Yan Wenhui, Cui Xin, Guo Tingli, Liu Na, Wang Zhuanzhuan, Sun Yuzhuo, Shang Yuanrui, Liu Jieyun, Zhu Yuanyuan, Zhang Yangyang, Chen Lina
Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China.
Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China.
Antioxid Redox Signal. 2025 Jan 16. doi: 10.1089/ars.2024.0670.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent hepatic disorder worldwide. Arachidonic acid 15-lipoxygenase (ALOX15), an enzyme catalyzing the peroxidation of polyunsaturated fatty acids, plays a crucial role in various diseases. Here, we sought to investigate the involvement of ALOX15 in MASLD. In this study, we observed upregulation of ALOX15 in the liver of high-fat diet (HFD)- and streptozotocin (STZ)-induced mice. Metabolomic analysis revealed elevated levels of ALOX15 metabolites, 12(S)-hydroperoxyeicosatetraenoic acid and 15(S)-hydroperoxyeicosatetraenoic acid. Transcriptomic analysis showed that the increased fatty acid uptake regulated by the PPARγ/CD36 pathway predominated in lipid accumulation. To elucidate the mechanism underlying ALOX15-induced lipid accumulation, HepG2 cells were transfected with a lentivirus expressing ALOX15 or small interfering RNA targeting ALOX15 and exposed to palmitic acid (PA). Both ALOX15 overexpression and PA exposure led to increased intracellular free fatty acid and triglyceride, resulting in lipotoxicity. ALOX15 overexpression aggravated the effect of PA, while the knockdown of ALOX15 attenuated PA-induced lipotoxicity. Moreover, the treatment with PPARγ antagonist GW9662 or CD36 inhibitor sulfosuccinimidyl oleate sodium effectively reduced lipid accumulation and lipotoxicity resulting from ALOX15 overexpression and PA exposure, indicating the involvement of the PPARγ/CD36 pathway in ALOX15-mediated lipid accumulation. Furthermore, liraglutide, a widely used glucagon-like peptide 1 receptor (GLP-1R) agonist (GLP-1RA), improved hepatic lipid accumulation in HFD/STZ-induced mice by suppressing the ALOX15/PPARγ/CD36 pathway. Our study underscores the potential of ALOX15 as an emerging therapeutic target for MASLD. In addition, the GLP-1RA may confer hepatoprotection by regulating ALOX15, enhancing our comprehension of the mechanisms underpinning their protection on MASLD. 00, 000-000.
代谢功能障碍相关脂肪性肝病（MASLD）是一种在全球范围内普遍存在的肝脏疾病。花生四烯酸15-脂氧合酶（ALOX15）是一种催化多不饱和脂肪酸过氧化的酶，在多种疾病中起关键作用。在此，我们试图研究ALOX15在MASLD中的作用。在本研究中，我们观察到高脂饮食（HFD）和链脲佐菌素（STZ）诱导的小鼠肝脏中ALOX15上调。代谢组学分析显示ALOX15代谢产物12（S）-氢过氧化二十碳四烯酸和15（S）-氢过氧化二十碳四烯酸水平升高。转录组学分析表明，由PPARγ/CD36途径调节的脂肪酸摄取增加在脂质积累中占主导地位。为了阐明ALOX15诱导脂质积累的机制，用表达ALOX15的慢病毒或靶向ALOX15的小干扰RNA转染HepG2细胞，并使其暴露于棕榈酸（PA）。ALOX15过表达和PA暴露均导致细胞内游离脂肪酸和甘油三酯增加，从而导致脂毒性。ALOX15过表达加剧了PA的作用，而敲低ALOX15则减轻了PA诱导的脂毒性。此外，用PPARγ拮抗剂GW9662或CD36抑制剂磺基琥珀酰亚胺油酸酯钠治疗可有效减少ALOX15过表达和PA暴露导致的脂质积累和脂毒性，表明PPARγ/CD36途径参与了ALOX15介导的脂质积累。此外，利拉鲁肽是一种广泛使用的胰高血糖素样肽1受体（GLP-1R）激动剂（GLP-1RA），通过抑制ALOX15/PPARγ/CD36途径改善HFD/STZ诱导的小鼠肝脏脂质积累。我们的研究强调了ALOX15作为MASLD新兴治疗靶点的潜力。此外，GLP-1RA可能通过调节ALOX15发挥肝脏保护作用，增强了我们对其保护MASLD机制的理解。00, 000 - 000。
