在Ldlr-/- Leiden小鼠饮食诱导的非酒精性脂肪性肝炎（NASH）发展过程中，肝脏、脂肪组织和肠道代谢功能障碍的时间动态变化的转化特征。

Translational characterization of the temporal dynamics of metabolic dysfunctions in liver, adipose tissue and the gut during diet-induced NASH development in Ldlr-/-.Leiden mice.

作者信息

Gart Eveline, van Duyvenvoorde Wim, Snabel Jessica M, de Ruiter Christa, Attema Joline, Caspers Martien P M, Lek Serene, van Heuven Bertie Joan, Speksnijder Arjen G C L, Giera Martin, Menke Aswin, Salic Kanita, Bence Kendra K, Tesz Gregory J, Keijer Jaap, Kleemann Robert, Morrison Martine C

机构信息

Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), 2333 CK Leiden, the Netherlands.

Human and Animal Physiology, Wageningen University, 6708 WD Wageningen, the Netherlands.

出版信息

Heliyon. 2023 Feb 24;9(3):e13985. doi: 10.1016/j.heliyon.2023.e13985. eCollection 2023 Mar.

BACKGROUND

NAFLD progression, from steatosis to inflammation and fibrosis, results from an interplay of intra- and extrahepatic mechanisms. Disease drivers likely include signals from white adipose tissue (WAT) and gut. However, the temporal dynamics of disease development remain poorly understood.

METHODS

High-fat-diet (HFD)-fed Ldlr-/-.Leiden mice were compared to chow-fed controls. At t = 0, 8, 16, 28 and 38w mice were euthanized, and liver, WAT depots and gut were analyzed biochemically, histologically and by lipidomics and transcriptomics together with circulating factors to investigate the sequence of pathogenic events and organ cross-talk during NAFLD development.

RESULTS

HFD-induced obesity was associated with an increase in visceral fat, plasma lipids and hyperinsulinemia at t = 8w, along with increased liver steatosis and circulating liver damage biomarkers. In parallel, upstream regulator analysis predicted that lipid catabolism regulators were deactivated and lipid synthesis regulators were activated. Subsequently, hepatocyte hypertrophy, oxidative stress and hepatic inflammation developed. Hepatic collagen accumulated from t = 16 w and became pronounced at t = 28-38 w. Epididymal WAT was maximally hypertrophic from t = 8 w, which coincided with inflammation development. Mesenteric and subcutaneous WAT hypertrophy developed slower and did not appear to reach a maximum, with minimal inflammation. In gut, HFD significantly increased permeability, induced a shift in microbiota composition from t = 8 w and changed circulating gut-derived metabolites.

CONCLUSION

HFD-fed Ldlr-/-.Leiden mice develop obesity, dyslipidemia and insulin resistance, essentially as observed in obese NAFLD patients, underlining their translational value. We demonstrate that marked epididymal-WAT inflammation, and gut permeability and dysbiosis precede the development of NAFLD stressing the importance of a multiple-organ approach in the prevention and treatment of NAFLD.

背景

非酒精性脂肪性肝病（NAFLD）从脂肪变性发展到炎症和纤维化，是肝内和肝外机制相互作用的结果。疾病驱动因素可能包括来自白色脂肪组织（WAT）和肠道的信号。然而，疾病发展的时间动态仍知之甚少。

方法

将高脂饮食（HFD）喂养的Ldlr-/- Leiden小鼠与正常饮食喂养的对照小鼠进行比较。在t = 0、8、16、28和38周时对小鼠实施安乐死，并对肝脏、WAT储存部位和肠道进行生化、组织学分析，以及脂质组学和转录组学分析，同时分析循环因子，以研究NAFLD发展过程中致病事件的顺序和器官间的相互作用。

结果

HFD诱导的肥胖与t = 8周时内脏脂肪增加、血脂升高和高胰岛素血症相关，同时肝脏脂肪变性和循环肝脏损伤生物标志物增加。与此同时，上游调节因子分析预测脂质分解调节因子失活，脂质合成调节因子激活。随后，肝细胞肥大、氧化应激和肝脏炎症出现。肝胶原从t = 16周开始积累，并在t = 28 - 38周时变得明显。附睾WAT从t = 8周开始最大程度地肥大，这与炎症发展同时发生。肠系膜和皮下WAT肥大发展较慢，似乎未达到最大值，炎症也很轻微。在肠道中，HFD显著增加通透性，从t = 8周开始诱导微生物群组成发生变化，并改变循环中源自肠道的代谢产物。