Inhibitory activity of diacylglycerol acyltransferase by cochlioquinones A and A1.

Triacylglycerol (TG) is the main storage form of energy. However, high TG level is known to be one of the major risk factors for coronary heart disease, obesity and hypertriglyceridemia1). TG synthesis has been assumed to occur primarily through acyl CoA: diacylglycerol acyltransferase (DGAT), a microsomal enzyme that catalyses the final and only committed step in the glycerol phosphate pathway2). Therefore, DGAT is considered as a potential target for the treatment of obesity, hypertriglyceridemia and type 2 diabetes3). In the course of our screening for DGAT enzyme inhibitors from microorganisms, an acetone extract of a fungal strain, Bipolaris zeicola exhibited a potent inhibitory activity on DGAT enzyme prepared from rat liver. Recently, we have reported that the new cochlioquinol derivative, cochlioquinone A1 (1) has been isolated as a new compound with inhibitory activity on in vitro angiogenesis of bovine aortic endothelial cells (BAECs)4). So far, there have been some reports regarding cochlioquinone A (2) as the diacylglycerol kinase inhibitor from Drechslera sacchari, Epi-cochlioquinone A as the acyl-CoA: cholesterol acyltransferase inhibitor from Stachybotrys bisbyi5,6). In this study, cochlioquinone A (2) has also shown to have activity as DGAT-inhibiting constituents by the bioassay. Cochlioquinone A (2) was previously reported as a phytotoxin produced by both Bipolaris bicolor and B. cynodontis7,8). This paper deals with the isolation of the active principle and the DGAT inhibitory effects of two cochlioquinone compounds. The fungal strain, B, zeicola which produced cochlioquinone A1 (1) was isolated from a maize grain by the blotter method9). To identify the strain, morphological observation and sequencing analysis of internal transcribed spacer (ITS-1 and ITS-2) region including the 5.8s gene were performed. The rDNA ITS region sequence of the strain showed >98% identity with Cochliobolus carbonum (AF158110) [a teliomorph of Bipolaris zeicola (G. L. Stout) Shoemaker], thus the strain was identified as B.