Division of Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Morioka, Japan.
J Gastroenterol Hepatol. 2019 Jul;34(7):1256-1262. doi: 10.1111/jgh.14461. Epub 2018 Sep 23.
Lipotoxicity causes liver inflammation, which leads to non-alcoholic steatohepatitis (NASH). Lysophosphatidylcholine (LPC) is a causal agent of lipotoxicity. Recently, lysophosphatidylcholine acyltransferase (LPCAT) was identified as an enzyme that catalyzes the esterification of LPC, which potentially decreases LPC levels. However, the effect of LPCAT in lipotoxicity of the liver is not fully understood. Our aim was to determine whether LPCAT attenuates lipotoxicity in the liver.
Mice fed a high-fat diet with sucrose (HFDS) or high-fat diet without sucrose, and Huh-7 cells treated with palmitate were used.
Mice-fed HFDS showed advanced liver fibrosis as compared with mice-fed high-fat diet or normal chow. Lysophosphatidylcholine acyltransferase 3 (LPCAT3) mRNA expression in the liver was significantly decreased in the HFDS liver, and LPC content in the HFDS liver was significantly increased as compared with the other groups. When Huh-7 cells with short hairpin RNA-mediated knockdown of LPCAT3 (shLPCAT3 cells) were treated with palmitate, the intracellular LPC concentration and cell death were significantly higher than those in wild-type Huh-7 cells. Palmitate-induced cell death in shLPCAT3 was attenuated by a combination of receptor-interacting protein kinase 1 inhibitor with pan-caspase inhibitor. In contrast, intracellular LPC and palmitate-induced cell death were significantly lower in LPCAT3-overexpressing Huh-7 cells than in wild-type cells.
Depletion of LPCAT3 in a mouse model of NASH leads to caspase-independent cell death, and LPCAT3 is a potential therapeutic target in NASH.
脂毒性导致肝脏炎症，进而引发非酒精性脂肪性肝炎（NASH）。溶血磷脂酰胆碱（LPC）是脂毒性的一个致病因子。最近，溶血磷脂酰胆碱酰基转移酶（LPCAT）被鉴定为一种能催化 LPC 酯化的酶，这可能会降低 LPC 水平。然而，LPCAT 在肝脏脂毒性中的作用尚未完全阐明。我们的目的是确定 LPCAT 是否能减轻肝脏的脂毒性。
使用高脂肪饮食加蔗糖（HFDS）喂养的小鼠和用棕榈酸处理的 Huh-7 细胞进行实验。
与高脂肪饮食或正常饲料喂养的小鼠相比，HFDS 喂养的小鼠肝脏纤维化程度更严重。HFDS 肝组织中 LPCAT3 mRNA 表达明显降低，LPC 含量明显高于其他组。用短发夹 RNA 介导的 LPCAT3 敲低（shLPCAT3 细胞）处理 Huh-7 细胞后，用棕榈酸处理时，细胞内 LPC 浓度和细胞死亡明显高于野生型 Huh-7 细胞。用受体相互作用蛋白激酶 1 抑制剂联合全半胱氨酸蛋白酶抑制剂可减轻 shLPCAT3 诱导的细胞死亡。相反，与野生型细胞相比，LPCAT3 过表达 Huh-7 细胞中的细胞内 LPC 和棕榈酸诱导的细胞死亡明显降低。
NASH 小鼠模型中 LPCAT3 的耗竭导致了 caspase 非依赖性细胞死亡，LPCAT3 是 NASH 的一个潜在治疗靶点。
