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Article | Open Access

Long term ingestion of dietary ALEs induces metabolic disorders in mice by inducing gut dysbiosis and inhibiting AMPK/SIRT1 pathway

Yaya Wanga, Tianchang Zhanga, Linqing Niea, Yan Zhanga, Junping Wangb, Shuo Wanga()
Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300071, China
State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Food Nutrition and Safety, Ministry of Education of China, College of Food Science and Engineering, Tianjin University of Science and Technology, Tianjin 300457, China

Peer review under responsibility of Tsinghua University Press.

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Statement of Significance

• Dietary Advanced lipoxidation end products (ALEs) induce lipid accumulation in the liver of mice at an early stage, and that continuous feeding of ALEs induces inflammation, oxidative stress and hepatic insulin resistance.

• The core cause of these adverse reactions is intestinal barrier damage caused by ALEs.

• The increase in lipopolysaccharides in the liver, resulting from damage to the intestinal barrier induces hepatic lipid accumulation by modulating hepatic lipid metabolism.

• ALEs play an important role in metabolic diseases by directly or indirectly inhibiting the AMPK/SIRT1 signaling pathway.

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Abstract

Advanced lipoxidation end products (ALEs) are formed by modifying proteins with lipid oxidation products. ALEs formed in the body have been linked to diabetes and hepatic disease. However, it is not known whether ALEs formed in heat-processed foods can induce metabolic diseases. Our results indicate that dietary ALEs induce lipid accumulation in the liver of mice at an early stage and continuous feeding of ALEs induces inflammation, oxidative stress and hepatic insulin resistance. The core reason for these adverse reactions is the damage to the intestinal barrier caused by ALEs. Due to the damage to the intestinal barrier, there is an increase in lipopolysaccharides (LPS) in the liver that induces hepatic lipid accumulation by modulating hepatic lipid metabolism. Furthermore, ALEs plays a major role in the regulation of metabolic diseases by directly or indirectly inhibiting AMP activated protein kinase (AMPK)/Sirtuin 1 (SIRT1) signaling through LPS.

Keywords

Dietary advanced lipoxidation end productsMetabolic disordersAMPK/SITR1 signaling pathwayGut dysbiosisIntestinal barrier

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References

[1]

R. Pamplona, Advanced lipoxidation end-products, Chem-Biol. Interact. 192 (2011) 14-20. https://doi.org/10.1016/j.cbi.2011.01.007.

Crossref Google Scholar
[2]

L. Lv, H. Lin, Z. Li, et al., Effect of 4-hydroxy-2-nonenal treatment on the IgE binding capacity and structure of shrimp (Metapenaeus ensis) tropomyosin, Food Chem. 212 (2016) 313-322. https://doi.org/ 10.1016/j.foodchem.2016.05.152.

Crossref Google Scholar
[3]

C. Chopin, M. Kone, T. Serot, et al., Study of the interaction of fish myosin with the products of lipid oxidation: the case of aldehydes, Food Chem. 105 (2007) 126-132. https://doi.org/10.1016/j.foodchem.2016.05.152.

Crossref Google Scholar
[4]

J. Zhao, G. Su, M. Zhao, et al., Physicochemical changes and in vitro gastric digestion of modified soybean protein induced by lipoxygenase catalyzed linoleic acid oxidation, J. Agric. Food Chem. 67 (2019) 13978-13985. https://doi.org/10.1021/acs.jafc.9b05843.

Crossref Google Scholar
[5]

Y. Zhuang, J. Dong, X. He, et al., Impact of heating temperature and fatty acid type on the formation of lipid oxidation products during thermal processing, Front. Nutr. 9 (2022) 913297. https://doi.org/10.3389/fnut.2022.913297.

Crossref Google Scholar
[6]

G.W. Wang, Y. Guo, T.M. Vondriska, et al., Acrolein consumption exacerbates myocardial ischemic injury and blocks nitric oxide-induced PKCε signaling and cardioprotection, J. Mol. Cell Cardiol. 44 (2008) 1016-1022. https://doi.org/10.1016/j.yjmcc.2008.03.020.

