Gluten worsens non-alcoholic fatty liver disease by affecting lipogenesis and fatty acid oxidation in diet-induced obese apolipoprotein E-deficient mice.

Publisher: Springer Country of Publication: Netherlands NLM ID: 0364456 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1573-4919 (Electronic) Linking ISSN: 03008177 NLM ISO Abbreviation: Mol Cell Biochem Subsets: MEDLINE

Publication: New York : Springer
Original Publication: The Hague, Dr. W. Junk B. V. Publishers.

Non-alcoholic Fatty Liver Disease*/metabolism ; Non-alcoholic Fatty Liver Disease*/etiology ; Non-alcoholic Fatty Liver Disease*/pathology ; Lipogenesis* ; Obesity*/metabolism ; Obesity*/etiology ; Obesity*/pathology ; Diet, High-Fat*/adverse effects ; Fatty Acids*/metabolism ; Glutens* ; Oxidation-Reduction*; Animals ; Mice ; Male ; Apolipoproteins E/deficiency ; Apolipoproteins E/metabolism ; Apolipoproteins E/genetics ; Liver/metabolism ; Liver/pathology ; Mice, Obese ; Mice, Inbred C57BL

Obesity is closely associated with non-alcoholic fatty liver disease (NAFLD), characterized by hepatic fat accumulation and hepatocyte injury. Preclinical studies have shown exacerbated weight gain associated with an obesogenic gluten-containing diet. However, whether gluten affects obesity-induced hepatic lipid accumulation still remains unclear. We hypothesized that gluten intake could affect fatty liver development in high-fat diet (HFD)-induced obese mice. Thus, we aimed to investigate the impact of gluten intake on NAFLD in HFD-induced obese mice. Male apolipoprotein E-deficient (Apoe-/-) mice were fed with a HFD containing (GD) or not (GFD) vital wheat gluten (4.5%) for 10 weeks. Blood and liver were collected for further analysis. We found that gluten exacerbated weight gain, hepatic fat deposition, and hyperglycemia without affecting the serum lipid profile. Livers of the GD group showed a larger area of fibrosis, associated with the expression of collagen and MMP9, and higher expression of apoptosis-related factors, p53, p21, and caspase-3. The expression of lipogenic factors, such as PPARγ and Acc1, was more elevated and factors related to beta-oxidation, such as PPARα and Cpt1, were lower in the GD group compared to the GFD. Further, gluten intake induced a more significant expression of Cd36, suggesting higher uptake of free fatty acids. Finally, we found lower protein expression of PGC1α followed by lower activation of AMPK. Our data show that gluten-containing high-fat diet exacerbated NAFLD by affecting lipogenesis and fatty acid oxidation in obese Apoe-/- mice through a mechanism involving lower activation of AMPK.
(© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K et al (2012) The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the american association for the study of liver diseases, American college of gastroenterology, and the American gastroenterological association. Hepatology 55:2005–2023. https://doi.org/10.1002/hep.25762. (PMID: 10.1002/hep.2576222488764)
Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M (2015) Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence incidence and outcomes. Hepatology. https://doi.org/10.1002/hep.28431/suppinfo. (PMID: 10.1002/hep.28431/suppinfo26274335)
