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Open Access 01-12-2021 | Insulins | Research

Insulin treatment improves liver histopathology and decreases expression of inflammatory and fibrogenic genes in a hyperglycemic, dyslipidemic hamster model of NAFLD

Authors: Victoria Svop Jensen, Christian Fledelius, Christina Zachodnik, Jesper Damgaard, Helle Nygaard, Kristina Steinicke Tornqvist, Rikke Kaae Kirk, Birgitte Martine Viuff, Erik Max Wulff, Jens Lykkesfeldt, Henning Hvid

Published in: Journal of Translational Medicine | Issue 1/2021

Abstract

Background

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are highly prevalent comorbidities in patients with Type 2 diabetes. While many of these patients eventually will need treatment with insulin, little is known about the effects of insulin treatment on histopathological parameters and hepatic gene expression in diabetic patients with co-existing NAFLD and NASH. To investigate this further, we evaluated the effects of insulin treatment in NASH diet-fed hamsters with streptozotocin (STZ) -induced hyperglycemia.

Methods

Forty male Syrian hamsters were randomized into four groups (n = 10/group) receiving either a NASH-inducing (high fat, fructose and cholesterol) or control diet (CTRL) for four weeks, after which they were treated with STZ or sham-injected and from week five treated with either vehicle (CTRL, NASH, NASH-STZ) or human insulin (NASH-STZ-HI) for four weeks by continuous s.c. infusion via osmotic minipumps.

Results

NASH-STZ hamsters displayed pronounced hyperglycemia, dyslipidemia and more severe liver pathology compared to both CTRL and NASH groups. Insulin treatment attenuated dyslipidemia in NASH-STZ-HI hamsters and liver pathology was considerably improved compared to the NASH-STZ group, with prevention/reversal of hepatic steatosis, hepatic inflammation and stellate cell activation. In addition, expression of inflammatory and fibrotic genes was decreased compared to the NASH-STZ group.

Conclusions

These results suggest that hyperglycemia is important for development of inflammation and profibrotic processes in the liver, and that insulin administration has beneficial effects on liver pathology and expression of genes related to inflammation and fibrosis in a hyperglycemic, dyslipidemic hamster model of NAFLD.

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Younossi ZM. Non-alcoholic fatty liver disease-a global public health perspective. J Hepatol. 2019;70:531–44.PubMedCrossRef

Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64:73–84.CrossRefPubMed

Younossi ZM, Golabi P, de Avila L, Paik JM, Srishord M, Fukui N, et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: a systematic review and meta-analysis. J Hepatol. 2019;71:793–801.PubMedCrossRef

Angulo P, Keach JC, Batts KP, Lindor KD. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology. 1999;30:1356–62.PubMedCrossRef

Stepanova M, Rafiq N, Makhlouf H, Agrawal R, Kaur I, Younoszai Z, et al. Predictors of all-cause mortality and liver-related mortality in patients with non-alcoholic fatty liver disease (NAFLD). Dig Dis Sci. 2013;58:3017–23.PubMedCrossRef

Nakahara T, Hyogo H, Yoneda M, Sumida Y, Eguchi Y, Fujii H, et al. Type 2 diabetes mellitus is associated with the fibrosis severity in patients with nonalcoholic fatty liver disease in a large retrospective cohort of Japanese patients. J Gastroenterol. 2014;49:1477–84.PubMedCrossRef

Targher G, Byrne CD, Lonardo A, Zoppini G, Barbui C. Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: a meta-analysis. J Hepatol. 2016;65:589–600.PubMedCrossRef

Wu S, Wu F, Ding Y, Hou J, Bi J, Zhang Z. Association of non-alcoholic fatty liver disease with major adverse cardiovascular events: a systematic review and meta-analysis. Sci Rep. 2016;6:33386.PubMedPubMedCentralCrossRef

Stefan N, Haring HU, Cusi K. Non-alcoholic fatty liver disease: causes, diagnosis, cardiometabolic consequences, and treatment strategies. Lancet Diabetes Endocrinol. 2019;7:313–24.PubMedCrossRef

10.

Santos RD, Valenti L, Romeo S. Does nonalcoholic fatty liver disease cause cardiovascular disease? Current knowledge and gaps. Atherosclerosis. 2019;282:110–20.PubMedCrossRef

11.

de Marco R, Locatelli F, Zoppini G, Verlato G, Bonora E, Muggeo M. Cause-specific mortality in type 2 diabetes. The Verona Diabetes Study. Diabetes Care. 1999;22:756–61.PubMedCrossRef

12.

