PDF(Pubmed)
Abstract：
AGPAT2 (1-acyl-sn-glycerol-3-phosphate-acyltransferase-2) converts lysophosphatidic acid (LPA) into phosphatidic acid (PA), and mutations of the AGPAT2 gene cause the most common form of congenital generalized lipodystrophy which leads to steatohepatitis. The underlying mechanism by which AGPAT2 deficiency leads to lipodystrophy and steatohepatitis has not been elucidated. We addressed this question using an antisense oligonucleotide (ASO) to knockdown expression of Agpat2 in the liver and white adipose tissue (WAT) of adult male Sprague-Dawley rats. Agpat2 ASO treatment induced lipodystrophy and inflammation in WAT and the liver, which was associated with increased LPA content in both tissues, whereas PA content was unchanged. We found that a controlled-release mitochondrial protonophore (CRMP) prevented LPA accumulation and inflammation in WAT whereas an ASO against glycerol-3-phosphate acyltransferase, mitochondrial (Gpam) prevented LPA content and inflammation in the liver in Agpat2 ASO-treated rats. In addition, we show that overnutrition, due to high sucrose feeding, resulted in increased hepatic LPA content and increased activated macrophage content which were both abrogated with Gpam ASO treatment. Taken together, these data identify LPA as a key mediator of liver and WAT inflammation and lipodystrophy due to AGPAT2 deficiency as well as liver inflammation due to overnutrition and identify LPA as a potential therapeutic target to ameliorate these conditions.
摘要：
AGPAT2（1-酰基-sn-甘油-3-磷酸-酰基转移酶-2）将溶血磷脂酸（LPA）转化为磷脂酸（PA），AGPAT2基因的突变会导致最常见的先天性全身性脂肪营养不良，从而导致脂肪性肝炎。AGPAT2缺乏导致脂肪营养不良和脂肪性肝炎的潜在机制尚未阐明。我们使用反义寡核苷酸（ASO）敲低成年雄性Sprague-Dawley大鼠的肝脏和白色脂肪组织（WAT）中Agpat2的表达来解决这个问题。Agpat2ASO治疗诱导脂肪营养不良和炎症在WAT和肝脏，这与两个组织中LPA含量的增加有关，而PA含量不变。我们发现，控释线粒体质子团（CRMP）可防止WAT中的LPA积累和炎症，而ASO可对抗甘油-3-磷酸酰基转移酶，线粒体（Gpam）可预防Agpat2ASO治疗大鼠肝脏中LPA含量和炎症。此外,我们展示了营养过剩，由于高蔗糖饲料，导致肝LPA含量增加和活化巨噬细胞含量增加，这两种方法均被GpamASO治疗废除。一起来看,这些数据确定LPA是AGPAT2缺乏引起的肝脏和WAT炎症和脂肪营养不良以及营养过剩引起的肝脏炎症的关键介质,并确定LPA是改善这些疾病的潜在治疗靶点.
