Lysophosphatidic acid receptor 1 antagonist (EPGN2154) causes regression of NASH in preclinical NASH models.
Lysophosphatidic acid receptor 1 antagonist (EPGN2154) causes regression of NASH in preclinical NASH models.
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DOI：
10.1097/hc9.0000000000000323
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发表时间：
2023-12-01
影响因子：
5.1
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NASH在美国造成巨大的医疗负担。在NASH临床试验中，胰高血糖素样肽-1激动剂Semaglutide（Sema）治疗导致肝脂肪变性减少。已知溶血磷脂酸受体1拮抗剂在几个器官中具有抗纤维化作用。我们测试了Sema和一种新型溶血磷脂酸受体1拮抗剂EPGN 2154，单独和联合使用，以评估它们在临床前模型中缓解NASH的疗效。在本研究中，我们使用（1）以高脂肪、高碳水化合物（HFHC）饮食喂养16周的C57 B16/J野生型小鼠和（2）以胰淀素肝脏NASH饮食喂养16周的瘦素缺陷小鼠（ob/ob）。16周后，将小鼠以相等数量随机分配到（1）无药物、（2）EPGN 2154、（3）Sema和（4）EPGN 2154 +Sema治疗组中，以10 mg/kg体重的剂量给予EPGN 2154，再持续8周17 μg/kg体重的Sema（每隔一天皮下注射，每周3天）。在野生型高脂肪、高碳水化合物模型中，我们观察到与其他治疗组相比，EPGN 2154 +Sema组合组中的体重减轻最多。与高脂肪、高碳水化合物喂养的野生型相比，所有组均导致丙氨酸转氨酶水平显著降低。然而，在治疗组之间未观察到丙氨酸转氨酶水平的显著差异。在ob/ob小鼠研究中，Sema没有引起体重减轻。此外，EPGN 2154组和联合组的NAFLD活动评分和晚期肝纤维化发生率低于Sema组。EPGN 2154在临床前NASH模型中表现出与体重减轻无关的肝脏保护作用。
NASH causes a tremendous health care burden in the United States. A glucagon-like peptide-1 agonist, semaglutide (Sema), treatment resulted in hepatic steatosis reduction in clinical trials of NASH. Lysophosphatidic acid receptor 1 antagonists are known to have antifibrotic effects in several organs. We tested Sema and a novel lysophosphatidic acid receptor 1 antagonist, EPGN2154, individually and in combination to evaluate their efficacy for NASH remission in preclinical models. In the present study, we used (1) C57Bl6/J wild-type mice fed on a high-fat, high-carbohydrate (HFHC) diet for 16 weeks and (2) leptin-deficient mice (ob/ob) fed on an Amylin liver NASH diet for 16 weeks. After 16 weeks, the mice were randomly distributed in equal numbers in (1) no-drug, (2) EPGN2154, (3) Sema, and (4) EPGN2154+Sema treatment groups for 8 additional weeks at a dosage of 10 mg/kg body weight for EPGN2154 (oral gavage, 5 days a week) and 6.17 μg/kg body weight of Sema (subcutaneous injection every alternate day, 3 days a week). In the wild-type-high-fat, high-carbohydrate model, we observed the most body weight loss in the EPGN2154+Sema combination group compared to the other treatment groups. All groups led to a significant reduction in alanine transaminase levels when compared to high-fat, high-carbohydrate–fed wild type. However, no significant difference in alanine transaminase levels was observed among the treatment groups. In the ob/ob mice study, Sema did not cause body weight loss. Moreover, the EPGN2154 and the combination groups had a lower NAFLD Activity Score and incidence of advanced-stage hepatic fibrosis than the Sema group. EPGN2154 demonstrated a hepato-protective effect independent of body weight loss in preclinical NASH models.