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氯沙坦通过抑制非酒精性脂肪性肝病小鼠模型中的 HIF-1α 预防肝脂肪变性和巨噬细胞极化。

Losartan Prevents Hepatic Steatosis and Macrophage Polarization by Inhibiting HIF-1α in a Murine Model of NAFLD.

机构信息

Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan City 333, Taiwan.

Graduate Institute of Traditional Chinese Medicine, School of Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan City 333, Taiwan.

出版信息

Int J Mol Sci. 2021 Jul 22;22(15):7841. doi: 10.3390/ijms22157841.

DOI:10.3390/ijms22157841
PMID:34360607
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8346090/
Abstract

Hypoxia and hepatosteatosis microenvironments are fundamental traits of nonalcoholic fatty liver disease (NAFLD). Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that controls the cellular response to hypoxia and is activated in hepatocytes of patients with NAFLD, whereas the route and regulation of lipid droplets (LDs) and macrophage polarization related to systemic inflammation in NAFLD is unknown. Losartan is an angiotensin II receptor antagonist, that approved portal hypertension and related HIF-1α pathways in hepatic injury models. Here, we show that losartan in a murine model of NAFLD significantly decreased hepatic de novo lipogenesis (DNL) as well as suppressed lipid droplets (LDs), LD-associated proteins, perilipins (PLINs), and cell-death-inducing DNA-fragmentation-factor (DFF45)-like effector (CIDE) family in liver and epididymal white adipose tissues (EWAT) of / mice. Obesity-mediated macrophage M1 activation was also required for HIF-1α expression in the liver and EWAT of / mice. Administration of losartan significantly diminishes obesity-enhanced macrophage M1 activation and suppresses hepatosteatosis. Moreover, HIF-1α-mediated mitochondrial dysfunction was reversed in / mice treated with losartan. Together, the regulation of HIF-1α controls LDs protein expression and macrophage polarization, which highlights a potential target for losartan in NAFLD.

摘要

缺氧和肝细胞脂肪变性微环境是非酒精性脂肪性肝病 (NAFLD) 的基本特征。缺氧诱导因子-1α (HIF-1α) 是一种转录因子，可控制细胞对缺氧的反应，在 NAFLD 患者的肝细胞中被激活，而与系统性炎症相关的脂滴 (LDs) 和巨噬细胞极化的途径和调节在 NAFLD 中尚不清楚。氯沙坦是一种血管紧张素 II 受体拮抗剂，已被批准用于治疗肝损伤模型中的门静脉高压和相关的 HIF-1α 途径。在这里，我们表明，氯沙坦在 NAFLD 的小鼠模型中显著降低了肝脏从头脂肪生成 (DNL)，并抑制了肝脏和附睾白色脂肪组织 (EWAT) 中的脂滴 (LDs)、LD 相关蛋白、围脂滴蛋白 (PLINs) 和细胞死亡诱导 DNA 片段化因子 (DFF45)-样效应物 (CIDE) 家族。肥胖介导的巨噬细胞 M1 激活也需要 HIF-1α在 / 小鼠的肝脏和 EWAT 中的表达。氯沙坦的给药显著减少了肥胖增强的巨噬细胞 M1 激活，并抑制了肝细胞脂肪变性。此外，氯沙坦治疗的 / 小鼠中 HIF-1α 介导的线粒体功能障碍得到逆转。综上所述，HIF-1α 的调节控制 LDs 蛋白表达和巨噬细胞极化，这突出了氯沙坦在 NAFLD 中的一个潜在靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/71d0/8346090/4dbe5a6b0001/ijms-22-07841-g007.jpg
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