Journal Home > Volume 11 , Issue 4

Atherosclerosis is driven both by hyperlipidemia and inflammation. Chitin oligosaccharides (NACOS) have shown pharmacological effects on multiple diseases via hypolipidemic and/or anti-inflammatory activities. The present study aims to evaluate whether NACOS treatment can prevent atherosclerosis induced by a high-fat-diet (HFD) in Apolipoprotein E-knockout (ApoE-/-) mice. Results showed that 300 and 900 mg/kg b.w./day NACOS supplementation for 14 weeks significantly decreased atherosclerotic lesions up to 45% and 67% in compared with the HFD (P < 0.05), as measured in the valve area of the aortic root. Further, NACOS supplementation significantly reduced the serum hyperlipidemia and circulating proinflammatory cytokines including interleukin-1β, interleukin-6, monocyte chemoattractant protein-1 and tumor necrosis factor-α. NACOS decreased the hepatic Hmgcr to reduce cholesterol synthesis, activated the genes involved in reverse cholesterol transport to enhance cholesterol efflux and excretion, and reduced the intestinal Npc1L1 to lower cholesterol absorption. Additionally, NACOS enhanced cecum short chain fatty acids production and intestinal integrity. Thus, NACOS supplementation ameliorated atherosclerosis via altering lipid metabolism and reducing inflammation. These findings indicate that NACOS may be a potential functional food material for attenuating atherosclerosis development.


menu
Abstract
Full text
Outline
About this article

Chitin oligosaccharides alleviate atherosclerosis progress in ApoE-/- mice by regulating lipid metabolism and inhibiting inflammation

Show Author's information Hongmin ZhenaQiaojuan YanbYihao LiubYanxiao LibShaoqing YangaZhengqiang Jianga( )
Key Laboratory of Food Bioengineering (China National Light Industry), College of Food Science & Nutritional Engineering, China Agricultural University, Beijing 100083, China
Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Engineering, China Agricultural University, Beijing 100083, China

Peer review under responsibility of KeAi Communications Co., Ltd.

Abstract

Atherosclerosis is driven both by hyperlipidemia and inflammation. Chitin oligosaccharides (NACOS) have shown pharmacological effects on multiple diseases via hypolipidemic and/or anti-inflammatory activities. The present study aims to evaluate whether NACOS treatment can prevent atherosclerosis induced by a high-fat-diet (HFD) in Apolipoprotein E-knockout (ApoE-/-) mice. Results showed that 300 and 900 mg/kg b.w./day NACOS supplementation for 14 weeks significantly decreased atherosclerotic lesions up to 45% and 67% in compared with the HFD (P < 0.05), as measured in the valve area of the aortic root. Further, NACOS supplementation significantly reduced the serum hyperlipidemia and circulating proinflammatory cytokines including interleukin-1β, interleukin-6, monocyte chemoattractant protein-1 and tumor necrosis factor-α. NACOS decreased the hepatic Hmgcr to reduce cholesterol synthesis, activated the genes involved in reverse cholesterol transport to enhance cholesterol efflux and excretion, and reduced the intestinal Npc1L1 to lower cholesterol absorption. Additionally, NACOS enhanced cecum short chain fatty acids production and intestinal integrity. Thus, NACOS supplementation ameliorated atherosclerosis via altering lipid metabolism and reducing inflammation. These findings indicate that NACOS may be a potential functional food material for attenuating atherosclerosis development.

Keywords: Inflammation, Atherosclerosis, Lipid metabolism, Chitin oligosaccharides, ApoE-/- mice

References(52)

[1]

P. Libby, J.E. Buring, L. Badimon, et al., Atherosclerosis, Nat. Rev. Dis. Primers. 5 (2019) 56. https://doi.org/10.1038/s41572-019-0106-z.

[2]

A. Gisterå, G.K. Hansson, The immunology of atherosclerosis, Nat. Rev. Nephrol. 13 (2017) 368-380. https://doi.org/10.1038/nrneph.2017.51.

[3]

M. Bäck, G.K. Hansson, Anti-inflammatory therapies for atherosclerosis, Nat. Rev. Cardiol. 12 (2015) 199-211. https://doi.org/10.1038/nrcardio.2015.5.

[4]

Y. Baumer, S. McCurdy, T.M. Weatherby, et al., Hyperlipidemia-induced cholesterol crystal production by endothelial cells promotes atherogenesis, Nat. Commun. 8 (2017) 1129. https://doi.org/10.1038/s41467-017-01186-z.

[5]

C. Muanprasat, V. Chatsudthipong, Chitosan oligosaccharide: biological activities and potential therapeutic applications, Pharmacol. Ther. 170 (2017) 80-97. https://doi.org/10.1016/j.pharmthera.2016.10.013.