Wójcik-Cichy K, Koślińska-Berkan E, Piekarska A (2018) The influence of NAFLD on the risk of atherosclerosis and cardiovascular diseases. Clin Exp Hepatol 4:1. https://doi.org/10.5114/CEH.2018.73155. (PMID: 10.5114/CEH.2018.73155295941925865905)
Ekstedt M, Hagström H, Nasr P, Fredrikson M, Stål P, Kechagias S et al (2015) Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology 61:1547–1554. https://doi.org/10.1002/HEP.27368. (PMID: 10.1002/HEP.2736825125077)
Aune D, Keum N, Giovannucci E, Fadnes LT, Boffetta P, Greenwood DC et al (2016) Whole grain consumption and risk of cardiovascular disease, cancer, and all cause and cause specific mortality: systematic review and dose-response meta-analysis of prospective studies. BMJ. https://doi.org/10.1136/bmj.i2716. (PMID: 10.1136/bmj.i2716273019754908315)
Monteiro CA, Moubarac JC, Cannon G, Ng SW, Popkin B (2013) Ultra-processed products are becoming dominant in the global food system. Obes Rev 14(Suppl 2):21–28. https://doi.org/10.1111/OBR.12107. (PMID: 10.1111/OBR.1210724102801)
Na W, Lee Y, Kim H, Kim YS, Sohn C (2021) High-fat foods and fodmaps containing gluten foods primarily contribute to symptoms of irritable bowel syndrome in Korean adults. Nutrients. https://doi.org/10.3390/NU13041308/S1. (PMID: 10.3390/NU13041308/S1346844858540639)
Ontiveros N, Rodríguez-Bellegarrigue C, Galicia-Rodríguez G, Vergara-Jiménez M, Zepeda-Gómez E, Arámburo-Galvez J, Gracia-Valenzuela M, Cabrera-Chávez F et al (2018) Prevalence of self-reported gluten-related disorders and adherence to a gluten-free diet in salvadoran adult population. Int J Environ Res Public Health. https://doi.org/10.3390/ijerph15040786. (PMID: 10.3390/ijerph15040786304002076266739)
Littlejohns TJ, Chong AY, Allen NE, Arnold M, Bradbury KE, Mentzer AJ et al (2021) Genetic, lifestyle, and health-related characteristics of adults without celiac disease who follow a gluten-free diet: a population-based study of 124,447 participants. Am J Clin Nutr 113:622–629. https://doi.org/10.1093/ajcn/nqaa291. (PMID: 10.1093/ajcn/nqaa29133184625)
Dall M, Calloe K, Haupt-Jorgensen M, Larsen J, Schmitt N, Josefsen K et al (2013) Gliadin fragments and a specific gliadin 33-mer peptide close KATP channels and induce insulin secretion in INS-1E cells and rat islets of langerhans. PLoS One 8:e66474. https://doi.org/10.1371/JOURNAL.PONE.0066474. (PMID: 10.1371/JOURNAL.PONE.0066474237855003681969)
Fasano A (2011) Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer. Physiol Rev 91:151–175. https://doi.org/10.1152/physrev.00003.2008. (PMID: 10.1152/physrev.00003.200821248165)
Hafström I, Ringertz B, Spångberg a, von Zweigbergk L, Brannemark S, Nylander I, et al (2001) A vegan diet free of gluten improves the signs and symptoms of rheumatoid arthritis: the effects on arthritis correlate with a reduction in antibodies to food antigens. Rheumatology (Oxford) 40:1175–9. https://doi.org/10.1093/rheumatology/40.10.1175. (PMID: 10.1093/rheumatology/40.10.117511600749)
Menta PLR, Andrade MER, Leocádio PCL, Fraga JR, Dias MTS, Cara DC et al (2019) Wheat gluten intake increases the severity of experimental colitis and bacterial translocation by weakening of the proteins of the junctional complex. Br J Nutr 121:361–373. https://doi.org/10.1017/S0007114518003422. (PMID: 10.1017/S000711451800342230554574)
