Loss of Ces1/Es-x in mice results in obesity, increased blood lipid levels and decreased energy expenditure

QUIROGA, ARIEL DARIO; LI, LENA; PROCTOR, SPENCER; KÖFELER, HC; LEHNER, RICHARD

Madison

Simposio; Steenbock Symposium; 2011

University of Wisconsin, Madison

Mouse carboxylesterase1/esterase-x (Ces1/Es-x) is a close homolog of carboxylesterase3/triacylglycerol (TG) hydrolase (Ces3/TGH). Its over-expression in McArdle-RH7777 (McArdle) cells led to decreased TG levels and to increased β-oxidation when incubated with oleic acid (Ko et al., 2009). We proposed that mice lacking the Ces1/Es-x gene would have altered lipid metabolism. Ces1/Es-x-/-mice on a chow diet presented increased body weight, increased adiposity and enlarged adipocytes despite the same level of food intake as wild-type mice. The Ces1/Es-x knockout mice accumulated more lipids in plasma and liver, and had increased chylomicron and VLDL secretion with delayed lipoprotein clearance. Hepatocytes from Ces1/Es-x-/-mice showed increased lipid biosynthesis, due to activation of the sterol regulatory binding protein-1c (SREBP-1c) and its target genes. Ces1/Es-x deficient mice also accumulated polyunsaturated fatty acid (PUFA) in TG. On the other hand, McArdle cells stably expressing Ces1/Es-x cDNA, presented with lower amounts of TG enriched in long chain fatty acids. These experiments suggested that Ces1/Es-x might be hydrolyzing long chain fatty acid-enriched TG, presumably, PUFA-enriched TG. In line with this potential mechanism, incubation of Ces1/Es-x-/- hepatocytes with PUFA decreased lipid synthesis to the same levels obtained in wild-type hepatocytes. In conclusion, Ces1/Es-x may regulate lipoprotein production/secretion and therefore fat accumulation. We found that Ces1/Es-x protein expression undergoes nutritional regulation and its activity seems to play a key role in modulating the expression of enzymes that control lipid biosynthesis. These results make Ces1/Es-x a striking pharmacological candidate for preventing hepatic steatosis and obesity.   Ko, K.W., Erickson, B., and Lehner, R. (2009). Es-x/Ces1 prevents triacylglycerol accumulation in McArdle-RH7777 hepatocytes. Biochimica et biophysica acta 1791, 1133-1143.