[6]

M. Rinaudo, Chitin and chitosan: properties and applications, Prog. Polym. Sci. 31 (2006) 603-632. https://doi.org/10.1016/j.progpolymsci.2006.06.001.

[7]

K. Azuma, T. Osaki, S. Minami, et al., Anticancer and anti-inflammatory properties of chitin and chitosan oligosaccharides, J. Funct. Biomater. 6 (2015) 33-49. https://doi.org/10.3390/jfb6010033.

[8]

L. Huang, J. Chen, P. Cao, et al., Anti-obese effect of glucosamine and chitosan oligosaccharide in high-fat diet-induced obese rats, Mar. Drugs. 13 (2015) 2732-2756. https://doi.org/10.3390/md13052732.

[9]

X. Wu, J. Wang, Y. Shi, et al., N-Acetyl-chitobiose ameliorates metabolism dysfunction through Erk/p38 MAPK and histone H3 phosphorylation in type 2 diabetes mice, J. Funct. Foods. 28 (2017) 96-105. https://doi.org/10.1016/j.jff.2016.11.012.

[10]

D.N. Ngo, S.H. Lee, M.M. Kim, et al., Production of chitin oligosaccharides with different molecular weights and their antioxidant effect in RAW 264.7 cells, J. Funct. Foods. 1 (2009) 188-198. https://doi.org/10.1016/j.jff.2009.01.008.

[11]

Y. Qu, J. Xu, H. Zhou, et al., Chitin oligosaccharide (COS) reduces antibiotics dose and prevents antibiotics-caused side effects in adolescent idiopathic scoliosis (AIS) patients with spinal fusion surgery, Mar. Drugs. 15 (2017) 70. https://doi.org/10.3390/md15030070.

[12]

B. Bahar, J.V. O'Doherty, S. Maher, et al., Chitooligosaccharide elicits acute inflammatory cytokine response through AP-1 pathway in human intestinal epithelial-like (Caco-2) cells, Mol. Immunol. 51 (2012) 283-291. https://doi.org/10.1016/j.molimm.2012.03.027.

[13]

C.L. Zong, Y. Yu, G.H. Song, et al., Chitosan oligosaccharides promote reverse cholesterol transport and expression of scavenger receptor BI and CYP7A1 in mice, Exp. Bio. Med. (Maywood). 237 (2012) 194-200. https://doi.org/10.1258/ebm.2011.011275.

[14]

Y. Yu, T. Luo, S. Liu, et al., Chitosan oligosaccharides attenuate atherosclerosis and decrease non-HDL in ApoE-/- Mice, J. Atheroscler. Thromb. 22 (2015) 926-941. https://doi.org/10.5551/jat.22939.

[15]

X. Yang, J. Zhang, L. Chen, et al., Chitosan oligosaccharides enhance lipid droplets via down-regulation of PCSK9 gene expression in HepG2 cells, Exp. Cell Res. 366 (2018) 152-160. https://doi.org/10.1016/j.yexcr.2018.03.013.

[16]

H. Yin, Y. Du, Z. Dong, Chitin oligosaccharide and chitosan oligosaccharide: two similar but different plant elicitors, Front. Plant Sci. 7 (2016) 522. https://doi.org/10.3389/fpls.2016.00522.

[17]

Y. Okawa, M. Kobayashi, S. Suzuki, et al., Comparative study of protective effects of chitin, chitosan, and N-acetyl chitohexaose against Pseudomonas aeruginosa and Listeria monocytogenes infections in mice, Biol. Pharm. Bull. 26 (2003) 902-904. https://doi.org/10.1248/bpb.26.902.

[18]

S. Davis, A.M. Cirone, J. Menzie, et al., Phagocytosis-mediated M1 activation by chitin but not by chitosan, Am. J. Physiol. -Cell Ph. 315 (2018) C62-C72. https://doi.org/10.1152/ajpcell.00268.2017.

[19]

F.I. Khan, S. Rahman, A. Queen, et al., Implications of molecular diversity of chitin and its derivatives, Appl. Microbiol. Biot. 101 (2017) 3513-3536. https://doi.org/10.1007/s00253-017-8229-1.

[20]

B.K. Park, M.M. Kim, Applications of chitin and its derivatives in biological medicine, Int. J. Mol. Sci. 11 (2010) 5152-5164. https://doi.org/10.3390/ijms11125152.

[21]

D.E. Threapleton, D.C. Greenwood, C.E.L. Evans, et al., Dietary fibre intake and risk of cardiovascular disease: systematic review and meta-analysis, Brit. Med. J. 347 (2013). https://doi.org/10.1136/bmj.f6879.

