Department of Gastroenterology and Hepatology, Hepatology Research Unit, Ghent University, Ghent, Belgium; Department of Medicine III, University Hospital Aachen, Aachen, Germany.
Department of Medicine III, University Hospital Aachen, Aachen, Germany; Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany.
J Hepatol. 2020 Oct;73(4):757-770. doi: 10.1016/j.jhep.2020.04.025. Epub 2020 Apr 29.
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.
Lanifibranor or selective PPARα (fenofibrate), PPARγ (pioglitazone) and PPARδ (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 (CCl). 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.
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 CCl 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 PPARδ-dependent fashion.
Pan-PPAR agonists combine the beneficial effects of selective PPAR agonists and may counteract inflammation and disease progression more potently. PPARδ agonism and lanifibranor directly modulate macrophage activation, but not infiltration, thereby synergizing with beneficial metabolic effects of PPARα/γ agonists.
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.
过氧化物酶体增殖物激活受体（PPARs）是全身代谢的重要调节剂，但也调节免疫细胞（尤其是巨噬细胞）中的炎症。我们比较了选择性 PPAR 激动剂与全 PPAR 激动剂利那列汀在非酒精性脂肪性肝病（NAFLD）中的作用，并研究了其对肝巨噬细胞生物学的同工型特异性影响。
在胆碱缺乏型、氨基酸定义的高脂肪饮食（CDAA-HFD）和西方饮食（WD）喂养的 NAFLD 小鼠模型中，用利那列汀或选择性 PPARα（非诺贝特）、PPARγ（吡格列酮）和 PPARδ（GW501516）激动剂进行治疗。用四氯化碳（CCl）诱导急性肝损伤。在棕榈酸刺激的分离肝巨噬细胞、骨髓来源的巨噬细胞和来自 NAFLD 患者的循环单核细胞中研究了 PPAR 对巨噬细胞功能的作用。
利那列汀改善了 CDAA-HFD 喂养小鼠的所有脂肪性肝炎组织学特征，包括肝纤维化，从而结合并超过了单一 PPAR 激动剂的特定作用。其在具有原代细胞的 3D 肝生物芯片模型中的强大抗脂肪变性作用得到了证实。在用 PPAR 激动剂治疗后，浸润性肝单核细胞衍生的巨噬细胞减少，尤其是利那列汀，即使在短期治疗后，也与改善的脂肪变性和肝炎平行。利那列汀在 WD 模型中同样减少了脂肪变性、肝损伤和单核细胞浸润。在急性 CCl 模型中，单一或全 PPAR 激动剂均不能直接影响单核细胞募集。来自 WD 喂养小鼠的肝巨噬细胞表现出代谢激活的表型。利那列汀以 PPARδ 依赖性方式减弱了两种小鼠棕榈酸刺激的骨髓来源的巨噬细胞以及患者来源的循环单核细胞中伴随的炎症激活。
全 PPAR 激动剂结合了选择性 PPAR 激动剂的有益作用，并且可能更有效地对抗炎症和疾病进展。PPARδ 激动剂和利那列汀直接调节巨噬细胞的激活，但不调节浸润，从而与 PPARα/γ 激动剂的有益代谢作用协同作用。
过氧化物酶体增殖物激活受体（PPARs）是代谢和炎症的重要调节剂。我们证明，全 PPAR 激动剂利那列汀在独立的实验性小鼠模型中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的特定极化状态，利那列汀改变这种状态以增加脂质处理基因的表达，从而减少炎症。PPAR 同工型对富含脂肪的肝细胞、活化的肝星状细胞和炎症性巨噬细胞具有不同的治疗作用，支持全 PPAR 激动剂的临床开发。
