Skip to main content
Top
Published in: Diabetology & Metabolic Syndrome 1/2018

Open Access 01-12-2018 | Research

Characterization of spontaneously-developed non-alcoholic fatty liver disease in aged rhesus monkeys

Authors: Wen Zheng, Yuli Liu, Haibao Shang, Yan Zhang, Dongwei Ma, Ning Hou, Jue Wang, Xueting Sun, Ying Peng, Lin Pan, Zhilong Wang, Xinran Tang, Rui-Ping Xiao, Xiuqin Zhang

Published in: Diabetology & Metabolic Syndrome | Issue 1/2018

Login to get access

Abstract

Background

Non-alcoholic fatty liver disease (NAFLD) is a global epidemic afflicting 20–30% in the general population. The animal model of NAFLD available at the present are less clinically relevant. In this study. We aimed to establish a NAFLD model of rhesus monkeys and develop an ultrasonographic steatosis score (USS) system to grade hepatic steatosis in this model.

Methods

We performed hepatic ultrasonography and blood biochemical tests on 86 rhesus monkeys with and without metabolic syndrome (MetS), among which 45 animals were further assessed by histopathological analysis.

Results

The liver histological features of rhesus monkeys NAFLD were resemble to those of NAFLD patients. There was a close correlation between the histological steatosis grade and the USS (Spearman’s coefficient, 0.705, p < 0.001). The USS sensitivity was 87.5% and the specificity was 94.6% when the cut-off was USS2. In addition, the prevalence of MetS was significantly higher in the USS2–3 group. Multiple risk factors of cardiometabolic disease, including obesity, insulin resistance and dyslipidemia were significantly correlated with the USS.

