Submitted to: Journal of Lipid Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/7/2005
Publication Date: 4/16/2005
Citation: Yen, C.E., Monetti, M., Burri, B.J., Farese, R.V. The triacylglycerol synthesis enzyme dgat1 also catalyzes the synthesis of diacylglycerols, waxes, and retinyl esters. Journal of Lipid Research 2005. 46:1502-1511.
Interpretive Summary: Vitamin A is required for normal eyesight, growth, and development. Poor vitamin A status is associated with increased risks for cancer and heart disease. Therefore we knew that vitamin A must be involved in many critical chemical processes in our bodies, but until recently we knew very little about how vitamin A was stored or how it worked. Answering the questions about where vitamin A is used and stored and how it works is important because these answers should help us understand how it is involved in preventing cancer, heart disease, and blindness. We used cell culture and mouse models to investigate a recently described protein that helps form triglycerides. We found that this protein also helps form retinyl esters, the type of vitamin A that is stored in the body. Thus, we have identified a new member of the small family of proteins that is involved in vitamin A storage and metabolism. These results may also explain why concentrations of vitamin A in the blood often seem to be related to concentrations of triglycerides.
Technical Abstract: The final step of triacylglycerol biosynthesis is catalyzed by acyl CoA:diacylglycerol acyltransferase (DGAT) enzymes. The two known DGATs, DGAT1 and DGAT2, are encoded by unrelated genes. Although both DGAT1 and DGAT2 knockout mice have reduced tissue triacylglycerol contents, they have disparate phenotypes, prompting us to investigate whether the two enzymes have unrecognized functional difference. We now report that DGAT1 exhibits additional acyltransferase activities in vitro, including those of acyl CoA:monoacylglycerol acyltransferase(MGAT), was monoester and wax diester synthases, and acyl CoA:retinol acyltransferase (ARAT), which catalyze the synthesis of diacylglycerols, wax esters, and retinyl esters, respectively. These activities were demonstrated in in vitro assays with membranes from insect cells or homogenates from COS7 cells overexpressing DGAT1. Wax synthase and ARAT activities were also demonstrated in intact COS7 cells expressinig DGAT1. Additionally, cells and tissues from DGAT1-deficient mice exhibited reduced ARAT activity, and the mice had increased levels of unesterified retinol in their livers on a high-retinol diet. Our findings indicate that DGAT1 can utilize a variety of acyl acceptors as substrates in vitro and suggest that these activities may be relevant to the in vivo functions of DGAT1.