinamide riboside protects from noise-induced hearing loss. Cell Metab 2014;20:1059-68.   DOI
22 Khan NA, Auranen M, Paetau I, Pirinen E, Euro L, Forsstrom S, Pasila L, Velagapudi V, Carroll CJ, Auwerx J, Suomalainen A. Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3. EMBO Mol Med 2014.6:721-31.   DOI
23 Trammell SA, Weidemann BJ, Chadda A, Yorek MS, Holmes A, Coppey LJ, Obrosov A, Kardon RH, Yorek MA, Brenner C. Nicotinamide riboside opposes type 2 diabetes and neuropathy in mice. Sci Rep 2016;6:26933.   DOI
24 Lee HJ, Hong YS, Jun W, Yang SJ. Nicotinamide riboside ameliorates hepatic metaflammation by modulating NLRP3 inflammasome in a rodent model of type 2 diabetes. J Med Food 2015;18:1207-13.   DOI
25 Gong B, Pan Y, Vempati P, Zhao W, Knable L, Ho L, Wang J, Sastre M, Ono K, Sauve AA, Pasinetti GM. Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-$\gamma$ coactivator $1{\alpha}$ regulated ${\beta}$-secretase 1 degradation and mitochondrial gene expression in Alzheimer's mouse models. Neurobiol Aging 2013;34:1581-8.   DOI
26 Fernandez-Marcos PJ, Auwerx J. Regulation of PGC-$1{\alpha}$, a nodal regulator of mitochondrial biogenesis. Am J Clin Nutr 2011;93: 884S-890S.   DOI
27 Aharoni-Simon M, Hann-Obercyger M, Pen S, Madar Z, Tirosh O. Fatty liver is associated with impaired activity of $PPAR{\gamma}$-coactivator $1{\alpha}$ ($PGC1{\alpha}$) and mitochondrial biogenesis in mice. Lab Invest 2011;91:1018-28.   DOI
28 Finck BN, Kelly DP. PGC-1 coactivators: inducible regulators of energy metabolism in health and disease. J Clin Invest 2006;116: 615-22.   DOI
29 Puigserver P. Tissue-specific regulation of metabolic pathways through the transcriptional coactivator PGC1-$\alpha$. Int J Obes (Lond) 2005;29 Suppl 1:S5-9.   DOI
30 Gariani K, Menzies KJ, Ryu D, Wegner CJ, Wang X, Ropelle ER, Moullan N, Zhang H, Perino A, Lemos V, Kim B, Park YK, Piersigilli A, Pham TX, Yang Y, Ku CS, Koo SI, Fomitchova A, Canto C, Schoonjans K, Sauve AA, Lee JY, Auwerx J. Eliciting the mitochondrial unfolded protein response by nicotinamide adenine dinucleotide repletion reverses fatty liver disease in mice. Hepatology 2016;63:1190-204.   DOI
31 Mukherjee S, Chellappa K, Moffitt A, Ndungu J, Dellinger RW, Davis JG, Agarwal B, Baur JA. Nicotinamide adenine dinucleotide biosynthesis promotes liver regeneration. Hepatology 2017;65:616-30.   DOI
32 Zhou CC, Yang X, Hua X, Liu J, Fan MB, Li GQ, Song J, Xu TY, Li ZY, Guan YF, Wang P, Miao CY. Hepatic $NAD^{+}$ deficiency as a therapeutic target for non-alcoholic fatty liver disease in ageing. Br J Pharmacol 2016;173:2352-68.   DOI
33 Stafeev IS, Menshikov MY, Tsokolaeva ZI, Shestakova MV, Parfyonova YV. Molecular mechanisms of latent inflammation in metabolic syndrome. possible role of sirtuins and peroxisome proliferatoractivated receptor type $\gamma$. Biochemistry (Mosc) 2015;80:1217-26.   DOI
34 Mendes KL, Lelis DF, Santos SH. Nuclear sirtuins and inflammatory signaling pathways. Cytokine Growth Factor Rev 2017;38:98-105.   DOI
35 Ding RB, Bao J, Deng CX. Emerging roles of SIRT1 in fatty liver diseases. Int J Biol Sci 2017;13:852-67.   DOI
36 Liu P, Huang G, Wei T, Gao J, Huang C, Sun M, Zhu L, Shen W. Sirtuin 3-induced macrophage autophagy in regulating NLRP3 inflammasome activation. Biochim Biophys Acta Mol Basis Dis 2018;1864:764-77.   DOI
37 Nemoto S, Fergusson MM, Finkel T. Nutrient availability regulates SIRT1 through a forkhead-dependent pathway. Science 2004;306: 2105-8.   DOI
38 Paulin R, Dromparis P, Sutendra G, Gurtu V, Zervopoulos S, Bowers L, Haromy A, Webster L, Provencher S, Bonnet S, Michelakis ED. Sirtuin 3 deficiency is associated with inhibited mitochondrial function and pulmonary arterial hypertension in rodents and humans. Cell Metab 2014;20:827-39.   DOI
39 Gleave JA, Arathoon LR, Trinh D, Lizal KE, Giguere N, Barber JH, Najarali Z, Khan MH, Thiele SL, Semmen MS, Koprich JB, Brotchie JM, Eubanks JH, Trudeau LE, Nash JE. Sirtuin 3 rescues neurons through the stabilisation of mitochondrial biogenetics in the virally-expressing mutant $\alpha$-synuclein rat model of parkinsonism. Neurobiol Dis 2017;106:133-46.   DOI
40 Li Y, Ye Z, Lai W, Rao J, Huang W, Zhang X, Yao Z, Lou T. Activation of sirtuin 3 by silybin attenuates mitochondrial dysfunction in cisplatin-induced acute kidney injury. Front Pharmacol 2017;8:178.