Conclusions

NAFLD was developed spontaneously among aging in rhesus monkeys (with increased prevalence in the MetS monkeys), which provided an ideal model for NAFLD. The newly developed USS system can be used to evaluate fatty liver in the rhesus monkey. The model as well as the noninvasive assessment methodology will provide a powerful tool for mechanistic studies and preclinical test of novel therapies for NAFLD.
Literature
3.
go back to reference Ramesh S, Sanyal AJ. Evaluation and management of non-alcoholic steatohepatitis. J Hepatol. 2005;42(Suppl):S2–12.CrossRefPubMed Ramesh S, Sanyal AJ. Evaluation and management of non-alcoholic steatohepatitis. J Hepatol. 2005;42(Suppl):S2–12.CrossRefPubMed
4.
go back to reference Choudhury J, Sanyal AJ. Insulin resistance and the pathogenesis of nonalcoholic fatty liver disease. Clin Liver Dis. 2004;8:575–594, ix.CrossRefPubMed Choudhury J, Sanyal AJ. Insulin resistance and the pathogenesis of nonalcoholic fatty liver disease. Clin Liver Dis. 2004;8:575–594, ix.CrossRefPubMed
5.
go back to reference Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, 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;140:124–31.CrossRefPubMed Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, 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;140:124–31.CrossRefPubMed
6.
go back to reference Zhu JZ, Dai YN, Wang YM, Zhou QY, Yu CH, Li YM. Prevalence of nonalcoholic fatty liver disease and economy. Dig Dis Sci. 2015;60:3194–202.CrossRefPubMed Zhu JZ, Dai YN, Wang YM, Zhou QY, Yu CH, Li YM. Prevalence of nonalcoholic fatty liver disease and economy. Dig Dis Sci. 2015;60:3194–202.CrossRefPubMed
7.
go back to reference Soderberg C, Stal P, Askling J, Glaumann H, Lindberg G, Marmur J, et al. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology. 2010;51:595–602.CrossRefPubMed Soderberg C, Stal P, Askling J, Glaumann H, Lindberg G, Marmur J, et al. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology. 2010;51:595–602.CrossRefPubMed
8.
go back to reference Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P, et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology. 2015;149(389–97):e10. Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P, et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology. 2015;149(389–97):e10.
9.
go back to reference Rafiq N, Bai C, Fang Y, Srishord M, McCullough A, Gramlich T, et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin Gastroenterol Hepatol. 2009;7:234–8.CrossRefPubMed Rafiq N, Bai C, Fang Y, Srishord M, McCullough A, Gramlich T, et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin Gastroenterol Hepatol. 2009;7:234–8.CrossRefPubMed
10.
go back to reference Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology. 2005;129:113–21.CrossRefPubMed Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology. 2005;129:113–21.CrossRefPubMed
11.
go back to reference Nagarajan P, Venkatesan R, Kumar M, Usmani A, Majumdar SS. Macaca radiata (bonnet monkey): a spontaneous model of nonalcoholic fatty liver disease. Liver Int. 2008;28:856–64.CrossRefPubMed Nagarajan P, Venkatesan R, Kumar M, Usmani A, Majumdar SS. Macaca radiata (bonnet monkey): a spontaneous model of nonalcoholic fatty liver disease. Liver Int. 2008;28:856–64.CrossRefPubMed
12.
go back to reference Dhawan V, Handu SS, Nain CK, Ganguly NK. Chronic l-arginine supplementation improves endothelial cell vasoactive functions in hypercholesterolemic and atherosclerotic monkeys. Mol Cell Biochem. 2005;269:1–11.CrossRefPubMed Dhawan V, Handu SS, Nain CK, Ganguly NK. Chronic l-arginine supplementation improves endothelial cell vasoactive functions in hypercholesterolemic and atherosclerotic monkeys. Mol Cell Biochem. 2005;269:1–11.CrossRefPubMed
13.
go back to reference Lee AS, Gutierrez-Arcelus M, Perry GH, Vallender EJ, Johnson WE, Miller GM, et al. Analysis of copy number variation in the rhesus macaque genome identifies candidate loci for evolutionary and human disease studies. Hum Mol Genet. 2008;17:1127–36.CrossRefPubMed Lee AS, Gutierrez-Arcelus M, Perry GH, Vallender EJ, Johnson WE, Miller GM, et al. Analysis of copy number variation in the rhesus macaque genome identifies candidate loci for evolutionary and human disease studies. Hum Mol Genet. 2008;17:1127–36.CrossRefPubMed
