Increased chylomicron production and adiposity in Es-x/Ces1 knockout mice

QUIROGA, ARIEL DARIO; LI, LENA; LEHNER, RICHARD

Windsor

Conferencia; Canadian Lipoprotein Conference; 2009

Esterase-x/carboxylesterase 1 (Es-x/Ces1) shares 76% protein sequence identity with triacylglycerol hydrolase/carboxylesterase 3 (TGH/Ces3), including the residues of the conserved esterase/lipase active site motif. We hypothesized that, like TGH, Es-x could play a role in triacylglycerol (TG) metabolism. McArdle-RH7777 cells stably transfected with Es-x cDNA accumulated significantly less TG when incubated with oleic acid, had increased fatty acid oxidation, and did not differ in total TG and apoB100 secretion when compared with control cells. In order to characterize the function of Es-x in lipid metabolism in vivo, we have generated Es-x knockout (KO) mice. Body weight of Es-x KO mice is increased compared to wild type (WT) mice in both males (23%) and females (93%). Es-x KO mice also accumulate significantly more hepatic TG  (150% in females and 200% in males) and cholesteryl esters (CE) (250% in females and 100% in males). Fasting plasma levels of apoB100 and apoB48 remain unchanged between WT and KO mice. However, chylomicron secretion was significantly increased in KO mice, following Poloxamer-P407 (i.p.) and [3H]-triolein (gavage) administration. Intestinal levels of microsomal triglyceride transfer protein (MTP) and apoB48 were increased in KO mice compared with WT mice. These data suggest that Es-x is playing a key role in hepatic, plasma and intestinal lipid metabolism. The lack of Es-x increases chylomicron assembly and secretion leading to weight gain and accumulation of hepatic neutral lipids.