Juurinen L, Tiikkainen M, Hakkinen AM, Hakkarainen A, Yki-Jarvinen H. Effects of insulin therapy on liver fat content and hepatic insulin sensitivity in patients with type 2 diabetes. Am J Physiol Endocrinol Metab. 2007;292:E829–35.PubMedCrossRef

13.

Tang A, Rabasa-Lhoret R, Castel H, Wartelle-Bladou C, Gilbert G, Massicotte-Tisluck K, et al. Effects of insulin glargine and liraglutide therapy on liver fat as measured by magnetic resonance in patients with type 2 diabetes: a randomized trial. Diabetes Care. 2015;38:1339–46.PubMedCrossRef

14.

Bi Y, Zhang B, Xu W, Yang H, Feng W, Li C, et al. Effects of exenatide, insulin, and pioglitazone on liver fat content and body fat distributions in drug-naive subjects with type 2 diabetes. Acta Diabetol. 2014;51:865–73.PubMedCrossRef

15.

Lingvay I, Roe ED, Duong J, Leonard D, Szczepaniak LS. Effect of insulin versus triple oral therapy on the progression of hepatic steatosis in type 2 diabetes. J Investig Med. 2012;60:1059–63.PubMedPubMedCentralCrossRef

16.

Lingvay I, Raskin P, Szczepaniak LS. Effect of insulin-metformin combination on hepatic steatosis in patients with type 2 diabetes. J Diabetes Complications. 2007;21:137–42.PubMedPubMedCentralCrossRef

17.

Cusi K, Sanyal AJ, Zhang S, Hoogwerf BJ, Chang AM, Jacober SJ, et al. Different effects of basal insulin peglispro and insulin glargine on liver enzymes and liver fat content in patients with type 1 and type 2 diabetes. Diabetes Obes Metab. 2016;18(Suppl 2):50–8.PubMedCrossRef

18.

Liu L, Yan H, Xia M, Zhao L, Lv M, Zhao N, et al. Efficacy of exenatide and insulin glargine on nonalcoholic fatty liver disease in patients with type 2 diabetes. Diabetes Metab Res Rev. 2020;36:e3292.PubMed

19.

Shao N, Kuang HY, Hao M, Gao XY, Lin WJ, Zou W. Benefits of exenatide on obesity and non-alcoholic fatty liver disease with elevated liver enzymes in patients with type 2 diabetes. Diabetes Metab Res Rev. 2014;30:521–9.PubMedCrossRef

20.

Frayn KN. Adipose tissue as a buffer for daily lipid flux. Diabetologia. 2002;45:1201–10.PubMedCrossRef

21.

Goh G, Pagadala M, Dasarathy J, Unalp-Arida A, Sargent R. Diabetes mellitus, insulin, sulfonylurea and advanced fibrosis in non-alcoholic fatty liver disease. J Diabetes Metab. 2014;5:2.

22.

Donadon V, Balbi M, Ghersetti M, Grazioli S, Perciaccante A, Della Valentina G, et al. Antidiabetic therapy and increased risk of hepatocellular carcinoma in chronic liver disease. World J Gastroenterol. 2009;15:2506–11.PubMedPubMedCentralCrossRef

23.

Zhou YY, Zhu GQ, Liu T, Zheng JN, Cheng Z, Zou TT, et al. Systematic review with network meta-analysis: antidiabetic medication and risk of hepatocellular carcinoma. Sci Rep. 2016;6:33743.PubMedPubMedCentralCrossRef

24.

Lo L, McLennan SV, Williams PF, Bonner J, Chowdhury S, McCaughan GW, et al. Diabetes is a progression factor for hepatic fibrosis in a high fat fed mouse obesity model of non-alcoholic steatohepatitis. J Hepatol. 2011;55:435–44.PubMedCrossRef

25.

Harada S, Miyagi K, Obata T, Morimoto Y, Nakamoto K, Kim KI, et al. Influence of hyperglycemia on liver inflammatory conditions in the early phase of non-alcoholic fatty liver disease in mice. J Pharm Pharmacol. 2017;69:698–705.PubMedCrossRef

26.