Crossref Google Scholar
[7]

M. Grootveld, B.C. Percival, K.L. Grootveld, Chronic non-communicable disease risks presented by lipid oxidation products in fried foods, Hepatobil. Surg. Nutr. 7 (2018) 305. https://doi.org/10.21037/hbsn.2018.04.01.

Crossref Google Scholar
[8]

L. Wang, Z. Xiang, S. Stevanovic, et al., Role of Chinese cooking emissions on ambient air quality and human health, Sci. Total Environ. 589 (2017) 173-181. https://doi.org/10.1016/j.scitotenv.2017.02.124.

Crossref Google Scholar
[9]

R.M. Domingues, P. Domingues, T. Melo, et al., Lipoxidation adducts with peptides and proteins: deleterious modifications or signaling mechanisms? J. Proteomics. 92 (2013) 110-131. https://doi.org/10.1016/j.jprot.2013.06.004.

Crossref Google Scholar
[10]

K.S. Fritz, D.R. Petersen, Exploring the biology of lipid peroxidation-derived protein carbonylation, Chem. Res. Toxicol. 24 (2011) 1411. https://doi.org/10.1021/tx200169n.

Crossref Google Scholar
[11]

M. Mol, G. Degani, C. Coppa, et al., Advanced lipoxidation end products (ALEs) as RAGE binders: mass spectrometric and computational studies to explain the reasons why, Redox Biol. 23 (2019) 101083. https://doi.org/10.1016/j.redox.2018.101083.

Crossref Google Scholar
[12]

S. Bengmark, Advanced glycation and lipoxidation end products-amplifiers of inflammation: the role of food, J. Parenter. Enter. Nutr. 31 (2007) 430-440. https://doi.org/10.1177/0148607107031005430.

Crossref Google Scholar
[13]

P.J. Thornalley, Dietary AGEs and ALEs and risk to human health by their interaction with the receptor for advanced glycation endproducts (RAGE)-an introduction, Mol. Nutr. Food. Res. 51 (2007) 1107-1110. https://doi.org/10.1002/mnfr.200700017.

Crossref Google Scholar
[14]

J. Girón-Calle, M. Alaiz, F. Millán, et al., Bound malondialdehyde in foods: bioavailability of the N-2-propenals of lysine, J. Agric. Food Chem. 50 (2002) 6194-6198. https://doi.org/10.1021/jf025681r.

Crossref Google Scholar
[15]

L.A. Piche, P.D. Cole, M. Hadley, et al., Identification of N-ε-(2-propenal) lysine as the main form of malondialdehyde in food digesta, Carcinogenesis 9 (1988) 473-477. https://doi.org/10.1093/carcin/9.3.473.

Crossref Google Scholar
[16]

G. Xu, Y. Liu, L.M. Sayre, Polyclonal antibodies to a fluorescent 4-hydroxy-2-nonenal (HNE)-derived lysine-lysine cross-link: characterization and application to HNE-treated protein and in vitro oxidized low-density lipoprotein, Chem. Res. Toxicol. 13 (2000) 406-413. https://doi.org/10.1021/tx990200s.

Crossref Google Scholar
[17]

W.T. Qu, C.X. Nie, J.S. Zhao, et al., Microbionne-metabolomics analysis of the impacts of long-term dietary advanced-glycation-end-product consumption on C57BL/6 Mouse fecal microbiota and metabolites, J. Agric. Food Chem. 66 (2018) 8864-8875. https://doi.org/10.1021/acs.jafc.8b01466.

Crossref Google Scholar
[18]

S. Lee, R. Muniyappa, X. Yan, et al., Comparison between surrogate indexes of insulin sensitivity and resistance and hyperinsulinemic euglycemic clamp estimates in mice, Am. J. Physiol-Endoc. M. 294 (2008) E261-E270. https://doi.org/10.1152/ajpendo.00397.2009.

