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

High-fat diet (HFD) feeding or leptin-deficient mice are extensively used as models resembling features of human nonalcoholic 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 promoted liver lipid accumulation only in the hyperphagic strain. Nevertheless, 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 including female models in the NAFLD research field. NEW & NOTEWORTHY This work provides new insight into the use of high-fat diet as a model to induce nonalcoholic fatty liver disease in wild-type and ob/ ob female mice. We show that high-fat diet induces steatosis only in ob/ ob mice while, surprisingly, several health indicators improve. Noteworthy, experiments with primary hepatocytes from male and female mice show that they express Takeda G protein-coupled bile acid receptor and that it and bile acid enterohepatic circulation might be accountable for sex dimorphism in nonalcoholic fatty liver disease development.

Cholesterol mobilization from hepatic lipid droplets during endotoxemia is altered in obese ob/ob mice.

The innate immune response to pathogens during the acute phase response includes lipid metabolism adaptations. Hepatic triacylglycerol (TG) and cholesteryl ester (CE) storage in and mobilization from lipid droplets (LDs) respond to metabolic changes under the control of liver X receptor (LXR) transactivation and cytokine transduction. To evaluate whether alterations of these mechanisms have an impact in the adaptive response to endotoxemia, we analysed liver metabolism changes in lipopolysaccharide (LPS)-treated ob/ob mice, which show altered metabolic and innate responses and a higher sensitivity to sepsis. Lipid composition of serum lipoproteins and hepatic LDs was determined in wild type and ob/ob mice 24 h after LPS treatment. Liver metabolic profiling was done by measuring enzyme activities and mRNA levels. Increased CE hydrolase activity in LDs from endotoxemic mice was accompanied by a lower content of CE and low or no induction of LXR-mediated expression of genes involved in HDL secretion. The attenuated response in liver lipid mobilization accompanied by the strain-specific cholesterol enrichment of secreted VLDL might lead to accumulation of LDL cholesterol. According to our findings, obese leptin-deficient mice present an altered control of hepatic lipid metabolism responses to LPS, which might be, in part at least, a consequence of impaired LXR.

Involvement of lipid droplets in hepatic responses to lipopolysaccharide treatment in mice.

Infection and inflammation induce important changes in lipid metabolism, which result in increased free fatty acids and triacylglycerol in plasma and altered high density lipoprotein (HDL) metabolism. Our aim was to elucidate whether hepatic lipid droplets (LDs) are involved in the adaptations of lipid metabolism to endotoxemia. We characterized the lipid content and several enzymatic activities in subcellular fractions and subpopulations of LDs from livers of mice 24h after lipopolysaccharide (LPS) treatment and analyzed the expression of key genes involved in lipid management. Endotoxemic mice showed lower lipid content in LDs with decreased molar fraction of cholesteryl ester and higher diacylglycerol/triacylglycerol ratio as compared to their controls. They also showed a decrease in cytosolic triacylglycerol hydrolase activity, specifically in dense LDs, and in microsomal and cytosolic diacylglycerol hydrolase activity; concomitantly neutral lipid biosynthetic capacity and triacylglycerol levels in plasma lipoproteins increased. Together with the overexpression of genes involved in lipogenesis and HDL formation our results suggest that altered hepatic management of LD lipids in LPS-treated mice might be related to the channeled mobilization of triacylglycerol for very low density lipoprotein assembly and to the induction of cholesterol export.