Esterase 22 and beta-glucuronidase hydrolyze retinoids in mouse liver

Abstract

This article is available online at http://www.jlr.org retinol is reesterifi ed ( 3-5 ) for the incorporation into chylomicrons and secreted ( 6 ). In the circulation, chylomicrons are depleted from triglycerides by lipoprotein lipase and are thereby transformed to chylomicron remnants ( 7 ). These remnants acquire apolipoprotein E and are then cleared mostly by parenchymal cells of the liver (i.e., hepatocytes) ( 8-10 ). In hepatocytes, REs are hydrolyzed, and unesterifi ed retinol is associated with retinol-binding protein 4 (RBP4) for secretion ( 11,12 ) or transferred to hepatic stellate cells for storage ( 10,13,14 ). These stellate cells store most of the total body vitamin A reserves ( ‫ف‬ 80%) in the form of retinyl palmitate in cytosolic lipid droplets ( 14 ).According to the body's demand, stored retinoids are released from the liver to facilitate a constant supply. In the circulation, the biologically inactive retinol is transported bound to RPB4 and delivered to target tissues. There, retinol is converted into its biologically active metabolites 11-cis retinaldehyde and retinoic acids, which act as h acceptor in the visual cycle and as ligand of nuclear receptors, respectively.The dynamic balance between synthesis and hydrolysis of RE determines the concentration of retinol in the circulation and also the availability of retinol for conversion in active metabolites in various cell types. Retinol is esterifi ed by the action of acyl-CoA:retinol acyltransferase (ARAT) or lecithin:retinol acyltransferase (LRAT) for storage in lipid droplets. Much work has focused on the understanding of how REs are released from lipid droplets and which Abstract Excess dietary vitamin A is esterifi ed with fatty acids and stored in the form of retinyl ester (RE) predominantly in the liver. According to the requirements of the body, liver RE stores are hydrolyzed and retinol is delivered to peripheral tissues. The controlled mobilization of retinol ensures a constant supply of the body with the vitamin. Currently, the enzymes catalyzing liver RE hydrolysis are unknown. In this study, we identifi ed mouse esterase 22 (Es22) as potent RE hydrolase highly expressed in the liver, particularly in hepatocytes. The enzyme is located exclusively at the endoplasmic reticulum (ER), implying that it is not involved in the mobilization of RE present in cytosolic lipid droplets. Nevertheless, cell culture experiments revealed that overexpression of Es22 attenuated the formation of cellular RE stores, presumably by counteracting retinol esterifi cation at the ER. Es22 was previously shown to form a complex with ␤ -glucuronidase (Gus). Our studies revealed that Gus colocalizes with Es22 at the ER but does not affect its RE hydrolase activity. Interestingly, however, Gus was capable of hydrolyzing the naturally occurring vitamin A metabolite retinoyl ␤ -glucuronide. In conclusion, our observations implicate that both Es22 and Gus play a role in liver retinoid metabolism. -Schreiber, R., U. Taschler

Carboxylesterases Are Uniquely Expressed among Tissues and Regulated by Nuclear Hormone Receptors in the Mouse

“…Recombinant mouse Ces1e (called Es22) enzyme shows robust retinyl ester hydrolysis activity and modest, albeit significant, activity as a cholesteryl ester hydrolase (Schreiber et al, 2009). It has been noted that several tissues exhibit triglyceride hydrolysis activity that cannot be accounted for by known lipases (e.g., ATGL, HSL, and others), thus supporting the existence of additional neutral lipases (Zechner et al, 2012).…”

“…Still, certain CES have long been recognized to play important roles in the biotransformation of ester-and amide-containing compounds to affect the detoxification and/or activation of a variety of xenobiotics, narcotics, and pharmacologic agents in liver and intestine Hosokawa, 1998, 2006). In addition, growing evidence suggests that some CES enzymes may contribute to aspects of lipid metabolism through triglyceride, cholesteryl ester, or retinyl ester hydrolysis (Schreiber et al, 2009;Parathath et al, 2011;Quiroga and Lehner, 2011;Ghosh, 2012).…”

Hepatic metabolism of retinoids and disease associations

“…In later in vitro studies, it was shown that rat liver carboxylesterases, ES-2 and ES-10 can function as neutral bile salt-independent REHs. More recently, ES-22 has been added to the list of hepatic REH that localize to the ER [24]. …”

Adipose Triglyceride Lipase (ATGL) and Hormone-Sensitive Lipase (HSL) Deficiencies Affect Expression of Lipolytic Activities in Mouse Adipose Tissues

“…Both proteins are homologous to Es 22 (31). Es22 has meanwhile been identified as a retinyl ester hydrolase (32). Triacylglycerol hydrolase (TGH) is a member of the carboxylesterase family which localizes to the lumen of the endoplasmatic reticulum and likely contributes to the hydrolysis of intracellular triacylglycerol in adipose tissue, adipocytes (33) and hepatocytes (34).…”