Crossref Google Scholar
[19]

B. Zhang, Y. Zhang, X. Liu, et al., Differential protective effect of resveratrol and its microbial metabolites on intestinal barrier dysfunction is mediated by the AMPK pathway, J. Agric. Food Chem. 70 (2022) 11301-11313. https://doi.org/ 10.1021/acs.jafc.2c04101.

Crossref Google Scholar
[20]

J. Kanner, Dietary advanced lipid oxidation endproducts are risk factors to human health, Mol. Nutr. Food. Res. 51 (2007) 1094-1101. https://doi.org/10.1002/mnfr.200600303.

Crossref Google Scholar
[21]

W. Choi, S. Yeruva, J.R. Turner, Contributions of intestinal epithelial barriers to health and disease, Exp. Cell Res. 358 (2017) 71-77. https://doi.org/10.1016/j.yexcr.2017.03.036.

Crossref Google Scholar
[22]

K. Dokladny, M.N. Zuhl, P.L. Moseley, Intestinal epithelial barrier function and tight junction proteins with heat and exercise, J. Appl. Physiol. 120 (2016) 692-701. https://doi.org/10.1152/japplphysiol.00536.2015.

Crossref Google Scholar
[23]

J. Nascimento, V. Matheus, R. Oliveira, et al., High-fat diet induces disruption of the tight junction-mediated paracellular barrier in the proximal small intestine before the onset of type 2 diabetes and endotoxemia, Digest. Dis. Sci. 66 (2021) 3359-3374. https://doi.org/10.1007/s10620-020-06664-x.

Crossref Google Scholar
[24]

Y. Wang, Y. Zou, J. Wang, et al., The protective effects of 2’-fucosyllactose against E. coli O157 infection are mediated by the regulation of gut microbiota and the inhibition of pathogen adhesion, Nutrients 12 (2020) 1284. https://doi.org/10.1007/s10620-020-06664-x.

Crossref Google Scholar
[25]

M. Ohhira, W. Motomura, M. Fukuda, et al., Lipopolysaccharide induces adipose differentiation-related protein expression and lipid accumulation in the liver through inhibition of fatty acid oxidation in mice, J. Gastroenterol. 42 (2007) 969-978. https://doi.org/10.1007/s00535-007-2119-8.

Crossref Google Scholar
[26]

A. Federico, M. Dallio, J. Godos, et al., Targeting gut-liver axis for the treatment of nonalcoholic steatohepatitis: translational and clinical evidence, Transl. Res. 167 (2016) 116-124. https://doi.org/10.1016/j.trsl.2015.08.002.

Crossref Google Scholar
[27]

J.M. Tishinsky, L.E. Robinson, D.J. Dyck, Insulin-sensitizing properties of adiponectin, Biochimie 94 (2012) 2131-2136. https://doi.org/10.1016/j.biochi.2012.01.017.

Crossref Google Scholar
[28]

J. Gao, T. Qian, W. Wang, CTRP3 activates the AMPK/SIRT1-PGC-1α pathway to protect mitochondrial biogenesis and functions in cerebral ischemic stroke, Neurochem. Res. 45 (2020) 3045-3058. https://doi.org/10.1007/s11064-020-03152-6.

Crossref Google Scholar
[29]

X. Jin, M. Chen, L. Yi, et al., Delphinidin-3-glucoside protects human umbilical vein endothelial cells against oxidized low-density lipoprotein-induced injury by autophagy upregulation via the AMPK/SIRT1 signaling pathway, Mol. Nutr. Food. Res. 58 (2014) 1941-1951. https://doi.org/10.1002/mnfr.201400161.

Crossref Google Scholar
[30]

A. Purushotham, T.T. Schug, Q. Xu, et al., Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation, Cell Metab. 9 (2009) 327-338. https://doi.org/10.1016/j.cmet.2009.02.006.

Crossref Google Scholar
[31]

J.T. Rodgers, C. Lerin, W. Haas, et al., Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1, Nature 434 (2005) 113-118. https://doi.org/10.1038/nature03354.

