Facultad de Ciencias Naturales y Ambientales, Universidad Internacional SEK , Quito , Ecuador.
Lipids and Liver Research Group, Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain.
Am J Physiol Gastrointest Liver Physiol. 2018 Nov 1;315(5):G772-G780. doi: 10.1152/ajpgi.00022.2018. Epub 2018 Aug 10.
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.
高脂肪饮食（HFD）喂养或瘦素缺乏的小鼠被广泛用作模拟人类非酒精性脂肪性肝病（NAFLD）特征的模型。实验因素（如脂肪含量和来源或总热量摄入）的并存导致肝脂肪变性和相关紊乱的发展存在显著差异。在这项工作中，我们描述了 HFD 在野生型（WT）和 ob/ob 小鼠中诱导的肝脂质积累，目的是区分对 HFD 的适应与由于瘦素缺乏相关的多食引起的过度喂养的特异性适应。鉴于大多数已发表的工作都是在雄性模型中完成的，我们使用雌性小鼠，旨在增加关于女性非酒精性脂肪性肝病的证据。HFD 仅在 Hyperphagic 品系中促进肝脏脂质积累。然而，在 WT 和肥胖动物中观察到与脂滴相关的胆固醇酯（CE）减少。这些变化伴随着脂蛋白谱的改善，该脂蛋白谱可在 ob/ob 小鼠的血浆中转运胆固醇和肝功能标志物，并降低肝指数。使用来自雌性小鼠的原代肝细胞，在存在特定的 Takeda G 蛋白偶联胆汁酸受体激动剂的情况下，由 0.4mM 油酸诱导的 CE 过度积累得到逆转。然而，来自雄性小鼠的肝细胞没有反应。这项研究表明，胆酸的肠肝循环可能是影响 NAFLD 发展性别二态性的因素之一，这强调了在 NAFLD 研究领域中纳入雌性模型的重要性。
本研究提供了对使用高脂肪饮食诱导野生型和 ob/ob 雌性小鼠非酒精性脂肪性肝病模型的新见解。我们表明，高脂肪饮食仅在 ob/ob 小鼠中诱导脂肪变性，而令人惊讶的是，一些健康指标得到改善。值得注意的是，来自雄性和雌性小鼠的原代肝细胞的实验表明，它们表达 Takeda G 蛋白偶联胆汁酸受体，并且胆汁酸肠肝循环可能是导致非酒精性脂肪性肝病发展性别二态性的原因。