Dal S, Jeandidier N, Seyfritz E, Bietiger W, Péronet C, Moreau F, et al. Featured article: oxidative stress status and liver tissue defenses in diabetic rats during intensive subcutaneous insulin therapy. Exp Biol Med. 2016;241:184–92.CrossRef

27.

Schaschkow A, Mura C, Dal S, Langlois A, Seyfritz E, Sookhareea C, et al. Impact of the type of continuous insulin administration on metabolism in a diabetic rat model. J Diabetes Res. 2016;2016:8310516.PubMedPubMedCentralCrossRef

28.

Ye P, Cheah IK, Halliwell B. High fat diets and pathology in the guinea pig. Atherosclerosis or liver damage? Biochim Biophys Acta. 2013;1832:355–64.PubMedCrossRef

29.

Guyard-Dangremont V, Desrumaux C, Gambert P, Lallemant C, Lagrost L. Phospholipid and cholesteryl ester transfer activities in plasma from 14 vertebrate species. Relation to atherogenesis susceptibility. Comp Biochem Physiol B: Biochem Mol Biol. 1998;120:517–25.CrossRef

30.

Zhao Y, Qu H, Wang Y, Xiao W, Zhang Y, Shi D. Small rodent models of atherosclerosis. Biomed Pharmacother. 2020;129:110426.PubMedCrossRef

31.

Liu GL, Fan LM, Redinger RN. The association of hepatic apoprotein and lipid metabolism in hamsters and rats. Comp Biochem Physiol, A: Comp Physiol. 1991;99:223–8.CrossRef

32.

Arbeeny CM, Meyers DS, Bergquist KE, Gregg RE. Inhibition of fatty acid synthesis decreases very low density lipoprotein secretion in the hamster. J Lipid Res. 1992;33:843–51.PubMedCrossRef

33.

Metzinger MN, Miramontes B, Zhou P, Liu Y, Chapman S, Sun L, et al. Correlation of X-ray computed tomography with quantitative nuclear magnetic resonance methods for pre-clinical measurement of adipose and lean tissues in living mice. Sensors (Basel). 2014;14:18526–42.PubMedPubMedCentralCrossRef

34.

Hvid H, Jensen SR, Witgen BM, Fledelius C, Damgaard J, Pyke C, et al. Diabetic phenotype in the small intestine of Zucker diabetic fatty rats. Digestion. 2016;94:199–214.PubMedCrossRef

35.

Beal SL. Ways to fit a PK model with some data below the quantification limit. J Pharmacokinet Pharmacodyn. 2001;28:481–504.PubMedCrossRef

36.

Hvid H, Blouin MJ, Birman E, Damgaard J, Poulsen F, Fels JJ, et al. Treatment with insulin analog X10 and IGF-1 increases growth of colon cancer allografts. PLoS ONE. 2013;8:e79710.PubMedPubMedCentralCrossRef

37.

Jensen VS, Tveden-Nyborg P, Zacho-Rasmussen C, Quaade ML, Ipsen DH, Hvid H, et al. Variation in diagnostic NAFLD/NASH read-outs in paired liver samples from rodent models. J Pharmacol Toxicol Methods. 2020;101:106651.PubMedCrossRef

38.

Team RC. R: A language and environment for statistical computing.. R Foundation for Statistical Computing, Vienna, Austria. URL http://www.R-project.org/(Date of access 01/12/2014). Accessed 01/12; 2014.

39.

Suppli MP, Rigbolt KT, Veidal SS, Heebøll S, Eriksen PL, Demant M, et al. Hepatic transcriptome signatures in patients with varying degrees of nonalcoholic fatty liver disease compared with healthy normal-weight individuals. Am J Physiol Gastrointest Liver Physiol. 2019;316:G462–72.PubMedCrossRef

40.

Lake AD, Novak P, Fisher CD, Jackson JP, Hardwick RN, Billheimer DD, et al. Analysis of global and absorption, distribution, metabolism, and elimination gene expression in the progressive stages of human nonalcoholic fatty liver disease. Drug Metab Dispos. 2011;39:1954–60.PubMedPubMedCentralCrossRef

41.

Morrison TB, Weis JJ, Wittwer CT. Quantification of low-copy transcripts by continuous SYBR Green I monitoring during amplification. Biotechniques. 1998;24:954–8.PubMed

42.