Crossref Google Scholar
[32]

F. Xu, Z. Gao, J. Zhang, et al., Lack of SIRT1 (Mammalian Sirtuin 1) activity leads to liver steatosis in the SIRT1+/- mice: a role of lipid mobilization and inflammation, Endocrinology 151 (2010) 2504-2514. https://doi.org/10.1210/en.2009-1013.

Crossref Google Scholar
[33]

D. Shi, L. Lü, D. Fang, et al., Administration of Lactobacillus salivarius LI01 or Pediococcus pentosaceus LI05 prevents CCl4-induced liver cirrhosis by protecting the intestinal barrier in rats, Sci. Rep.-UK 7 (2017) 1-13. https://doi.org/10.1038/s41598-017-07091-1.

Crossref Google Scholar
[34]

F. Yan, D.B. Polk, Probiotics as functional food in the treatment of diarrhea, Curr. Opin. Clin. Nutr. Care 9 (2006) 717-721. https://doi.org/10.1097/01.mco.0000247477.02650.51.

Crossref Google Scholar
[35]

A. Mattar, D.H. Teitelbaum, R. Drongowski, et al., Probiotics up-regulate MUC-2 mucin gene expression in a Caco-2 cell-culture model, Pediatr. Surg. Int. 18 (2002) 586-590. https://doi.org/10.1007/s00383-002-0855-7.

Crossref Google Scholar
[36]

S.M. Finegold, S.E. Dowd, V. Gontcharova, et al., Pyrosequencing study of fecal microflora of autistic and control children, Anaerobe 16 (2010) 444-453. https://doi.org/10.1016/j.anaerobe.2010.06.008.

Crossref Google Scholar
[37]

P.D. Cani, J. Amar, M.A. Iglesias, et al., Metabolic endotoxemia initiates obesity and insulin resistance, Diabetes 56 (2007) 1761-1772. https://doi.org/10.2337/db06-1491.

Crossref Google Scholar
[38]

C. Cao, L. Wang, C. Ai, et al., Impact of Lycium barbarum arabinogalactan on the fecal metabolome in a DSS-induced chronic colitis mouse model, Food Funct. 13 (2022) 8703-8716. https://doi.org/10.1039/d2fo01283a.

Crossref Google Scholar
[39]
W. Qu, X. Yuan, J. Zhao, et al., Dietary advanced glycation end products modify gut microbial composition and partially increase colon permeability in rats, Mol. Nutr. Food. Res. 61 (2017) 118. https://doi.org/1700118.10.1002/mnfr.201700118.
Crossref
[40]

E.E. Noble, T.M. Hsu, R.B. Jones, et al., Early-life sugar consumption affects the rat microbiome independently of obesity, J. Nutr. 147 (2017) 20-28. https://doi.org/10.1002/mnfr.201700118.

Crossref Google Scholar
[41]

R.J. Chiodini, S.E. Dowd, W.M. Chamberlin, et al., Microbial population differentials between mucosal and submucosal intestinal tissues in advanced Crohn’s disease of the ileum, PLoS One 10 (2015) e0134382. https://doi.org/10.1371/journal.pone.0134382.

Crossref Google Scholar
[42]

Y. Gu, C. Liu, N. Zheng, et al., Metabolic and gut microbial characterization of obesity-prone mice under a high-fat diet, J. Phys. Chem. Lett. 18 (2019) 1703-1714. https://doi.org/10.1021/acs.jproteome.8b00945.

Crossref Google Scholar
Food Science and Human Wellness
Volume 14 Issue 2,
February 2025
Article number: 9250029
DOI: 10.26599/FSHW.2024.9250029
Cite this article:
Wang Y, Zhang T, Nie L, et al. Long term ingestion of dietary ALEs induces metabolic disorders in mice by inducing gut dysbiosis and inhibiting AMPK/SIRT1 pathway. Food Science and Human Wellness, 2025, 14(2): 9250029. https://doi.org/10.26599/FSHW.2024.9250029
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