Endotoxin Generated Lipid Second Messengers

超出规定的空间。引发和促进动脉粥样硬化发生的事件尚不清楚，但在易发生病变的部位，LDL在血管壁的隔离是其中之一。结合的LDL氧化成促动脉粥样硬化的形式，与CD36等清道夫受体结合，导致不适当的细胞内脂质积累和泡沫细胞形成。动脉粥样硬化病变可含有肺炎衣原体，这种感染构成动脉粥样硬化的危险因素。巨噬细胞感染肺炎球菌导致泡沫细胞形成，暴露于其纯化的脂多糖（LPS）也是如此。脂多糖如何诱导脂质积累或刺激基因转录尚不清楚。我们发现LPS诱导单核细胞中CD36清道夫受体基因的表达，导致表面表达增强，细胞内脂滴积聚和泡沫细胞形成。CD36受转录因子PPRE控制，我们发现LPS出人意料地激活了PPAR反应元件（PPRE）报告因子。事实上，LPS通过其PPRE激活CD36启动子。pparty被脂质配体激活；合成药物可以做到这一点，但高亲和力的生理性PPAR3配体尚不清楚。LPS不结合PPAR /，因此诱导内源性激动剂的形成。我们发现溶血磷脂酸（LPA）是一种PPAR y配体和激动剂-提供了第一个证据，证明它可能是这种转录因子长期寻求的生理激动剂。LPA刺激ppre驱动的报告细胞，诱导CD36表达，并将单核细胞分化为泡沫细胞。我们发现这种信号在几个方面独立于Edg（表面LPA受体）信号。我们发现LPS增加了细胞内LPA水平，并且通过转染的LPA酰基转移酶代谢这种细胞内LPA可阻断PPAR7的激活和功能。在这里，我们建议定义LPS诱导LPA积累的方式，并确定LPA激活胞内核激素受体/转录因子对泡沫细胞形成的影响。了解生理配体的身份使我们能够为合理设计的PPAR抑制剂建立高通量筛选。一种不可水解的LPA类似物阻断了pparty的功能，可能定义了一类新的抗炎、抗脂类药物。PERFORMANCSEITE (S) (organizationc、密度、状态)埃克尔斯大学人类遗传学研究所的犹他州,盐湖城犹他84112 - 5330 KEYPERSONNELS ======================================== 节结束 ===========================================

EXCEEDTHE SPACE PROVIDED. The events that initiate and promote atherogenesis are not well defined, but sequestration of LDL in the vascular wall at sites prone to lesion development is one. Bound LDL oxidizes to a pro-atherogenic form that is bound by scavenger receptors like CD36, leading to inappropriate intracellular lipid accumulation and foam cell formation. Atherosclerotic lesions can contain Chlamydia pneumoniae, and such infections constitute a risk factor for atherosclerosis. Macrophage infection by C. pneumoniae results in foam cell formation, as does exposure to its purified lipopolysaccharide (LPS). How LPS induces lipid accumulation or stimulates gene transcription is unknown. We find that LPS induces expression of the CD36 scavenger receptor gene in monocytes, leading to enhanced surface expression, and to intracellular lipid droplet accumulation and foam cell formation. CD36 is controlled by the transcription factor PPARy, and we find that LPS, unexpectedly, activates a PPAR responsive element (PPRE)-reporter. In fact, LPS activates the CD36 promoter through its PPRE. PPARy is activated by lipid ligands; synthetic drugs do this, but high affinity physiologic PPAR3, ligands are unknown. LPS does not bind PPAR,/, so it induced the formation of an endogenous agonist. We find that lysophosphatidic acid (LPA) is a PPAR y ligand and agonist --providing the first evidence that this might be the long sought after physiologic agonist for this transcription factor. LPA stimulates PPRE-driven reporters, induces CD36 expression, and differentiates monocytes to foam cells. We show this signaling is independent of Edg (surface LPA receptors) signaling in several ways. We find that LPS increases cellular LPA levels, and that metabolizing this intracellular LPA by transfected LPA acyltransferase blocks PPAR7 activation and function. Here we propose to define the way in which LPS induces LPA accumulation, and determine the consequences of LPA activation of an intracellular nuclear hormone receptor/transcription factor on foam cell formation. Knowing the identity of the physiologic ligand has allowed us to establish a high throughput screen for rationally designed PPAR't inhibitors. One non-hydrolyzable LPA analog blocks PPARy function and might define a new class of anti-infiammatory, anti-lipidic agents. PERFORMANCSEITE(S)(organizationc,ity,state) Eccles Institute of Human Genetics University of Utah, Salt Lake City UT 84112-5330 KEYPERSONNELS ========================================Section End===========================================