[22]

H.E. Bays, J.L. Evans, K.C. Maki, et al., Chitin-glucan fiber effects on oxidized low-density lipoprotein: a randomized controlled trial, Eur. J. Clin. Nutr. 67 (2013) 2-7. https://doi.org/10.1038/ejcn.2012.121.

[23]

A. Berecochea-Lopez, K. Decordé, E. Ventura, et al., Fungal ChitinGlucan from Aspergillus niger Efficiently reduces aortic fatty streak accumulation in the high-fat fed hamster, an animal model of nutritionally induced atherosclerosis, J. Agr. Food Chem. 57 (2009) 1093-1098. https://doi.org/10.1021/jf803063v.

[24]

J. Zheng, G. Cheng, Q. Li, et al., Chitin oligosaccharide modulates gut microbiota and attenuates high-fat-diet-induced metabolic syndrome in mice, Mar. Drugs. 16 (2018) 66. https://doi.org/10.3390/md16020066.

[25]

S. Yang, X. Fu, Q. Yan, et al., Cloning, expression, purification and application of a novel chitinase from a thermophilic marine bacterium Paenibacillus barengoltzii, Food Chem. 192 (2016) 1041-1048. https://doi.org/10.1016/j.foodchem.2015.07.092.

[26]

L.R. Hoving, S. Katiraei, M. Heijink, et al., Dietary mannan oligosaccharides modulate gut microbiota, increase fecal bile acid excretion, and decrease plasma cholesterol and atherosclerosis development, Mol. Nutr. Food Res. (2018) 1700942. https://doi.org/10.1002/mnfr.201700942.

[27]

A. Daugherty, A.R. Tall, M.J.A.P. Daemen, et al., Recommendation on design, execution, and reporting of animal atherosclerosis studies: a scientific statement from the American Heart Association, Circ. Res. 121 (2017) e53-e79.

[28]

J. Li, S. Lin, P.M. Vanhoutte, et al., Akkermansia Muciniphila protects against atherosclerosis by preventing metabolic endotoxemia-induced inflammation in ApoE-/- mice, Circulation 133 (2016) 2434-2446. https://doi.org/10.1161/CIRCULATIONAHA.115.019645.

[29]

S. Salmon, S. Goldstein, D. Pastier, et al., Monoclonal antibodies to low density lipoprotein used for the study of low- and very-low-density lipoproteins, in "ELISA" and immunoprecipitation technics, Biochem. Biophys. Res. Commun. 125 (1984) 704-711. https://doi.org/10.1016/0006-291X(84)90596-5.

[30]

D. Zhu, Q. Yan, Y. Li, et al., Effect of Konjac Mannan oligosaccharides on glucose homeostasis via the improvement of insulin and leptin resistance in vitro and in vivo, Nutrients 11 (2019) 1705. https://doi.org/10.3390/nu11081705.

[31]

C.L. Millar, G.H. Norris, C. Jiang, et al., Long-term supplementation of black elderberries promotes hyperlipidemia, but reduces liver inflammation and improves HDL function and atherosclerotic plaque stability in apolipoprotein E-knockout mice, Mol. Nutr. Food Res. 62 (2018) 1800404. https://doi.org/10.1002/mnfr.201800404.

[32]

A. Dostal, J. Baumgartner, N. Riesen, et al., Effects of iron supplementation on dominant bacterial groups in the gut, faecal SCFA and gut inflammation: a randomised, placebo-controlled intervention trial in South African children, B. J. Nutr. 112 (2014) 547-556. https://doi.org/10.1017/S0007114514001160.

[33]

S. von Vietinghoff, E.K. Koltsova, Inflammation in atherosclerosis: a key role for cytokines, Cytokine. 122 (2019) 154819. https://doi.org/10.1016/j.cyto.2019.154819.

[34]

H.H. Wang, G. Garruti, M. Liu, et al., Cholesterol and lipoprotein metabolism and atherosclerosis: recent advances in reverse cholesterol transport, Ann. Hepatol. 16 (2017) s27-s42. https://doi.org/10.5604/01.3001.0010.5495.

[35]

S. Sanna, N.R. van Zuydam, A. Mahajan, et al., Causal relationships among the gut microbiome, short-chain fatty acids and metabolic diseases, Nat. Genet. 51 (2019) 600-605. https://doi.org/10.1038/s41588-019-0350-x.

[36]

E.S. Chambers, T. Preston, G. Frost, et al., Role of gut microbiota-generated short-chain fatty acids in metabolic and cardiovascular health, Curr. Nutr. Rep. 7 (2018) 198-206. https://doi.org/10.1007/s13668-018-0248-8.