14.
go back to reference Bergen WG, Mersmann HJ. Comparative aspects of lipid metabolism: impact on contemporary research and use of animal models. J Nutr. 2005;135:2499–502.CrossRefPubMed Bergen WG, Mersmann HJ. Comparative aspects of lipid metabolism: impact on contemporary research and use of animal models. J Nutr. 2005;135:2499–502.CrossRefPubMed
15.
go back to reference Rhesus Macaque Genome S, Analysis C, Gibbs RA, Rogers J, Katze MG, Bumgarner R, et al. Evolutionary and biomedical insights from the rhesus macaque genome. Science. 2007;316:222–34.CrossRef Rhesus Macaque Genome S, Analysis C, Gibbs RA, Rogers J, Katze MG, Bumgarner R, et al. Evolutionary and biomedical insights from the rhesus macaque genome. Science. 2007;316:222–34.CrossRef
16.
go back to reference Pawlosky RJ, Salem N Jr. Development of alcoholic fatty liver and fibrosis in rhesus monkeys fed a low n-3 fatty acid diet. Alcohol Clin Exp Res. 2004;28:1569–76.CrossRefPubMed Pawlosky RJ, Salem N Jr. Development of alcoholic fatty liver and fibrosis in rhesus monkeys fed a low n-3 fatty acid diet. Alcohol Clin Exp Res. 2004;28:1569–76.CrossRefPubMed
17.
go back to reference Ivester P, Shively CA, Register TC, Grant KA, Reboussin DM, Cunningham CC. The effects of moderate ethanol consumption on the liver of the monkey, Macaca fascicularis. Alcohol Clin Exp Res. 2003;27:1831–7.CrossRefPubMed Ivester P, Shively CA, Register TC, Grant KA, Reboussin DM, Cunningham CC. The effects of moderate ethanol consumption on the liver of the monkey, Macaca fascicularis. Alcohol Clin Exp Res. 2003;27:1831–7.CrossRefPubMed
18.
go back to reference Tigno XT, Gerzanich G, Hansen BC. Age-related changes in metabolic parameters of nonhuman primates. J Gerontol A Biol Sci Med Sci. 2004;59:1081–8.CrossRefPubMed Tigno XT, Gerzanich G, Hansen BC. Age-related changes in metabolic parameters of nonhuman primates. J Gerontol A Biol Sci Med Sci. 2004;59:1081–8.CrossRefPubMed
19.
go back to reference Zhang X, Zhang R, Raab S, Zheng W, Wang J, Liu N, et al. Rhesus macaques develop metabolic syndrome with reversible vascular dysfunction responsive to pioglitazone. Circulation. 2011;124:77–86.CrossRefPubMedPubMedCentral Zhang X, Zhang R, Raab S, Zheng W, Wang J, Liu N, et al. Rhesus macaques develop metabolic syndrome with reversible vascular dysfunction responsive to pioglitazone. Circulation. 2011;124:77–86.CrossRefPubMedPubMedCentral
20.
go back to reference Zhang SJ, Liu CJ, Shi M, Kong L, Chen JY, Zhou WZ, et al. RhesusBase: a knowledgebase for the monkey research community. Nucleic Acids Res. 2013;41:D892–905.CrossRefPubMed Zhang SJ, Liu CJ, Shi M, Kong L, Chen JY, Zhou WZ, et al. RhesusBase: a knowledgebase for the monkey research community. Nucleic Acids Res. 2013;41:D892–905.CrossRefPubMed
21.
go back to reference Zhang SJ, Liu CJ, Yu P, Zhong X, Chen JY, Yang X, et al. Evolutionary interrogation of human biology in well-annotated genomic framework of rhesus macaque. Mol Biol Evol. 2014;31:1309–24.CrossRefPubMedPubMedCentral Zhang SJ, Liu CJ, Yu P, Zhong X, Chen JY, Yang X, et al. Evolutionary interrogation of human biology in well-annotated genomic framework of rhesus macaque. Mol Biol Evol. 2014;31:1309–24.CrossRefPubMedPubMedCentral
22.
go back to reference Zhong X, Peng J, Shen QS, Chen JY, Gao H, Luan X, et al. RhesusBase PopGateway: genome-wide population genetics atlas in rhesus macaque. Mol Biol Evol. 2016;33:1370–5.CrossRefPubMedPubMedCentral Zhong X, Peng J, Shen QS, Chen JY, Gao H, Luan X, et al. RhesusBase PopGateway: genome-wide population genetics atlas in rhesus macaque. Mol Biol Evol. 2016;33:1370–5.CrossRefPubMedPubMedCentral
23.
