Abstract
Approximately 80-90% of all retinoids in the body are stored as retinyl esters (REs) in the liver. Adipose tissue also contributes significantly 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 influence 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-deficient mice display significantly 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-deficient 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 Pparδ and its downstream Pdk4 target, suggesting a role for RA in these processes in vivo.
Highlights
80–90% of all retinoids in the body are stored as retinyl esters (REs) in the liver
diacylglycerol acyltransferase 1 (DGAT1), which is expressed in the liver, has been shown to be a physiologically significant acyl-CoA:retinol acyltransferase (ARAT) in the intestine and skin [24, 25]
We investigated these possibilities in matched male WT, LratϪ/Ϫ, Dgat1Ϫ/Ϫ, and LratϪ/Ϫ/Dgat1Ϫ/Ϫ mice fed a diet containing a 25-fold excess of retinol compared with standard dietary levels for 4 weeks
Summary
The mutant mouse lines we employed have all been described in the literature and include LratϪ/Ϫ [16, 17], CrbpIϪ/Ϫ [34], Dgat1Ϫ/Ϫ [35], Rbp4Ϫ/Ϫ [36], and LratϪ/Ϫ/Dgat1Ϫ/Ϫ [24] mice. The LratϪ/Ϫ and CrbpIϪ/Ϫ mice originally described for a mixed C57Bl/6J/129sv genetic background were employed in our studies. Dgat1Ϫ/Ϫ mice were obtained from Jackson Labs in the C57Bl/6J genetic background. Using conventional breeding protocols we generated LratϪ/Ϫ/CrbpIϪ/Ϫ mice. Genotypes of the mice were determined by protocols already described in the literature [16, 34,35,36]. Male and/or female mice at 3 months of age were employed and routinely sacrificed in the morning between 10:00 and 11:00 AM. The animal experiments described in this report were conducted in accordance with the National Research Council’s Guide for the Care and Use of Laboratory Animals [37] and were approved by the Columbia University Institutional Animal Care and Use Committee
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