Carpino G, Morini S, Ginanni Corradini S, Franchitto A, Merli M, Siciliano M, et al. Alpha-SMA expression in hepatic stellate cells and quantitative analysis of hepatic fibrosis in cirrhosis and in recurrent chronic hepatitis after liver transplantation. Dig Liver Dis. 2005;37:349–56.PubMedCrossRef

43.

Williams KH, Shackel NA, Gorrell MD, McLennan SV, Twigg SM. Diabetes and nonalcoholic Fatty liver disease: a pathogenic duo. Endocr Rev. 2013;34:84–129.PubMedCrossRef

44.

Kadowaki T, Kasuga M, Akanuma Y, Ezaki O, Takaku F. Decreased autophosphorylation of the insulin receptor-kinase in streptozotocin-diabetic rats. J Biol Chem. 1984;259:14208–16.PubMedCrossRef

45.

Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest. 2004;114:147–52.PubMedPubMedCentralCrossRef

46.

Mohanty P, Hamouda W, Garg R, Aljada A, Ghanim H, Dandona P. Glucose challenge stimulates reactive oxygen species (ROS) generation by leucocytes. J Clin Endocrinol Metab. 2000;85:2970–3.PubMedCrossRef

47.

Esposito K, Nappo F, Marfella R, Giugliano G, Giugliano F, Ciotola M, et al. Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress. Circulation. 2002;106:2067–72.PubMedCrossRef

48.

Dhindsa S, Tripathy D, Mohanty P, Ghanim H, Syed T, Aljada A, et al. Differential effects of glucose and alcohol on reactive oxygen species generation and intranuclear nuclear factor-kappaB in mononuclear cells. Metabolism. 2004;53:330–4.PubMedCrossRef

49.

Dandona P, Mohanty P, Chaudhuri A, Garg R, Aljada A. Insulin infusion in acute illness. J Clin Invest. 2005;115:2069–72.PubMedPubMedCentralCrossRef

50.

Morgan MJ, Liu ZG. Crosstalk of reactive oxygen species and NF-kappaB signaling. Cell Res. 2011;21:103–15.PubMedCrossRef

51.

Farrell GC, van Rooyen D, Gan L, Chitturi S. NASH is an inflammatory disorder: pathogenic, prognostic and therapeutic implications. Gut Liver. 2012;6:149–71.PubMedPubMedCentralCrossRef

52.

Kamada Y, Akita M, Takeda Y, Yamada S, Fujii H, Sawai Y, et al. Serum fucosylated haptoglobin as a novel diagnostic biomarker for predicting hepatocyte ballooning and nonalcoholic steatohepatitis. PLoS ONE. 2013;8:e66328.PubMedPubMedCentralCrossRef

53.

Gadd VL, Skoien R, Powell EE, Fagan KJ, Winterford C, Horsfall L, et al. The portal inflammatory infiltrate and ductular reaction in human nonalcoholic fatty liver disease. Hepatology. 2014;59:1393–405.PubMedCrossRef

54.

Kazankov K, Jørgensen SMD, Thomsen KL, Møller HJ, Vilstrup H, George J, et al. The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Nat Rev Gastroenterol Hepatol. 2019;16:145–59.PubMedCrossRef

55.

Schuppan D, Surabattula R, Wang XY. Determinants of fibrosis progression and regression in NASH. J Hepatol. 2018;68:238–50.CrossRefPubMed

56.

Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med. 2011;43:617–49.PubMedCrossRef

57.

Friedman SL. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J Biol Chem. 2000;275:2247–50.PubMedCrossRef

58.

Schuppan D, Ruehl M, Somasundaram R, Hahn EG. Matrix as a modulator of hepatic fibrogenesis. Semin Liver Dis. 2001;21:351–72.PubMedCrossRef

59.

Sugimoto R, Enjoji M, Kohjima M, Tsuruta S, Fukushima M, Iwao M, et al. High glucose stimulates hepatic stellate cells to proliferate and to produce collagen through free radical production and activation of mitogen-activated protein kinase. Liver Int. 2005;25:1018–26.PubMedCrossRef

60.

Lin J, Chen A. Curcumin diminishes the impacts of hyperglycemia on the activation of hepatic stellate cells by suppressing membrane translocation and gene expression of glucose transporter-2. Mol Cell Endocrinol. 2011;333:160–71.PubMedCrossRef

61.

Paradis V, Dargere D, Vidaud M, De Gouville AC, Huet S, Martinez V, et al. Expression of connective tissue growth factor in experimental rat and human liver fibrosis. Hepatology. 1999;30:968–76.PubMedCrossRef

62.