41 Noriega LG, Feige JN, Canto C, Yamamoto H, Yu J, Herman MA, Mataki C, Kahn BB, Auwerx J. CREB and ChREBP oppositely regulate SIRT1 expression in response to energy availability. EMBO Rep 2011;12:1069-76.   DOI
42 Hayashida S, Arimoto A, Kuramoto Y, Kozako T, Honda S, Shimeno H, Soeda S. Fasting promotes the expression of SIRT1, an NAD+-dependent protein deacetylase, via activation of $PPAR{\alpha}$ in mice. Mol Cell Biochem 2010;339:285-92.   DOI
43 Okazaki M, Iwasaki Y, Nishiyama M, Taguchi T, Tsugita M, Nakayama S, Kambayashi M, Hashimoto K, Terada Y. $PPAR{\beta}/\delta$ regulates the human SIRT1 gene transcription via Sp1. Endocr J 2010;57:403-13.   DOI
44 Kim EJ, Kho JH, Kang MR, Um SJ. Active regulator of SIRT1 cooperates with SIRT1 and facilitates suppression of p53 activity. Mol Cell 2007;28:277-90.   DOI
45 Han L, Zhou R, Niu J, McNutt MA, Wang P, Tong T. SIRT1 is regulated by a $PPAR{\gamma}$-SIRT1 negative feedback loop associated with senescence. Nucleic Acids Res 2010;38:7458-71.   DOI
46 Sasaki T, Maier B, Koclega KD, Chruszcz M, Gluba W, Stukenberg PT, Minor W, Scrable H. Phosphorylation regulates SIRT1 function. PLoS One 2008;3:e4020.   DOI
47 Nasrin N, Kaushik VK, Fortier E, Wall D, Pearson KJ, de Cabo R, Bordone L. JNK1 phosphorylates SIRT1 and promotes its enzymatic activity. PLoS One 2009;4:e8414.   DOI
48 Guo X, Williams JG, Schug TT, Li X. DYRK1A and DYRK3 promote cell survival through phosphorylation and activation of SIRT1. J Biol Chem 2010;285:13223-32.   DOI
49 Yang Y, Fu W, Chen J, Olashaw N, Zhang X, Nicosia SV, Bhalla K, Bai W. SIRT1 sumoylation regulates its deacetylase activity and cellular response to genotoxic stress. Nat Cell Biol 2007;9:1253-62.   DOI
50 Trammell SA, Yu L, Redpath P, Migaud ME, Brenner C. Nicotinamide riboside is a major NAD+ precursor vitamin in cow milk. J Nutr 2016;146:957-63.   DOI
51 Belenky P, Racette FG, Bogan KL, McClure JM, Smith JS, Brenner C. Nicotinamide riboside promotes Sir2 silencing and extends lifespan via Nrk and Urh1/Pnp1/Meu1 pathways to NAD+. Cell 2007;129:473-84.   DOI
52 Bieganowski P, Brenner C. Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss-Handler independent route to NAD+ in fungi and humans. Cell 2004;117: 495-502.   DOI
53 Julius U. Niacin as antidyslipidemic drug. Can J Physiol Pharmacol 2015;93:1043-54.   DOI
54 Bogan KL, Brenner C. Nicotinic acid, nicotinamide, and nicotinamide riboside: a molecular evaluation of NAD+ precursor vitamins in human nutrition. Annu Rev Nutr 2008;28:115-30.   DOI
55 Yang SJ, Choi JM, Kim L, Park SE, Rhee EJ, Lee WY, Oh KW, Park SW, Park CY. Nicotinamide improves glucose metabolism and affects the hepatic NAD-sirtuin pathway in a rodent model of obesity and type 2 diabetes. J Nutr Biochem 2014;25:66-72.   DOI