Abstract
Although non-alcoholic and alcoholic fatty liver disease have been intensively studied, concerning pathophysiological mechanisms are still incompletely understood. This may be due to the use of different animal models and resulting model-associated variation. Therefore, this study aimed to compare three frequently used wild type mouse strains in their susceptibility to develop diet-induced features of non-alcoholic/alcoholic fatty liver disease. Fatty liver disease associated clinical, biochemical, and histological features in C57BL/6, CD-1, and 129Sv WT mice were induced by (i) high-fat diet feeding, (ii) ethanol feeding only, and (iii) the combination of high-fat diet and ethanol feeding. Hepatic and subcutaneous adipose lipid profiles were compared in CD-1 and 129Sv mice. Additionally hepatic fatty acid composition was determined in 129Sv mice. In C57BL/6 mice dietary regimens resulted in heterogeneous hepatic responses, ranging from pronounced steatosis and inflammation to a lack of any features of fatty liver disease. Liver-related serum biochemistry showed high deviations within the regimen groups. CD-1 mice did not exhibit significant changes in metabolic and liver markers and developed no significant steatosis or inflammation as a response to dietary regimens. Although 129Sv mice showed no weight gain, this strain achieved most consistent features of fatty liver disease, apparent from concentration alterations of liver-related serum biochemistry as well as moderate steatosis and inflammation as a result of all dietary regimens. Furthermore, the hepatic lipid profile as well as the fatty acid composition of 129Sv mice were considerably altered, upon feeding the different dietary regimens. Accordingly, diet-induced non-alcoholic/alcoholic fatty liver disease is most consistently promoted in 129Sv mice compared to C57BL/6 and CD-1 mice. As a conclusion, this study demonstrates the importance of genetic background of used mouse strains for modeling diet-induced non-alcoholic/alcoholic fatty liver disease.
Highlights
Non-alcoholic (NAFLD) as well as alcoholic fatty liver disease (AFLD) range among the most prevalent liver diseases and are associated with considerable health and socioeconomic burden in many populations worldwide [1,2,3,4,5,6]
Single nucleotide polymorphisms (SNPs) involved in NAFLD development and progression include e.g. variants in insulin receptor substrate-1 (IRS1) and glucose transporter solute carrier family 2 member 1 gene (SLC2A1) [20,21,22], while AFLD is associated with allelic variations in class I alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) [23]
For C57BL/6 as well as CD-1 mice, body weight increase of the groups fed high-fat diet (HF) and HF + EtOH was significantly increased compared to mice fed EtOH only at time point 7 weeks (Fig 1A and 1B). 129Sv mice showed no significant differences in weight gain between the dietary groups (Fig 1C)
Summary
Non-alcoholic (NAFLD) as well as alcoholic fatty liver disease (AFLD) range among the most prevalent liver diseases and are associated with considerable health and socioeconomic burden in many populations worldwide [1,2,3,4,5,6]. NAFLD, associated with insulin resistance, represents the hepatic manifestation of the metabolic syndrome (MS) [1, 2, 7, 8], while AFLD is caused by excessive alcohol consumption [5, 6]. Both conditions comprise a spectrum of liver diseases, ranging from steatosis to steatohepatitis and cirrhosis in humans [6, 9,10,11,12]. SNPs involved in NAFLD development and progression include e.g. variants in insulin receptor substrate-1 (IRS1) and glucose transporter solute carrier family 2 member 1 gene (SLC2A1) [20,21,22], while AFLD is associated with allelic variations in class I alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) [23]
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