Experimental non-alcoholic steatohepatitis in Göttingen Minipigs: consequences of high fat-fructose-cholesterol diet and diabetes.

Publisher: BioMed Central Country of Publication: England NLM ID: 101190741 Publication Model: Electronic Cited Medium: Internet ISSN: 1479-5876 (Electronic) Linking ISSN: 14795876 NLM ISO Abbreviation: J Transl Med Subsets: MEDLINE

Original Publication: [London] : BioMed Central, 2003-

Diet, High-Fat* ; Disease Models, Animal* ; Swine, Miniature*; Cholesterol, Dietary/*pharmacology ; Diabetes Mellitus/*pathology ; Fructose/*pharmacology ; Non-alcoholic Fatty Liver Disease/*pathology; Diabetes Complications/pathology ; Diabetes Mellitus/etiology ; Dietary Carbohydrates/pharmacology ; Dietary Fats/pharmacology ; Hepatocytes/drug effects ; Hepatocytes/pathology ; Liver/drug effects ; Liver/pathology ; Non-alcoholic Fatty Liver Disease/etiology ; Obesity/pathology ; Animals ; Male ; Swine

Background: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in humans, and ranges from steatosis to non-alcoholic steatohepatitis (NASH), the latter with risk of progression to cirrhosis. The Göttingen Minipig has been used in studies of obesity and diabetes, but liver changes have not been described. The aim of this study was to characterize hepatic changes in Göttingen Minipigs with or without diabetes, fed a diet high in fat, fructose, and cholesterol to see if liver alterations resemble features of human NAFLD/NASH.
Methods: Fifty-four male castrated minipigs (age 6 to 7 months) were distributed into four groups and diet-fed for 13 months. Groups were: lean controls fed standard diet (SD, n = 8), a group fed high fat/fructose/cholesterol diet (FFC, n = 16), a group fed high fat/fructose/cholesterol diet but changed to standard diet after 7 months (diet normalization, FFC/SD, n = 16), and a streptozotocin-induced diabetic group fed high fat/fructose/cholesterol diet (FFCDIA, n = 14). At termination, blood samples for analyses of circulating biomarkers and liver tissue for histopathological assessment and analyses of lipids and glycogen content were collected.
Results: In comparison with SD and FFC/SD, FFC and FFCDIA pigs developed hepatomegaly with increased content of cholesterol, whereas no difference in triglyceride content was found. FFC and FFCDIA groups had increased values of circulating total cholesterol and triglycerides and the hepatic circulating markers alkaline phosphatase and glutamate dehydrogenase. In the histopathological evaluation, fibrosis (mainly located periportally) and inflammation along with cytoplasmic alterations (characterized by hepatocytes with pale, granulated cytoplasm) were found in FFC and FFCDIA groups compared to SD and FFC/SD. Interestingly, FFC/SD also had fibrosis, a feature not seen in SD. Only two FFC and three FFCDIA pigs had > 5% steatosis, and no hepatocellular ballooning or Mallory-Denk bodies were found in any of the pigs.
Conclusions: Fibrosis, inflammation and cytoplasmic alterations were characteristic features in the livers of FCC and FFCDIA pigs. Overall, diabetes did not exacerbate the hepatic changes compared to FFC. The limited presence of the key human-relevant pathological hepatic findings of steatosis and hepatocellular ballooning and the variation in the model, limits its use in preclinical research without further optimisation.

Metabolism. 2011 May;60(5):735-9. (PMID: 20817213)
PLoS One. 2015 May 15;10(5):e0124173. (PMID: 25978364)
Am J Nucl Med Mol Imaging. 2014 Aug 15;4(5):448-58. (PMID: 25143863)
Clin Sci (Lond). 2017 Nov 6;131(22):2701-2704. (PMID: 29109303)
Hepatology. 2016 Jul;64(1):73-84. (PMID: 26707365)
Hepatology. 2005 Jun;41(6):1313-21. (PMID: 15915461)
Hepatology. 2005 Sep;42(3):641-9. (PMID: 16116629)
Nutrients. 2017 Sep 27;9(10):. (PMID: 28953222)
Exp Mol Pathol. 2014 Jun;96(3):382-92. (PMID: 24747241)
J Atheroscler Thromb. 2017 Nov 1;24(11):1150-1166. (PMID: 28496045)
Sci Rep. 2015 Sep 11;5:13980. (PMID: 26358367)
Nutr Metab (Lond). 2016 Aug 09;13:51. (PMID: 27512407)
PLoS One. 2016 Nov 30;11(11):e0167285. (PMID: 27902747)
Hepatology. 2014 Jul;60(1):169-78. (PMID: 24519272)
Dig Dis Sci. 2017 Sep;62(9):2569-2577. (PMID: 28577247)
Int J Cardiol. 2016 Dec 15;225:387-391. (PMID: 27768965)
Hepatology. 2018 Jan;67(1):328-357. (PMID: 28714183)
Lab Invest. 2013 Feb;93(2):230-41. (PMID: 23212097)
J Hepatol. 2008 May;48(5):821-8. (PMID: 18329127)
Hum Pathol. 2012 Jun;43(6):790-800. (PMID: 22036053)
Hepatology. 2014 Aug;60(2):565-75. (PMID: 24753132)
Nutr Metab (Lond). 2018 Sep 25;15:64. (PMID: 30263039)
Nat Rev Gastroenterol Hepatol. 2013 Jun;10(6):330-44. (PMID: 23507799)
Comp Med. 2001 Apr;51(2):150-5. (PMID: 11922179)
Diabetes Care. 2007 May;30(5):1212-8. (PMID: 17277038)
Intern Med J. 2015 Jul;45(7):777-9. (PMID: 26134697)
Comp Med. 2007 Oct;57(5):493-504. (PMID: 17974133)
Hepatology. 2009 Jul;50(1):56-67. (PMID: 19434740)
Transl Res. 2016 Feb;168:146-160. (PMID: 26518991)
Hepatology. 2003 Jun;37(6):1286-92. (PMID: 12774006)
Toxicol Pathol. 2014 Oct;42(7):1058-68. (PMID: 24705882)
J Nutr Biochem. 2017 Feb;40:62-69. (PMID: 27863346)
J Pathol. 2017 Jan;241(1):36-44. (PMID: 27757953)
J Hepatol. 2016 Sep;65(3):579-88. (PMID: 27261415)
Curr Opin Gastroenterol. 2012 May;28(3):209-16. (PMID: 22450891)
Diabetes. 2001 Jul;50(7):1654-65. (PMID: 11423488)
Diabetologia. 1985 Jul;28(7):412-9. (PMID: 3899825)
Gastroenterology. 2012 Jan;142(1):8-11. (PMID: 22107717)
Cell Tissue Res. 1993 Aug;273(2):227-37. (PMID: 7689937)
J Nutr. 2005 Nov;135(11):2499-502. (PMID: 16251600)
J Nutr Biochem. 2016 Feb;28:51-60. (PMID: 26878782)
J Immunol Methods. 2009 Apr 15;343(2):112-8. (PMID: 19236874)
Metabolism. 2016 Aug;65(8):1096-108. (PMID: 26856933)

Keywords: Animal model; Diabetes; Dietary cholesterol; Metabolic syndrome; NAFLD; NASH; Obesity; Porcine

0 (Cholesterol, Dietary)
0 (Dietary Carbohydrates)
0 (Dietary Fats)
30237-26-4 (Fructose)

Date Created: 20190405 Date Completed: 20200504 Latest Revision: 20200504

20260130

PMC6448276

10.1186/s12967-019-1854-y

30943987