Shimada S, Tanigawa T, Watanabe T, Nakata A, Sugimura N, Itani S et al (2019) Involvement of gliadin, a component of wheat gluten, in increased intestinal permeability leading to non-steroidal anti-inflammatory drug-induced small-intestinal damage. PLoS One. https://doi.org/10.1371/JOURNAL.PONE.0211436. (PMID: 10.1371/JOURNAL.PONE.0211436316482856812872)
Biesiekierski JR, Newnham ED, Irving PM, Barrett JS, Haines M, Doecke JD et al (2011) Gluten causes gastrointestinal symptoms in subjects without celiac disease: a double-blind randomized placebo-controlled trial. Am J Gastroenterol 106:508–514. https://doi.org/10.1038/AJG.2010.487. (PMID: 10.1038/AJG.2010.48721224837)
Hansen CHF, Krych Ł, Buschard K, Metzdorff SB, Nellemann C, Hansen LH et al (2014) A maternal gluten-free diet reduces inflammation and diabetes incidence in the offspring of NOD Mice. Diabetes 63:2821–2832. https://doi.org/10.2337/db13-1612. (PMID: 10.2337/db13-161224696449)
Marietta EV, Gomez AM, Yeoman C, Tilahun AY, Clark CR, Luckey DH et al (2013) Low incidence of spontaneous type 1 diabetes in non-obese diabetic mice raised on gluten-free diets is associated with changes in the intestinal microbiome. PLoS One. https://doi.org/10.1371/JOURNAL.PONE.0078687. (PMID: 10.1371/JOURNAL.PONE.0078687242360373827256)
Freire RH, Fernandes LR, Silva RB, Coelho BSL, De Araújo LPT, Ribeiro LS et al (2016) Wheat gluten intake increases weight gain and adiposity associated with reduced thermogenesis and energy expenditure in an animal model of obesity. Int J Obes 40:479–486. https://doi.org/10.1038/ijo.2015.204. (PMID: 10.1038/ijo.2015.204)
Soares FLP, de Oliveira MR, Teixeira LG, Menezes Z, Pereira SS, Alves AC et al (2013) Gluten-free diet reduces adiposity, inflammation and insulin resistance associated with the induction of PPAR-alpha and PPAR-gamma expression. J Nutr Biochem 24:1105–1111. https://doi.org/10.1016/j.jnutbio.2012.08.009. (PMID: 10.1016/j.jnutbio.2012.08.00923253599)
Haupt-Jorgensen M, Buschard K, Hansen AK, Josefsen K, Antvorskov JC (2016) Gluten-free diet increases beta-cell volume and improves glucose tolerance in an animal model of type 2 diabetes. Diabetes Metab Res Rev 32:675–684. https://doi.org/10.1002/DMRR.2802. (PMID: 10.1002/DMRR.280226991675)
Aguilar EC, Navia-Pelaez JM, Fernandes-Braga W, Soares FLP, dos Santos LC, Leonel AJ et al (2020) Gluten exacerbates atherosclerotic plaque formation in ApoE -/- mice with diet-induced obesity. Nutrition. https://doi.org/10.1016/J.NUT.2019.110658. (PMID: 10.1016/J.NUT.2019.11065832305657)
Aguilar EC, Fernandes-Braga W, Leocádio PCL, Campos GP, Lemos VS, de Oliveira RP et al (2023) Dietary gluten worsens hepatic steatosis by increasing inflammation and oxidative stress in ApoE−/− mice fed a high-fat diet. Food Funct 14:3332–3347. https://doi.org/10.1039/D3FO00149K. (PMID: 10.1039/D3FO00149K36940107)
Lu W, Mei J, Yang J, Wu Z, Liu J, Miao P et al (2020) ApoE deficiency promotes non-alcoholic fatty liver disease in mice via impeding AMPK/mTOR mediated autophagy. Life Sci 252:117601. https://doi.org/10.1016/j.lfs.2020.117601. (PMID: 10.1016/j.lfs.2020.11760132304762)
Eng J (2003) Sample size estimation: how many individuals should be studied? Radiology 227:309–13. https://doi.org/10.1148/RADIOL.2272012051. (PMID: 10.1148/RADIOL.227201205112732691)
