Differential effects of selective- and pan-PPAR agonists on experimental steatohepatitis and hepatic macrophages
Differential effects of selective- and pan-PPAR agonists on experimental steatohepatitis and hepatic macrophages
复制标题
DOI：
10.1016/j.jhep.2020.04.025
复制
发表时间：
2020-10-01
影响因子：
25.7
通讯作者：
Tacke, Frank
中科院分区：
文献类型：
--
作者：
Lefere, Sander;Puengel, Tobias;Tacke, Frank
背景与目的：过氧化物酶体增殖物激活受体(PPAR)是全身代谢的重要调节因子，也调节免疫细胞特别是巨噬细胞的炎症反应。我们比较了选择性PPAR激动剂和PAN-PPAR激动剂Lanifibror在非酒精性脂肪性肝病(NAFLD)中的作用，并研究了其对肝脏巨噬细胞生物学的特异性影响。方法：在胆碱缺乏、氨基酸限定的高脂饮食(CDAA-HFD)和西方饮食(WD)喂养的NAFLD小鼠模型中，给予Lanifibror或选择性PPARα(非诺贝特)、PPARγ(吡格列酮)和PPAR Delta(GW501516)激动剂进行治疗。四氯化碳(CCl4)诱导大鼠急性肝损伤。在分离的肝巨噬细胞、棕榈酸刺激的骨髓源性巨噬细胞和NAFLD患者的循环单核细胞中，研究了PPAR对巨噬细胞功能的影响。结果：拉尼非诺改善了CDAA-HFD喂养的小鼠脂肪性肝炎的所有组织学特征，包括肝纤维化，从而合并并超过了单一PPAR激动剂的特异性作用。其强大的抗脂肪变性的功效在带有原代细胞的3D肝脏生物芯片模型中得到了证实。给予PPAR激动剂后，浸润性肝单核细胞来源的巨噬细胞减少，尤其是使用拉尼非诺，即使在短期治疗后，与之平行的是改善脂肪变性和肝炎。在WD模型中，拉尼非诺类似地减少了脂肪变性、肝损伤和单核细胞浸润。在急性CCl4模型中，单一或泛PPAR激动剂都不直接影响单核细胞的募集。从WD喂养的小鼠分离的肝巨噬细胞表现出代谢激活的表型。结论：PAN-PPAR激动剂结合了选择性PPAR激动剂的有益作用，可能更有效地对抗炎症和疾病进展。PPARβ激动剂和拉尼菲诺直接调节巨噬细胞的活化，而不是渗透，从而与PPARα/γ激动剂有益的代谢效应协同作用。我们在独立的实验小鼠模型中证明了PAN-PPAR激动剂lanifibror改善了非酒精性脂肪性肝病的所有方面。非酒精性脂肪性肝病和脂肪酸诱导巨噬细胞处于一种特殊的极化状态，这种状态被羊膜蛋白改变，从而增加脂质处理基因的表达，从而减轻炎症。PPAR亚型对高脂肝细胞、活化的肝星状细胞和炎性巨噬细胞具有不同的治疗作用，支持PAN-PPAR激动剂的临床开发。(C)2020年欧洲肝脏研究协会。爱思唯尔出版，版权所有。
Background & Aims: Peroxisome proliferator-activated receptors (PPARs) are essential regulators of whole-body metabolism, but also modulate inflammation in immune cells, notably macrophages. We compared the effects of selective PPAR agonists to those of the pan-PPAR agonist lanifibranor in non-alcoholic fatty liver disease (NAFLD), and studied isoform-specific effects on hepatic macrophage biology.Methods: Lanifibranor or selective PPAR alpha (fenofibrate), PPAR gamma (pioglitazone) and PPAR delta (GW501516) agonists were therapeutically administered in choline-deficient, amino acid-defined high-fat diet (CDAA-HFD)- and Western diet (WD)-fed mouse models of NAFLD. Acute liver injury was induced by carbon tetrachloride (CCl4). The role of PPARs on macrophage functionality was studied in isolated hepatic macrophages, bone marrow-derived macrophages stimulated with palmitic acid, and circulating monocytes from patients with NAFLD.Results: Lanifibranor improved all histological features of steatohepatitis in CDAA-HFD-fed mice, including liver fibrosis, thereby combining and exceeding specific effects of the single PPAR agonists. Its potent anti-steatotic efficacy was confirmed in a 3D liver biochip model with primary cells. Infiltrating hepatic monocyte-derived macrophages were reduced following PPAR agonist administration, especially with lanifibranor, even after short-term treatment, paralleling improved steatosis and hepatitis. Lanifibranor similarly decreased steatosis, liver injury and monocyte infiltration in the WD model. In the acute CCl4 model, neither single nor pan-PPAR agonists directly affected monocyte recruitment. Hepatic macrophages isolated from WD-fed mice displayed a metabolically activated phenotype. Lanifibranor attenuated the accompanying inflammatory activation in both murine palmitic acid-stimulated bone marrow-derived macrophages, as well as patient-derived circulating monocytes, in a PPARS-dependent fashion.Conclusion: Pan-PPAR agonists combine the beneficial effects of selective PPAR agonists and may counteract inflammation and disease progression more potently. PPAR delta agonism and lanifibranor directly modulate macrophage activation, but not infiltration, thereby synergizing with beneficial metabolic effects of PPAR alpha/gamma agonists.Lay summary: Peroxisome proliferated-activated receptors (PPARs) are essential regulators of metabolism and inflammation. We demonstrated that the pan-PPAR agonist lanifibranor ameliorated all aspects of non-alcoholic fatty liver disease in independent experimental mouse models. Non-alcoholic fatty liver disease and fatty acids induce a specific polarization status in macrophages, which was altered by lanifibranor to increase expression of lipid handling genes, thereby decreasing inflammation. PPAR isoforms have differential therapeutic effects on fat-laden hepatocytes, activated hepatic stellate cells and inflammatory macrophages, supporting the clinical development of pan-PPAR agonists. (C) 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.