Carboxylesterases in lipid metabolism: from mouse to human

Mammalian carboxylesterases hydrolyze a wide range of xenobiotic and endogenous compounds, including lipid esters. Physiological functions of carboxylesterases in lipid metabolism and energy homeostasis in vivo have been demonstrated by genetic manipulations and chemical inhibition in mice, and in vitro through (over)expression, knockdown of expression, and chemical inhibition in a variety of cells. Recent research advances have revealed the relevance of carboxylesterases to metabolic diseases such as obesity and fatty liver disease, suggesting these enzymes might be potential targets for treatment of metabolic disorders. In order to translate pre-clinical studies in cellular and mouse models to humans, differences and similarities of carboxylesterases between mice and human need to be elucidated. This review presents and discusses the research progress in structure and function of mouse and human carboxylesterases, and the role of these enzymes in lipid metabolism and metabolic disorders.

Anticalmodulin drugs due to the net effects cannot antagonize dibutyryl - CAMP - mediated suppression of de novosynthesized lipid secretion in both cultured McArdle Cells and rat hepatocytes.

The effects and interaction between cAMP-analogue dibutyryl-cAMP and calmodulin antagonists were investigated on de novo synthesis and secretion of lipids in cultures of hepatoma MeArdle-RH7777 cells and normal rat hepatocytes. Dibutyryl-cAMP caused a significant decrease in the secretion of de novo synthesized triacy1[3H]glycerol in both cultures of McArdle cells and rat hepatocytes. The inhibitory effect of dibutyryl-cAMP was concentration-dependent and appeared at the lowest concentration examined, 5 mirco M. Dibutyryl-cAMP at a concentration of 50 mirco M suppressed secretion of triacylglycerol by approximately 38% [p<0.05] and secretion of phosphatidylcholine by 30% [p<0.05]. Dibutyryl-cAMP did not affect the synthesis of triacylglycerol and phosophatidylcholine, except at the highest concentration tested, 500 mirco M, where both triacylglycerol and phosphatidylcholine synthesis were suppressed significantly. Anticalmodulin W-7 also inhibited secretion of newly made triacylglycerol in a concentration-dependent manner in both cultures of McArdle cells and rat hepatocytes. W-7 at a concentration of 20 mirco M suppressed triacylglycerol secretion by about 37% [p<0.05], while the secretion of phosphatidylcholine and synthesis of triacylglycerol and phosphatidylcholine were not affected, unless at more than 20 mirco M concentration, at which both triacylglycerol and phosphatidylcholine synthesis were decreased significantly. The inhibitory effect elicited by dibutyryl-cAMP [100 mirco M] was not abolished in the presence of calmodulin antagonists, W-7 [20 mirco M], trifluoperazine [20 mirco M] and chlorpromazine [20 mirco M]. The simultaneous effects of dibutyryl-cAMP and either calmodulin antagonists were not additive or synergistic. None of the the calmodulin antagonists affected the cellular content of de novo synthesized triacylglycerol and phosphatidylcholine significantly. Neither dibutyryl-cAMP nor any calmodulin antagonist or their combination did affect the overall rate of de nove synthesis of triacylglycerol and phosphatidylcholine. All calmodulin antagonists examined alone had a net significant inhibitory effect on the secretion of newly made triacylglycerol. The results presented here suggest that calmodulin antagonists have net direct effects and hence could not overcome dibutyryl-cAMP-induced suppressive effects on the secretion of newly made triacylglycerol. The cell types, normal hepatocytes relative to hepatomas, did not influence the results