High-fat diet overfeeding promotes nondetrimental liver steatosis in female mice

Abstract

High-fat diet overfeeding promotes nondetrimental liver steatosis in female mice. Am J Physiol Gastrointest Liver Physiol 315: G772– G780, 2018. First published August 10, 2018; doi:10.1152/ajpgi. 00022.2018.—High-fat diet (HFD) feeding or leptin-deficient mice

are extensively used as models resembling features of human nonal- coholic fatty liver disease (NAFLD). The concurrence of experimental

factors as fat content and source or total caloric intake leads to prominent differences in the development of the hepatic steatosis and related disturbances. In this work, we characterized the hepatic lipid accumulation induced by HFD in wild-type (WT) and ob/ob mice with the purpose of differentiating adaptations to HFD from those specific of increased overfeeding due to leptin deficiency-associated hyperphagia. Given that most published works have been done in male models, we used female mice with the aim of increasing the

body of evidence regarding NAFLD in female subjects. HFD pro- moted liver lipid accumulation only in the hyperphagic strain. Nev- ertheless, a decrease of lipid droplet-associated cholesteryl ester (CE)

in both WT and obese animals was observed. These changes were accompanied by an improvement in the profile of lipoproteins that transport cholesterol and liver function markers in plasma from ob/ob mice and a lower hepatic index. Using primary hepatocytes from female mice, overaccumulation of CE induced by 0.4 mM oleic acid reversed in the presence of a specific Takeda G protein-coupled bile acid receptor agonist. Nevertheless, hepatocytes from male mice were not responsive. This study suggests that enterohepatic circulation of bile acids might be one of the factors that can affect sex dimorphism in NAFLD development, which underlines the importance of includ- ing female models in the NAFLD research field.