Cholesterol Accumulation as a Driver of Hepatic Inflammation Under Translational Dietary Conditions Can Be Attenuated by a Multicomponent Medicine.
Cholesterol Accumulation as a Driver of Hepatic Inflammation Under Translational Dietary Conditions Can Be Attenuated by a Multicomponent Medicine.
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DOI：
10.3389/fendo.2021.601160
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发表时间：
2021
影响因子：
5.2
通讯作者：
Morrison MC
中科院分区：
文献类型：
--
作者：
Mueller AM;Kleemann R;Gart E;van Duyvenvoorde W;Verschuren L;Caspers M;Menke A;Krömmelbein N;Salic K;Burmeister Y;Seilheimer B;Morrison MC
非酒精性脂肪性肝病(NAFLD)是一种复杂的多因素疾病，其特征是脂代谢和胆固醇稳态失调，以及相关的慢性炎症反应。非酒精性脂肪肝已成为许多国家慢性肝病的最常见原因，其患病率在肥胖率上升的同时继续上升。在这里，我们评估了一种由24种天然成分组成的多组分药物对NAFLD的假定减弱效果：复方肝素(HC-24)。LDLR-/-.Leiden小鼠被喂以大量营养素成分和胆固醇含量与人类饮食相当的高脂肪饮食(HFD)24周，以诱导肥胖相关的代谢功能障碍，包括肝脏脂肪变性和炎症。在研究的最后18周，HC-24或赋形剂对照组每周给药3次(1.5ml/kg)。肝脏和脂肪组织的组织学分析与广泛的肝脏转录分析相结合。转录本结果通过酶联免疫吸附试验、免疫组织化学和肝脂分析进一步证实。高脂饲料喂养导致肥胖和代谢功能障碍，包括脂肪组织炎症和肠道通透性增加。在肝脏中，喂食高脂饮食会导致胆固醇稳态的紊乱和相关的炎症反应。HC-24不影响体重、代谢危险因素、脂肪组织炎症或肠道通透性。虽然HC-24没有改变总的肝脏脂肪变性，但在HC-24处理的动物中，小叶炎症显著减少，这与参与炎症(例如，中性粒细胞趋化因子CXCL1)和胆固醇稳态(即，基于与胆固醇处理相关的基因表达变化预测对作为上游调节因子的胆固醇的影响)的基因和蛋白质有关。CXCL1-EL ISA、中性粒细胞免疫组织化学染色和肝脏游离胆固醇含量的生化分析证实了上述作用。肝内游离胆固醇水平与肝脏中炎症聚集物的数量显著相关，从而为观察到的HC-24的抗炎作用提供了潜在的理论基础。Ldlr-/-.Leiden小鼠在生理性翻译饮食条件下，肝脏中的游离胆固醇积累，这与肝脏炎症的发展有关。多组分药物HC-24减少游离胆固醇的积累，并在肝脏具有分子和细胞抗炎作用。
Non-alcoholic fatty liver disease (NAFLD) is a complex multifactorial disorder that is characterised by dysfunctional lipid metabolism and cholesterol homeostasis, and a related chronic inflammatory response. NAFLD has become the most common cause of chronic liver disease in many countries, and its prevalence continues to rise in parallel with increasing rates of obesity. Here, we evaluated the putative NAFLD-attenuating effects of a multicomponent medicine consisting of 24 natural ingredients: Hepar compositum (HC-24). Ldlr-/-.Leiden mice were fed a high-fat diet (HFD) with a macronutrient composition and cholesterol content comparable to human diets for 24 weeks to induce obesity-associated metabolic dysfunction, including hepatic steatosis and inflammation. HC-24 or vehicle control was administered intraperitoneally 3 times/week (1.5 ml/kg) for the last 18 weeks of the study. Histological analyses of liver and adipose tissue were combined with extensive hepatic transcriptomics analysis. Transcriptomics results were further substantiated with ELISA, immunohistochemical and liver lipid analyses. HFD feeding induced obesity and metabolic dysfunction including adipose tissue inflammation and increased gut permeability. In the liver, HFD-feeding resulted in a disturbance of cholesterol homeostasis and an associated inflammatory response. HC-24 did not affect body weight, metabolic risk factors, adipose tissue inflammation or gut permeability. While HC-24 did not alter total liver steatosis, there was a pronounced reduction in lobular inflammation in HC-24-treated animals, which was associated with modulation of genes and proteins involved in inflammation (e.g., neutrophil chemokine Cxcl1) and cholesterol homeostasis (i.e., predicted effect on ‘cholesterol’ as an upstream regulator, based on gene expression changes associated with cholesterol handling). These effects were confirmed by CXCL1 ELISA, immunohistochemical staining of neutrophils and biochemical analysis of hepatic free cholesterol content. Intrahepatic free cholesterol levels were found to correlate significantly with the number of inflammatory aggregates in the liver, thereby providing a potential rationale for the observed anti-inflammatory effects of HC-24. Free cholesterol accumulates in the liver of Ldlr-/-.Leiden mice under physiologically translational dietary conditions, and this is associated with the development of hepatic inflammation. The multicomponent medicine HC-24 reduces accumulation of free cholesterol and has molecular and cellular anti-inflammatory effects in the liver.
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影响因子：
82.9
作者：
Friedman SL;Neuschwander-Tetri BA;Rinella M;Sanyal AJ
通讯作者：
Sanyal AJ
影响因子：
5
作者：
Liang, Wen;Lindeman, Jan H.;Kleemann, Robert
通讯作者：
Kleemann, Robert
影响因子：
--
作者：
Jeon D;Kim SJ;Kim HS
通讯作者：
Kim HS
影响因子：
2.3
作者：
Jaeschke, H
通讯作者：
Jaeschke, H
影响因子：
13.5
作者：
Kleiner, DE;Brunt, EM;Sanyal, AJ
通讯作者：
Sanyal, AJ