go back to reference Arienti V, Aluigi L, Pretolani S, Accogli E, Polimeni L, Domanico A, et al. Ultrasonography (US) and non-invasive diagnostic methods for non-alcoholic fatty liver disease (NAFLD) and early vascular damage. Possible application in a population study on the metabolic syndrome (MS). Intern Emerg Med. 2012;7(Suppl 3):S283–90.CrossRefPubMed Arienti V, Aluigi L, Pretolani S, Accogli E, Polimeni L, Domanico A, et al. Ultrasonography (US) and non-invasive diagnostic methods for non-alcoholic fatty liver disease (NAFLD) and early vascular damage. Possible application in a population study on the metabolic syndrome (MS). Intern Emerg Med. 2012;7(Suppl 3):S283–90.CrossRefPubMed
24.
go back to reference Clark JM, Brancati FL, Diehl AM. Nonalcoholic fatty liver disease. Gastroenterology. 2002;122:1649–57.CrossRefPubMed Clark JM, Brancati FL, Diehl AM. Nonalcoholic fatty liver disease. Gastroenterology. 2002;122:1649–57.CrossRefPubMed
25.
go back to reference Hamaguchi M, Kojima T, Itoh Y, Harano Y, Fujii K, Nakajima T, et al. The severity of ultrasonographic findings in nonalcoholic fatty liver disease reflects the metabolic syndrome and visceral fat accumulation. Am J Gastroenterol. 2007;102:2708–15.CrossRefPubMed Hamaguchi M, Kojima T, Itoh Y, Harano Y, Fujii K, Nakajima T, et al. The severity of ultrasonographic findings in nonalcoholic fatty liver disease reflects the metabolic syndrome and visceral fat accumulation. Am J Gastroenterol. 2007;102:2708–15.CrossRefPubMed
26.
go back to reference Saverymuttu SH, Joseph AE, Maxwell JD. Ultrasound scanning in the detection of hepatic fibrosis and steatosis. BMJ. 1986;292:13–5.CrossRefPubMed Saverymuttu SH, Joseph AE, Maxwell JD. Ultrasound scanning in the detection of hepatic fibrosis and steatosis. BMJ. 1986;292:13–5.CrossRefPubMed
27.
go back to reference Shannon A, Alkhouri N, Carter-Kent C, Monti L, Devito R, Lopez R, et al. Ultrasonographic quantitative estimation of hepatic steatosis in children with NAFLD. J Pediatr Gastroenterol Nutr. 2011;53:190–5.CrossRefPubMedPubMedCentral Shannon A, Alkhouri N, Carter-Kent C, Monti L, Devito R, Lopez R, et al. Ultrasonographic quantitative estimation of hepatic steatosis in children with NAFLD. J Pediatr Gastroenterol Nutr. 2011;53:190–5.CrossRefPubMedPubMedCentral
28.
go back to reference Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–21.CrossRefPubMed Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–21.CrossRefPubMed
29.
go back to reference Bril F, Ortiz-Lopez C, Lomonaco R, Orsak B, Freckleton M, Chintapalli K, et al. Clinical value of liver ultrasound for the diagnosis of nonalcoholic fatty liver disease in overweight and obese patients. Liver Int. 2015;35:2139–46.CrossRefPubMed Bril F, Ortiz-Lopez C, Lomonaco R, Orsak B, Freckleton M, Chintapalli K, et al. Clinical value of liver ultrasound for the diagnosis of nonalcoholic fatty liver disease in overweight and obese patients. Liver Int. 2015;35:2139–46.CrossRefPubMed
30.
go back to reference Chaves GV, Pereira SE, Saboya CJ, Cortes C, Ramalho R. Abdominal ultrasound and magnetic resonance imaging: a comparative study on the non-alcoholic fatty liver disease diagnosis in morbidly obese patients. Rev Assoc Med Bras. 2009;55:45–9.CrossRefPubMed Chaves GV, Pereira SE, Saboya CJ, Cortes C, Ramalho R. Abdominal ultrasound and magnetic resonance imaging: a comparative study on the non-alcoholic fatty liver disease diagnosis in morbidly obese patients. Rev Assoc Med Bras. 2009;55:45–9.CrossRefPubMed
31.
go back to reference Li CM, Sheng JH, Zhang HG, Qiu CW, Huang XY, Yang LJ, et al. The development of a clinical score for the prediction of nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease using routine parameters. Turkish J Gastroenterol. 2015;26:408–16.CrossRef Li CM, Sheng JH, Zhang HG, Qiu CW, Huang XY, Yang LJ, et al. The development of a clinical score for the prediction of nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease using routine parameters. Turkish J Gastroenterol. 2015;26:408–16.CrossRef
32.
