Carboxylesterase 1 family knockout alters drug disposition and lipid metabolism

The mammalian carboxylesterase 1 (Ces1/CES1) family comprises several enzymes that hydrolyze many xenobiotic chemicals and endogenous lipids. To investigate the pharmacological and physiological roles of Ces1/CES1, we generated Ces1 cluster knockout (Ces1 -/- ) mice, and a hepatic human CES1 transgenic model in the Ces1 -/- background (TgCES1). Ces1 -/- mice displayed profoundly decreased conversion of the anticancer prodrug irinotecan to SN-38 in plasma and tissues. TgCES1 mice exhibited enhanced metabolism of irinotecan to SN-38 in liver and kidney. Ces1 and hCES1 activity increased irinotecan toxicity, likely by enhancing the formation of pharmacodynamically active SN-38. Ces1 -/- mice also showed markedly increased capecitabine plasma exposure, which was moderately decreased in TgCES1 mice. Ces1 -/- mice were overweight with increased adipose tissue, white adipose tissue inflammation (in males), a higher lipid load in brown adipose tissue, and impaired blood glucose tolerance (in males). These phenotypes were mostly reversed in TgCES1 mice. TgCES1 mice displayed increased triglyceride secretion from liver to plasma, together with higher triglyceride levels in the male liver. These results indicate that the carboxylesterase 1 family plays essential roles in drug and lipid metabolism and detoxification. Ces1 -/- and TgCES1 mice will provide excellent tools for further study of the in vivo functions of Ces1/CES1 enzymes.

Liver-specific Reduction of Mfn2 Protein by RNAi Results in Impaired Glycometabolism and Lipid Homeostasis in BALB/c Mice / 华中科技大学学报（医学）（英德文版）

Mitofusin-2 (Mfn2) gene expression is positively correlated with insulin sensitivity in patients with type 2 diabetes. However,it is unclear if Mfn2 is involved in carbohydrate metabolism and lipid homeostasis. In order to investigate the specific functions of Mfn2 in glycometabolism and lipid homeostasis in BALB/c mice,a RNA interference technique-mediated hydrodynamic injection was developed,in which short hairpin RNAs (shRNAs) were used to inhibit the Mfn2 expression in vivo. Seventy-two mice were randomly divided into two groups:the Mfn2 reduction group (Mfn2/shRNA) and the negative control group (NC). Intraperitoneal glucose tolerance tests and intraperitoneal insulin tolerance tests were used to evaluate glycometabolism and insulin sensitivity.D-(3-3H) glucose or 3H2O was injected into the tail vein or intraperitoneally to facilitate the calculation of the rate of hepatic glucose production and fatty acid synthesis in vivo. The results showed that,in Mfn2/shRNA mice,the liver Mfn2 protein was significantly decreased,and fasting blood glucose concentrations were increased by approximately 48%,when compared with the NC mice. In parallel with the changes in fasting glucose levels,hepatic glucose production was significantly elevated in Mfn2/shRNA mice. When insulin was administrated,these mice exhibited impaired insulin tolerance.It was also found that the reduction of Mfn2 markedly decreased the rate of fatty acid synthesis in the liver,and the Mfn2/shRNA mice exhibited hypertriglyceridema. Taken together,our results indicate that Mfn2 plays an important role in maintaining glucose and lipid homeostasis,and in the development of insulin resistance in vivo.