TY - JOUR

T1 - Experimental non-alcoholic steatohepatitis in Göttingen Minipigs

T2 - Consequences of high fat-fructose-cholesterol diet and diabetes

AU - Schumacher-Petersen, Camilla

AU - Christoffersen, Berit Ostergaard

AU - Kirk, Rikke Kaae

AU - Ludvigsen, Trine Pagh

AU - Zois, Nora Elisabeth

AU - Pedersen, Henrik Duelund

AU - Vyberg, Mogens

AU - Olsen, Lisbeth Høier

PY - 2019

Y1 - 2019

N2 - 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 (FFC DIA , 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 FFC DIA pigs developed hepatomegaly with increased content of cholesterol, whereas no difference in triglyceride content was found. FFC and FFC DIA 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 FFC DIA groups compared to SD and FFC/SD. Interestingly, FFC/SD also had fibrosis, a feature not seen in SD. Only two FFC and three FFC DIA 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 FFC DIA 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.

AB - 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 (FFC DIA , 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 FFC DIA pigs developed hepatomegaly with increased content of cholesterol, whereas no difference in triglyceride content was found. FFC and FFC DIA 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 FFC DIA groups compared to SD and FFC/SD. Interestingly, FFC/SD also had fibrosis, a feature not seen in SD. Only two FFC and three FFC DIA 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 FFC DIA 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.

KW - Animal model

KW - Diabetes

KW - Dietary cholesterol

KW - Metabolic syndrome

KW - NAFLD

KW - NASH

KW - Obesity

KW - Porcine

U2 - 10.1186/s12967-019-1854-y

DO - 10.1186/s12967-019-1854-y

M3 - Journal article

C2 - 30943987

AN - SCOPUS:85063930967

VL - 17

JO - Journal of Translational Medicine

JF - Journal of Translational Medicine

SN - 1479-5876

IS - 1

M1 - 110

ER -