Genetic dissection of retinoid esterification and accumulation in the liver and adipose tissue

Abstract

Approximately 80-90% of all retinoids in the body are stored as retinyl esters (REs) in the liver. Adipose tissue also contributes signifi cantly to RE storage. The present studies, employing genetic and nutritional interventions, explored factors that are responsible for regulating RE accumulation in the liver and adipose tissue and how these infl uence levels of retinoic acid (RA) and RA-responsive gene expression. Our data establish that acyl-CoA:retinol acyltransferase (ARAT) activity is not involved in RE synthesis in the liver, even when mice are nutritionally stressed by feeding a 25-fold excess retinol diet or upon ablation of cellular retinol-binding protein type I (CRBPI), which is proposed to limit retinol availability to ARATs. Unlike the liver, where lecithin:retinol acyltransferase (LRAT) is responsible for all RE synthesis, this is not true for adipose tissue where Lrat -defi cient mice display signifi cantly elevated RE concentrations. However, when CrbpI is also absent, RE levels resemble wild-type levels, suggesting a role for CrbpI in RE accumulation in adipose tissue. Although expression of several RA-responsive genes is elevated in Lrat -defi cient liver, employing a sensitive liquid chromatography tandem mass spectrometry protocol and contrary to what has been assumed for many years, we did not detect elevated concentrations of all- trans -RA. The elevated RA-responsive gene expression was associated with elevated hepatic triglyceride levels and decreased expression of Ppar - and its downstream Pdk4 target, suggesting a role for RA in these processes in vivo. Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.