Folch J, Lees M, Stanley GHS (1956) A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem. https://doi.org/10.1016/S0021-9258(18)64849-5. (PMID: 10.1016/S0021-9258(18)64849-5)
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25:402–408. https://doi.org/10.1006/METH.2001.1262. (PMID: 10.1006/METH.2001.126211846609)
Capettini LSA, Cortes SF, Silva JF, Alvarez-Leite JI, Lemos VS (2011) Decreased production of neuronal NOS-derived hydrogen peroxide contributes to endothelial dysfunction in atherosclerosis. Br J Pharmacol 164:1738. https://doi.org/10.1111/J.1476-5381.2011.01500.X. (PMID: 10.1111/J.1476-5381.2011.01500.X216157223230819)
Hu X, Beeton C (2010) Detection of functional matrix metalloproteinases by zymography. J Vis Exp. https://doi.org/10.3791/2445. (PMID: 10.3791/2445211789543159593)
Kurzepa J, Agnieszka M, Czechowska G, Kurzepa J, Celiński K, Kazmierak W et al (2014) Role of MMP-2 and MMP-9 and their natural inhibitors in liver fibrosis, chronic pancreatitis and non-specific inflammatory bowel diseases. Hepatobiliary Pancreat Dis Int 13:570–9. https://doi.org/10.1016/S1499-3872(14)60261-7. (PMID: 10.1016/S1499-3872(14)60261-725475858)
Strzyz P (2020) AMPK against NASH. Nat Rev Mol Cell Biol 21(4):181–181. https://doi.org/10.1038/s41580-020-0225-0. (PMID: 10.1038/s41580-020-0225-032071435)
Smith BK, Marcinko K, Desjardins EM, Lally JS, Ford RJ, Steinberg GR (2016) Treatment of nonalcoholic fatty liver disease: role of AMPK. Am J Physiol Endocrinol Metab 311:E730–E740. https://doi.org/10.1152/AJPENDO.00225.2016. (PMID: 10.1152/AJPENDO.00225.201627577854)
Shabalala SC, Dludla PV, Mabasa L, Kappo AP, Basson AK, Pheiffer C et al (2020) The effect of adiponectin in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and the potential role of polyphenols in the modulation of adiponectin signaling. Biomed Pharmacother. https://doi.org/10.1016/J.BIOPHA.2020.110785. (PMID: 10.1016/J.BIOPHA.2020.11078533152943)
Olivares M, Rodriguez J, Pötgens SA, Neyrinck AM, Cani PD, Bindels LB et al (2019) The janus face of cereals: wheat-derived prebiotics counteract the detrimental effect of gluten on metabolic homeostasis in mice fed a high-fat/high-sucrose diet. Mol Nutr Food Res 63:1900632. https://doi.org/10.1002/MNFR.201900632. (PMID: 10.1002/MNFR.201900632316085627003472)
Kershenobich Stalnikowitz D, Weissbrod AB (2003) Liver fibrosis and inflammation. A Rev Ann Hepatol 2:159–163. https://doi.org/10.1016/S1665-2681(19)32127-1. (PMID: 10.1016/S1665-2681(19)32127-1)
Kanda T, Matsuoka S, Yamazaki M, Shibata T, Nirei K, Takahashi H et al (2018) Apoptosis and non-alcoholic fatty liver diseases. World J Gastroenterol 24:2661–2672. https://doi.org/10.3748/WJG.V24.I25.2661. (PMID: 10.3748/WJG.V24.I25.2661299918726034146)
Thapaliya S, Wree A, Povero D, Inzaugarat ME, Berk M, Dixon L et al (2014) Caspase 3 inactivation protects against hepatic cell death and ameliorates fibrogenesis in a diet-induced NASH model. Dig Dis Sci 59:1197–1206. https://doi.org/10.1007/S10620-014-3167-6. (PMID: 10.1007/S10620-014-3167-6247950364512760)
Derdak Z, Villegas KA, Harb R, Wu AM, Sousa A, Wands JR (2013) Inhibition of p53 attenuates steatosis and liver injury in a mouse model of non-alcoholic fatty liver disease. J Hepatol 58:785–791. https://doi.org/10.1016/J.JHEP.2012.11.042. (PMID: 10.1016/J.JHEP.2012.11.04223211317)