[37]

Cholesterol Treatment Trialists' (CTT) Collaboration, Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170000 participants in 26 randomised trials, The Lancet 376 (2010) 1670-1681. https://doi.org/10.1016/S0140-6736(10)61350-5.

[38]

R.A.K. Srivastava, Dysfunctional HDL in diabetes mellitus and its role in the pathogenesis of cardiovascular disease, Mol. Cell. Biochem. 440 (2018) 167-187. https://doi.org/10.1007/s11010-017-3165-z.

[39]

B.K. Gillard, C. Rosales, B. Xu, et al., Rethinking reverse cholesterol transport and dysfunctional high-density lipoproteins, J. Clin. Lipidol. 12 (2018) 849-856. https://doi.org/10.1016/j.jacl.2018.04.001.

[40]

X. Zhang, C. Fernández-Hernando, The Janus-faced role of SR-BI in atherosclerosis, Nat. Metab. 1 (2019) 586-587. https://doi.org/10.1038/s42255-019-0072-5.

[41]

M. Ge, R. Shao, H. He, Advances in understanding the regulatory mechanism of cholesterol 7α-hydroxylase, Biochem. Pharmacol. 164 (2019) 152-164. https://doi.org/10.1016/j.bcp.2019.04.008.

[42]

J.H. Yang, M.A. Bang, C.H. Jang, et al., Alginate oligosaccharide enhances LDL uptake via regulation of LDLR and PCSK9 expression, J. Nutr. Biochem. 26 (2015) 1393-1400. https://doi.org/10.1016/j.jnutbio.2015.07.009.

[43]

E.P. Demina, V.V. Miroshnikova, A.L. Schwarzman, Role of the ABC transporters A1 and G1, key reverse cholesterol transport proteins, in atherosclerosis, Mol. Biol. 50 (2016) 193-199. https://doi.org/10.1134/S0026893316020047.

[44]

L. Jia, J.L. Betters, L. Yu, Niemann-pick c1-like 1 (NPC1L1) protein in intestinal and hepatic cholesterol transport, Ann. Rev. Physiol. 73 (2011) 239-259. https://doi.org/10.1146/annurev-physiol-012110-142233.

[45]

M. Bäck, A. Yurdagul, I. Tabas, et al., Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities, Nat. Rev. Cardiol. 16 (2019) 389-406. https://doi.org/10.1038/s41569-019-0169-2.

[46]

M.O. Pentikainen, K. Oorni, M. Ala-Korpela, et al., Modified LDL-trigger of atherosclerosis and inflammation in the arterial intima, J. Intern. Med. 247 (2000) 359-370. https://doi.org/10.1046/j.1365-2796.2000.00655.x.

[47]

S. Ascher, C. Reinhardt, The gut microbiota: an emerging risk factor for cardiovascular and cerebrovascular disease, Eur. J. Immunol. 48 (2018) 564-575. https://doi.org/10.1002/eji.201646879.

[48]

B.R. Stevens, R. Goel, K. Seungbum, et al., Increased human intestinal barrier permeability plasma biomarkers zonulin and FABP2 correlated with plasma LPS and altered gut microbiome in anxiety or depression, Gut. 67 (2018) 1555-1557. https://doi.org/10.1136/gutjnl-2017-314759.

[49]

P.D. Cani, S. Possemiers, T. Van de Wiele, et al., Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability, Gut 58 (2009) 1091-1103. https://doi.org/10.1136/gut.2008.165886.

[50]

K. Kasahara, K.A. Krautkramer, E. Org, et al., Interactions between Roseburia intestinalis and diet modulate atherogenesis in a murine model, Nat. Microbiol. 3 (2018) 1461-1471. https://doi.org/10.1038/s41564-018-0272-x.

[51]

R.X. Wang, J.S. Lee, E.L. Campbell, et al., Microbiota-derived butyrate dynamically regulates intestinal homeostasis through regulation of actin-associated protein synaptopodin, PNAS 117 (2020) 11648-11657. https://doi.org/10.1073/pnas.1917597117.

[52]

Y. Yao, X. Cai, W. Fei, et al., The role of short-chain fatty acids in immunity, inflammation and metabolism, Crit. Rev. Food Sci. Nutr. (2020). https://doi.org/10.1080/10408398.2020.1854675.

Publication history
Copyright
Acknowledgements
Rights and permissions

Publication history

Received: 02 November 2020
Revised: 06 December 2020
Accepted: 06 January 2021
Published: 28 April 2022
Issue date: July 2022

Copyright

© 2022 Beijing Academy of Food Sciences. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.

Acknowledgements

Acknowledgements

This research was financially supported by the National Science Found for Excellent Young Scholars (No. 31822037) and National Natural Science Foundation of China (No. 21576283).

Rights and permissions

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Return