go back to reference Mishra P, Younossi ZM. Abdominal ultrasound for diagnosis of nonalcoholic fatty liver disease (NAFLD). Am J Gastroenterol. 2007;102:2716–7.CrossRefPubMed Mishra P, Younossi ZM. Abdominal ultrasound for diagnosis of nonalcoholic fatty liver disease (NAFLD). Am J Gastroenterol. 2007;102:2716–7.CrossRefPubMed
33.
go back to reference Lupsor M, Badea R. Imaging diagnosis and quantification of hepatic steatosis: is it an accepted alternative to needle biopsy? Rom J Gastroenterol. 2005;14:419–25.PubMed Lupsor M, Badea R. Imaging diagnosis and quantification of hepatic steatosis: is it an accepted alternative to needle biopsy? Rom J Gastroenterol. 2005;14:419–25.PubMed
34.
go back to reference Dasarathy S, Dasarathy J, Khiyami A, Joseph R, Lopez R, McCullough AJ. Validity of real time ultrasound in the diagnosis of hepatic steatosis: a prospective study. J Hepatol. 2009;51:1061–7.CrossRefPubMedPubMedCentral Dasarathy S, Dasarathy J, Khiyami A, Joseph R, Lopez R, McCullough AJ. Validity of real time ultrasound in the diagnosis of hepatic steatosis: a prospective study. J Hepatol. 2009;51:1061–7.CrossRefPubMedPubMedCentral
35.
go back to reference Diez JJ, Iglesias P. The role of the novel adipocyte-derived hormone adiponectin in human disease. Eur J Endocrinol. 2003;148:293–300.CrossRefPubMed Diez JJ, Iglesias P. The role of the novel adipocyte-derived hormone adiponectin in human disease. Eur J Endocrinol. 2003;148:293–300.CrossRefPubMed
36.
go back to reference Cusi K, Chang Z, Harrison S, Lomonaco R, Bril F, Orsak B, et al. Limited value of plasma cytokeratin-18 as a biomarker for NASH and fibrosis in patients with non-alcoholic fatty liver disease. J Hepatol. 2014;60:167–74.CrossRefPubMed Cusi K, Chang Z, Harrison S, Lomonaco R, Bril F, Orsak B, et al. Limited value of plasma cytokeratin-18 as a biomarker for NASH and fibrosis in patients with non-alcoholic fatty liver disease. J Hepatol. 2014;60:167–74.CrossRefPubMed
38.
39.
go back to reference Ballestri S, Zona S, Targher G, Romagnoli D, Baldelli E, Nascimbeni F, et al. Nonalcoholic fatty liver disease is associated with an almost twofold increased risk of incident type 2 diabetes and metabolic syndrome. Evidence from a systematic review and meta-analysis. J Gastroenterol Hepatol. 2016;31:936–44.CrossRefPubMed Ballestri S, Zona S, Targher G, Romagnoli D, Baldelli E, Nascimbeni F, et al. Nonalcoholic fatty liver disease is associated with an almost twofold increased risk of incident type 2 diabetes and metabolic syndrome. Evidence from a systematic review and meta-analysis. J Gastroenterol Hepatol. 2016;31:936–44.CrossRefPubMed
40.
go back to reference Marchesini G, Bugianesi E, Forlani G, Cerrelli F, Lenzi M, Manini R, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology. 2003;37:917–23.CrossRefPubMed Marchesini G, Bugianesi E, Forlani G, Cerrelli F, Lenzi M, Manini R, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology. 2003;37:917–23.CrossRefPubMed
41.
go back to reference Bellentani S, Saccoccio G, Masutti F, Croce LS, Brandi G, Sasso F, et al. Prevalence of and risk factors for hepatic steatosis in Northern Italy. Ann Intern Med. 2000;132:112–7.CrossRefPubMed Bellentani S, Saccoccio G, Masutti F, Croce LS, Brandi G, Sasso F, et al. Prevalence of and risk factors for hepatic steatosis in Northern Italy. Ann Intern Med. 2000;132:112–7.CrossRefPubMed
42.
43.
go back to reference Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology. 2004;40:1387–95.CrossRefPubMed Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology. 2004;40:1387–95.CrossRefPubMed
Metadata
Title
Characterization of spontaneously-developed non-alcoholic fatty liver disease in aged rhesus monkeys
Authors
Wen Zheng
Yuli Liu
Haibao Shang
Yan Zhang
Dongwei Ma
Ning Hou
Jue Wang
Xueting Sun
Ying Peng
Lin Pan
Zhilong Wang
Xinran Tang
Rui-Ping Xiao
Xiuqin Zhang
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Diabetology & Metabolic Syndrome / Issue 1/2018
Electronic ISSN: 1758-5996
DOI
https://doi.org/10.1186/s13098-018-0370-1

Other articles of this Issue 1/2018

Diabetology & Metabolic Syndrome 1/2018 Go to the issue