GPAT3 regulates the synthesis of lipid intermediate LPA and exacerbates Kupffer cell inflammation mediated by the ERK signaling pathway

作者：Guoqiang Fan, Yanfei Li, Yibo Zong, Xiaoyi Suo, Yimin Jia, Mingming Gao, Xiaojing Yang · 发表于：Cell Death and Disease · 年份：2023 · DOI：10.1038/s41419-023-05741-z · 被引用次数：24 · 研究领域：Lipid metabolism and biosynthesis、Sphingolipid Metabolism and Signaling、Liver Disease Diagnosis and Treatment

In the process of inflammatory activation, macrophages exhibit lipid metabolism disorders and accumulate lipid droplets. Kupffer cells (KCs) are the resident hepatic macrophage with critical defense functions in the pathogenesis of several types of liver disease. How dysregulated lipid metabolism contributes to perturbed KCs functions remains elusive. Here we report that glycerol-3-phosphate acyltransferase 3 (GPAT3) plays a key role in KCs inflammation response. Our findings indicate that lipopolysaccharide (LPS)-mediated inflammatory activation markedly increased lipid droplets (LDs) accumulation in KCs. This increase could be attributed to significantly up-regulated GPAT3. The loss of GPAT3 function obviously reduced KCs inflammation reaction both in vivo and in vitro, and was accompanied by improved mitochondrial function and decreased production of lysophosphatidic acid (LPA), in turn inhibiting extracellular regulated protein kinases (ERK) signaling pathway. Overall, this study highlights the role of GPAT3 in inflammatory activation of KCs and could thus be a potential therapeutic target for the treatment of inflammation-related liver disease.