Matsuzaka T, Shimano H (2011) Molecular mechanisms involved in hepatic steatosis and insulin resistance. J Diabetes Investig 2:170. https://doi.org/10.1111/J.2040-1124.2011.00111.X. (PMID: 10.1111/J.2040-1124.2011.00111.X248434784014913)
Lian CY, Zhai ZZ, Li ZF, Wang L (2020) High fat diet-triggered non-alcoholic fatty liver disease: a review of proposed mechanisms. Chem Biol Interact. https://doi.org/10.1016/J.CBI.2020.109199. (PMID: 10.1016/J.CBI.2020.10919932805210)
Yu S, Matsusue K, Kashireddy P, Cao WQ, Yeldandi V, Yeldandi AV et al (2003) Adipocyte-specific gene expression and adipogenic steatosis in the mouse liver due to peroxisome proliferator-activated receptor gamma1 (PPARgamma1) overexpression. J Biol Chem 278:498–505. https://doi.org/10.1074/JBC.M210062200. (PMID: 10.1074/JBC.M21006220012401792)
Montagner A, Polizzi A, Fouché E, Ducheix S, Lippi Y, Lasserre F et al (2016) Liver PPARα is crucial for whole-body fatty acid homeostasis and is protective against NAFLD. Gut 65:1202–1214. https://doi.org/10.1136/GUTJNL-2015-310798. (PMID: 10.1136/GUTJNL-2015-31079826838599)
Cheng CF, Ku HC, Lin H (2018) PGC-1α as a pivotal factor in lipid and metabolic regulation. Int J Mol Sci. https://doi.org/10.3390/IJMS19113447. (PMID: 10.3390/IJMS19113447305774526337294)
Aharoni-Simon M, Hann-Obercyger M, Pen S, Madar Z, Tirosh O (2011) Fatty liver is associated with impaired activity of PPARγ-coactivator 1α (PGC1α) and mitochondrial biogenesis in mice. Lab Investig 91(7):1018–28. https://doi.org/10.1038/labinvest.2011.55. (PMID: 10.1038/labinvest.2011.5521464822)
Croce MA, Eagon JC, LaRiviere LL, Korenblat KM, Klein S, Finck BN (2007) Hepatic lipin 1beta expression is diminished in insulin-resistant obese subjects and is reactivated by marked weight loss. Diabetes 56:2395–2399. https://doi.org/10.2337/DB07-0480. (PMID: 10.2337/DB07-048017563064)
Rada P, González-Rodríguez Á, García-Monzón C, Valverde ÁM (2020) Understanding lipotoxicity in NAFLD pathogenesis: is CD36 a key driver? Cell Death Dis. https://doi.org/10.1038/S41419-020-03003-W. (PMID: 10.1038/S41419-020-03003-W329783747519685)
Inoue M, Ohtake T, Motomura W, Takahashi N, Hosoki Y, Miyoshi S et al (2005) Increased expression of PPARgamma in high fat diet-induced liver steatosis in mice. Biochem Biophys Res Commun 336:215–222. https://doi.org/10.1016/J.BBRC.2005.08.070. (PMID: 10.1016/J.BBRC.2005.08.07016125673)
Wondmkun YT (2020) Obesity, insulin resistance, and type 2 diabetes: associations and therapeutic implications. Diabetes Metab Syndr Obes 13:3611. https://doi.org/10.2147/DMSO.S275898. (PMID: 10.2147/DMSO.S275898331167127553667)
Zhang W, Patil S, Chauhan B, Guo S, Powell DR, Le J et al (2006) FoxO1 regulates multiple metabolic pathways in the liver: effects on gluconeogenic, glycolytic, and lipogenic gene expression. J Biol Chem 281:10105–10117. https://doi.org/10.1074/JBC.M600272200. (PMID: 10.1074/JBC.M60027220016492665)
Pan X, Zhang Y, Kim HG, Liangpunsakul S, Dong XC (2017) FOXO transcription factors protect against the diet-induced fatty liver disease. Sci Rep 7:1–12. https://doi.org/10.1038/srep44597. (PMID: 10.1038/srep44597)
Mu J, Wang X, Wang Q, Cheng F, Zhu W, Li C et al (2019) Molecular mechanism of non-alcoholic fatty liver disease induced and aggravated by chronic stress through HSL/ATGL-FFA which promotes fat mobilization. J Traditi Chin Med Sci 6:315–324. https://doi.org/10.1016/J.JTCMS.2019.08.001. (PMID: 10.1016/J.JTCMS.2019.08.001)
