Acid sphingomyelinase plays important roles in ceramide homeostasis, which has been proposed to be linked to insulin resistance. To test this association in vivo, acid sphingomyelinase deletion (asm ؊/؊ ) was transferred to mice lacking the low density lipoprotein receptor (ldlr ؊/؊ ), and then offsprings were placed on control or modified (enriched in saturated fat and cholesterol) diets for 10 weeks. The modified diet caused hypercholesterolemia in all genotypes; however, in contrast to asm ؉/؉ /ldlr ؊/؊ , the acid sphingomyelinase-deficient littermates did not display hepatic triacylglyceride accumulation, although sphingomyelin and other sphingolipids were substantially elevated, and the liver was enlarged. asm ؊/؊ /ldlr ؊/؊ mice on a modified diet did not accumulate body fat and were protected against diet-induced hyperglycemia and insulin resistance. Experiments with hepatocytes revealed that acid sphingomyelinase regulates the partitioning of the major fatty acid in the modified diet, palmitate, into two competitive and inversely related pools, triacylglycerides and sphingolipids, apparently via modulation of serine palmitoyltransferase, a rate-limiting enzyme in de novo sphingolipid synthesis. These studies provide evidence that acid sphingomyelinase activity plays an essential role in the regulation of glucose metabolism by regulating the hepatic accumulation of triacylglycerides and sphingolipids during consumption of a diet rich in saturated fats.

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This review merely scratches the surface of some of the actions of sPLA(2)s in innate immunity, inflammation, and atherosclerosis. The goal is to provide an overview of recent findings involving sPLA(2)s and to point to potential pathophysiologic mechanisms that may become targets for therapy.

Objectives-Secretory phospholipase A 2 (sPLA 2 ) enzymes hydrolyze the sn-2 fatty acyl ester bond of phospholipids to produce a free fatty acid and a lysophospholid. Group V sPLA 2 is expressed in cultured macrophage cells and has high affinity for phosphatidyl choline-containing substrates. The present study assesses the presence of group V sPLA 2 in human and mouse atherosclerotic lesions and its activity toward low-density lipoprotein (LDL) particles. Methods and Results-Group V sPLA 2 was detected in human and mouse atherosclerotic lesions by immunohistochemical staining. Electron microscopic analysis showed that mouse group V sPLA 2 -modified LDL is significantly smaller (mean diameterϮSEMϭ25.3Ϯ0.25 nm) than native LDL (mean diameterϮSEMϭ27.7Ϯ0.29 nm). Hydrolysis by group V sPLA 2 induced spontaneous particle aggregation; the extent of aggregation was directly proportional to the degree of LDL hydrolysis. Group V sPLA 2 modification of LDL led to enhanced lipid accumulation in cultured mouse peritoneal macrophage cells. Conclusions-Group V sPLA 2 may play an important role in promoting atherosclerotic lesion development by modifying LDL particles in the arterial wall, thereby enhancing particle aggregation, retention, and macrophage uptake. Key Words: atherosclerosis Ⅲ group V secretory phospholipase A 2 Ⅲ LDL aggregation Ⅲ macrophages A critical event in early atherogenesis is the retention of low-density lipoprotein (LDL) particles in the subendothelium. Accumulating evidence points to LDL aggregation and LDL fusion as key elements of atherogenic lipid accumulation in the artery wall. 1 Aggregated lipoproteins that appear to be derived from LDL are prominent in early atherosclerotic lesions. 2,3 Aggregated LDL is taken-up by macrophages in vitro at an enhanced rate compared with non-aggregated LDL, leading to macrophage cholesterol accumulation and foam cell formation. 4,5 Because native LDL particles do not form aggregates, LDL modification appears to be a prerequisite for aggregation/fusion. Studies in vitro indicate that hydrolysis of LDL by secretory phospholipases A 2 (sPLA 2 ) may be linked to LDL aggregation and/or fusion and enhanced retention in the subendothelium. 3,6 The sPLA 2 family comprises a group of enzymes that hydrolyze the fatty acid esterified at the sn-2 position of glycerophospholipids. 7 The secreted enzymes are of low molecular weight (14 kDa), highly enriched in disulfide bonds, and require 1 to 10 mmol/L calcium for activity. The major secreted form present in synovial fluid, termed group IIa, has been proposed to act as a mediator of inflammatory responses. During acute or chronic inflammation, the concentration of group IIa sPLA 2 can increase by Ͼ100-fold in inflammatory fluids and plasma. 8,9 Immunohistochemistry studies have established that group IIa sPLA 2 is present in normal arterial tissue and increased in atherosclerotic lesions. 10 -12 We recently reported that macrophage expression of human group IIa sPLA 2 significantly enhances atherosclerotic lesion formation in...