Shen Chuangpeng, Pan Zhisen, Xie Wenmin, Zhao Jian, Miao Deyu, Zhao Ling, Liu Min, Zhong Yanhua, Zhong Chong, Gonzalez Frank J, Wang Wei, Gao Yong, Liu Changhui
State Key Laboratory of Traditional Chinese Medicine Syndrome, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405,China; ShenShan Hospital, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Shanwei 516600,China.
State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, China.
Metabolism. 2025 Jan;162:156054. doi: 10.1016/j.metabol.2024.156054. Epub 2024 Nov 1.
The protein Solute carrier family 27 member 4 (SLC27A4) is crucial for fatty acid synthesis and β-oxidation, but its role in hepatic steatosis and nonalcoholic fatty liver disease (NAFLD) progression is not fully understood.
Mice with AAV-mediated overexpression of Slc27a4 in liver and hepatocytes-specific deletion of Slc27a4 were fed a standard chow diet, a high-fat diet (HFD), or a methionine and choline-deficient diet (MCD). Serum and liver tissues were collected and analyzed by biochemical assay, histology, lipidomic analysis, RNA-seq analysis, qPCR, western blot and immunofluorescence.
This study found elevated expression of SLC27A4 in individuals with NAFLD and OAPA-treated MPHs cells, leading to increased lipid accumulation and diet-induced liver steatosis, inflammation, and fibrosis. Conversely, hepatocyte-specific deletion of Slc27a4 improved the development of both NAFLD and NASH. SLC27A4 overexpression resulted in increased hepatic pregnane X receptor (PXR) expression and accumulation of phosphatidylcholine (PC), which activates PXR signaling and inducing SLC27A4 expression. PXR overexpression hinders the protective impact of Slc27a4 deletion on lipid accumulation and inflammation, whereas its deficiency in mice reduces the effect of Slc27a4 overexpression on NAFLD development.
These results indicate that SLC27A4 plays a critical role of lipid accumulation and inflammation, and is implicated in the development of NAFLD progression, rendering it potentially actionable target for NAFLD treatment.
溶质载体家族27成员4（SLC27A4）蛋白对脂肪酸合成和β-氧化至关重要，但其在肝脂肪变性和非酒精性脂肪性肝病（NAFLD）进展中的作用尚未完全明确。
用腺相关病毒介导肝脏中Slc27a4过表达以及肝细胞特异性缺失Slc27a4的小鼠，分别给予标准饲料、高脂饮食（HFD）或蛋氨酸和胆碱缺乏饮食（MCD）。收集血清和肝脏组织，通过生化检测、组织学、脂质组学分析、RNA测序分析、定量聚合酶链反应（qPCR）、蛋白质免疫印迹法和免疫荧光法进行分析。
本研究发现，NAFLD患者以及经奥氮平处理的人多能肝细胞（MPHs）中SLC27A4表达升高，导致脂质蓄积增加以及饮食诱导的肝脂肪变性、炎症和纤维化。相反，肝细胞特异性缺失Slc27a4可改善NAFLD和非酒精性脂肪性肝炎（NASH）的发展。SLC27A4过表达导致肝脏孕烷X受体（PXR）表达增加和磷脂酰胆碱（PC）蓄积，激活PXR信号并诱导SLC27A4表达。PXR过表达阻碍Slc27a4缺失对脂质蓄积和炎症的保护作用，而其在小鼠中的缺乏则降低了Slc27a4过表达对NAFLD发展的影响。
这些结果表明，SLC27A4在脂质蓄积和炎症中起关键作用，并与NAFLD进展的发生有关，使其成为NAFLD治疗潜在的可作用靶点。