Xia B, Cai GH, Yang H, Wang SP, Mitchell GA, Wu JW (2017) Adipose tissue deficiency of hormone-sensitive lipase causes fatty liver in mice. PLoS Genet. https://doi.org/10.1371/JOURNAL.PGEN.1007110. (PMID: 10.1371/JOURNAL.PGEN.1007110292327025741266)
Deng T, Shan S, Li PP, Shen ZF, Lu XP, Cheng J et al (2006) Peroxisome proliferator-activated receptor-gamma transcriptionally up-regulates hormone-sensitive lipase via the involvement of specificity protein-1. Endocrinology 147:875–884. https://doi.org/10.1210/EN.2005-0623. (PMID: 10.1210/EN.2005-062316269451)
Xu H, Zhao Q, Song N, Yan Z, Lin R, Wu S et al (2020) AdipoR1/AdipoR2 dual agonist recovers nonalcoholic steatohepatitis and related fibrosis via endoplasmic reticulum-mitochondria axis. Nat Commun 11:1–16. https://doi.org/10.1038/s41467-020-19668-y. (PMID: 10.1038/s41467-020-19668-y)
Shan L, Qiao SW, Arentz-Hansen H, Molberg Ø, Gray GM, Sollid LM et al (2005) Identification and analysis of multivalent proteolytically resistant peptides from gluten: implications for celiac sprue. J Proteome Res 4:1732–1741. https://doi.org/10.1021/PR050173T/SUPPL_FILE/PR050173TSI20050611_110731.PDF. (PMID: 10.1021/PR050173T/SUPPL_FILE/PR050173TSI20050611_110731.PDF162124271343496)
Kõiv V, Tenson T (2021) Gluten-degrading bacteria: availability and applications. Appl Microbiol Biotechnol 105:3045–3059. https://doi.org/10.1007/S00253-021-11263-5. (PMID: 10.1007/S00253-021-11263-5338378308053163)
Zhang L, Andersen D, Roager HM, Bahl MI, Hansen CHF, Danneskiold-Samsøe NB et al (2017) Effects of gliadin consumption on the intestinal microbiota and metabolic homeostasis in mice fed a high-fat diet. Sci Rep. https://doi.org/10.1038/SREP44613. (PMID: 10.1038/SREP44613292737895741771)
Bruun SW, Josefsen K, Tanassi JT, Marek A, Pedersen MHF, Sidenius U et al (2016) Large gliadin peptides detected in the pancreas of nod and healthy mice following oral administration. J Diabetes Res. https://doi.org/10.1155/2016/2424306. (PMID: 10.1155/2016/2424306277959595067331)
Haupt-Jorgensen M, Larsen J, Josefsen K, Jørgensen TZ, Antvorskov JC, Hansen AK et al (2018) Gluten-free diet during pregnancy alleviates signs of diabetes and celiac disease in NOD mouse offspring. Diabetes Metab Res Rev. https://doi.org/10.1002/DMRR.2987. (PMID: 10.1002/DMRR.298729392873)
Drago S, El Asmar R, Di Pierro M, Clemente MG, Tripathi A, Sapone A et al (2006) Gliadin, zonulin and gut permeability: effects on celiac and non-celiac intestinal mucosa and intestinal cell lines. Scand J Gastroenterol 41:408–419. https://doi.org/10.1080/00365520500235334. (PMID: 10.1080/0036552050023533416635908)
Galiero R, Caturano A, Vetrano E, Cesaro A, Rinaldi L, Salvatore T et al (2021) Pathophysiological mechanisms and clinical evidence of relationship between nonalcoholic fatty liver disease (NAFLD) and cardiovascular disease. Rev Cardiovasc Med. https://doi.org/10.31083/j.rcm2203082. (PMID: 10.31083/j.rcm220308234565074)

Keywords: AMPK; High-fat diet; Lipogenesis; NAFLD; Wheat gluten; β-oxidation

0 (Fatty Acids)
8002-80-0 (Glutens)
0 (Apolipoproteins E)
0 (Apoe protein, mouse)

Date Created: 20230704 Date Completed: 20240704 Latest Revision: 20240729

20240729

10.1007/s11010-023-04802-3

37402020