Williams EJ, Gaca MD, Brigstock DR, Arthur MJ, Benyon RC. Increased expression of connective tissue growth factor in fibrotic human liver and in activated hepatic stellate cells. J Hepatol. 2000;32:754–61.PubMedCrossRef

63.

Paradis V, Perlemuter G, Bonvoust F, Dargere D, Parfait B, Vidaud M, et al. High glucose and hyperinsulinemia stimulate connective tissue growth factor expression: a potential mechanism involved in progression to fibrosis in nonalcoholic steatohepatitis. Hepatology. 2001;34:738–44.PubMedCrossRef

64.

Yeh MM, Brunt EM. Pathology of nonalcoholic fatty liver disease. Am J Clin Pathol. 2007;128:837–47.PubMedCrossRef

65.

Ferre P, Foufelle F. Hepatic steatosis: a role for de novo lipogenesis and the transcription factor SREBP-1c. Diabetes Obes Metab. 2010;12(Suppl 2):83–92.PubMedCrossRef

66.

Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005;115:1343–51.PubMedPubMedCentralCrossRef

67.

Hamaguchi E, Takamura T, Sakurai M, Mizukoshi E, Zen Y, Takeshita Y, et al. Histological course of nonalcoholic fatty liver disease in Japanese patients: tight glycemic control, rather than weight reduction, ameliorates liver fibrosis. Diabetes Care. 2010;33:284–6.PubMedCrossRef

68.

Staten NR, Welsh EA, Sidik K, McDonald SA, Dufield DR, Maqsodi B, et al. Multiplex transcriptional analysis of paraffin-embedded liver needle biopsy from patients with liver fibrosis. Fibrogenesis Tissue Repair. 2012;5:21.PubMedPubMedCentralCrossRef

69.

Herbst H, Wege T, Milani S, Pellegrini G, Orzechowski HD, Bechstein WO, et al. Tissue inhibitor of metalloproteinase-1 and -2 RNA expression in rat and human liver fibrosis. Am J Pathol. 1997;150:1647–59.PubMedPubMedCentral

70.

Benyon RC, Iredale JP, Goddard S, Winwood PJ, Arthur MJ. Expression of tissue inhibitor of metalloproteinases 1 and 2 is increased in fibrotic human liver. Gastroenterology. 1996;110:821–31.PubMedCrossRef

71.

Mehta MB, Shewale SV, Sequeira RN, Millar JS, Hand NJ, Rader DJ. Hepatic protein phosphatase 1 regulatory subunit 3B (Ppp1r3b) promotes hepatic glycogen synthesis and thereby regulates fasting energy homeostasis. J Biol Chem. 2017;292:10444–54.PubMedPubMedCentralCrossRef

72.

Petersen MC, Vatner DF, Shulman GI. Regulation of hepatic glucose metabolism in health and disease. Nat Rev Endocrinol. 2017;13:572–87.PubMedPubMedCentralCrossRef

73.

Huang Y, He S, Li JZ, Seo YK, Osborne TF, Cohen JC, et al. A feed-forward loop amplifies nutritional regulation of PNPLA3. Proc Natl Acad Sci USA. 2010;107:7892–7.PubMedCrossRefPubMedCentral

74.

Shimano H, Yahagi N, Amemiya-Kudo M, Hasty AH, Osuga J, Tamura Y, et al. Sterol regulatory element-binding protein-1 as a key transcription factor for nutritional induction of lipogenic enzyme genes. J Biol Chem. 1999;274:35832–9.PubMedCrossRef

75.

Xiong X, Kuang H, Ansari S, Liu T, Gong J, Wang S, et al. Landscape of intercellular crosstalk in healthy and NASH liver revealed by single-cell secretome gene analysis. Mol Cell. 2019;75(644–60):e5.

76.

Jiang Y, Sun A, Zhao Y, Ying W, Sun H, Yang X, et al. Proteomics identifies new therapeutic targets of early-stage hepatocellular carcinoma. Nature. 2019;567:257–61.PubMedCrossRef

77.

Khoury T, Chadha K, Javle M, Donohue K, Levea C, Iyer R, et al. Expression of intestinal trefoil factor (TFF-3) in hepatocellular carcinoma. Int J Gastrointest Cancer. 2005;35:171–7.PubMedCrossRef

78.

