溶血磷脂酸
内分泌学
内科学
白色脂肪组织
脂肪性肝炎
磷脂酸
炎症
营养过剩
酰基转移酶
脂肪组织
生物
化学
脂肪肝
生物化学
医学
磷脂
酶
肥胖
膜
受体
疾病
作者
Ichiro Sakuma,Rafael Calais Gaspar,Panu K. Luukkonen,Mario Kahn,Dongyan Zhang,Xuchen Zhang,Sue Murray,Jaya Prakash Golla,Daniel F. Vatner,Varman T. Samuel,Kitt Falk Petersen,Gerald I. Shulman
标识
DOI:10.1073/pnas.2312666120
摘要
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.
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