Syn WK, Agboola KM, Swiderska M, Michelotti GA, Liaskou E, Pang H, et al. NKT-associated hedgehog and osteopontin drive fibrogenesis in non-alcoholic fatty liver disease. Gut. 2012;61:1323–9.PubMedCrossRef

79.

Lorena D, Darby IA, Gadeau AP, Leen LL, Rittling S, Porto LC, et al. Osteopontin expression in normal and fibrotic liver. altered liver healing in osteopontin-deficient mice. J Hepatol. 2006;44:383–90.PubMedCrossRef

80.

Gerhard GS, Legendre C, Still CD, Chu X, Petrick A, DiStefano JK. Transcriptomic profiling of obesity-related nonalcoholic steatohepatitis reveals a core set of fibrosis-specific genes. J Endocr Soc. 2018;2:710–26.PubMedPubMedCentralCrossRef

81.

Graveel CR, Jatkoe T, Madore SJ, Holt AL, Farnham PJ. Expression profiling and identification of novel genes in hepatocellular carcinomas. Oncogene. 2001;20:2704–12.PubMedCrossRef

82.

Okada H, Kimura MT, Tan D, Fujiwara K, Igarashi J, Makuuchi M, et al. Frequent trefoil factor 3 (TFF3) overexpression and promoter hypomethylation in mouse and human hepatocellular carcinomas. Int J Oncol. 2005;26:369–77.PubMed

83.

Katayama A, Nakatsuka A, Eguchi J, Murakami K, Teshigawara S, Kanzaki M, et al. Beneficial impact of Gpnmb and its significance as a biomarker in nonalcoholic steatohepatitis. Sci Rep. 2015;5:16920.PubMedPubMedCentralCrossRef

84.

Mao XM, Liu H, Tao XJ, Yin GP, Li Q, Wang SK. Independent anti-inflammatory effect of insulin in newly diagnosed type 2 diabetes. Diabetes Metab Res Rev. 2009;25:435–41.PubMedCrossRef

85.

Dandona P, Aljada A, Mohanty P, Ghanim H, Hamouda W, Assian E, et al. Insulin inhibits intranuclear nuclear factor kappaB and stimulates IkappaB in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect? J Clin Endocrinol Metab. 2001;86:3257–65.PubMed

86.

Seki E, Schwabe RF. Hepatic inflammation and fibrosis: functional links and key pathways. Hepatology. 2015;61:1066–79.PubMedCrossRef

87.

Imajo K, Fujita K, Yoneda M, Nozaki Y, Ogawa Y, Shinohara Y, et al. Hyperresponsivity to low-dose endotoxin during progression to nonalcoholic steatohepatitis is regulated by leptin-mediated signaling. Cell Metab. 2012;16:44–54.PubMedCrossRef

88.

Miura K, Yang L, van Rooijen N, Ohnishi H, Seki E. Hepatic recruitment of macrophages promotes nonalcoholic steatohepatitis through CCR2. Am J Physiol Gastrointest Liver Physiol. 2012;302:G1310–21.PubMedPubMedCentralCrossRef

89.

Veyel D, Wenger K, Broermann A, Bretschneider T, Luippold AH, Krawczyk B, et al. Biomarker discovery for chronic liver diseases by multi-omics-a preclinical case study. Sci Rep. 2020;10:1314.PubMedPubMedCentralCrossRef

90.

Bertola A, Bonnafous S, Anty R, Patouraux S, Saint-Paul MC, Iannelli A, et al. Hepatic expression patterns of inflammatory and immune response genes associated with obesity and NASH in morbidly obese patients. PLoS ONE. 2010;5:e13577.PubMedPubMedCentralCrossRef

Title: Insulin treatment improves liver histopathology and decreases expression of inflammatory and fibrogenic genes in a hyperglycemic, dyslipidemic hamster model of NAFLD
Authors: Victoria Svop Jensen
Christian Fledelius
Christina Zachodnik
Jesper Damgaard
Helle Nygaard
Kristina Steinicke Tornqvist
Rikke Kaae Kirk
Birgitte Martine Viuff
Erik Max Wulff
Jens Lykkesfeldt
Henning Hvid
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Insulins
Fatty Liver
Hyperglycemia
Insulins
Published in: Journal of Translational Medicine / Issue 1/2021
Electronic ISSN: 1479-5876
DOI: https://doi.org/10.1186/s12967-021-02729-1

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