DGAT1-deficiency affects the cellular distribution of hepatic retinoid and attenuates the progression of CCl4-induced liver fibrosis

Background: Diacylglycerol O-acyltransferase 1 (DGAT1) catalyzes the final step of triglyceride synthesis,transferring an acyl group from acyl-CoA to diacylglycerol. DGAT1 also catalyzes the acyl-CoA-dependentformation of retinyl esters in vitro and in mouse intestine and skin. Although DGAT1 is expressed in bothhepatocytes and hepatic stellate cells (HSCs), we reported genetic and nutritional studies that establishedthat DGAT1 does not contribute to retinyl ester formation in the liver.Methods: We now have explored in more depth the role(s) of DGAT1 in hepatic retinoid metabolism andstorage.Results: Our data show that DGAT1 affects the cellular distribution between hepatocytes and HSCsof stored and newly absorbed dietary retinol. For livers of Dgat1-deficient mice, a greater percentage ofstored retinyl ester is present in HSCs at the expense of hepatocytes. This is also true for newly absorbedoral [3H]retinol. These differences are associated with significantly increased expression, by 2.8-fold, ofcellular retinol-binding protein, type I (RBP1) in freshly isolated HSCs from Dgat1-deficient mice, raisingthe possibility that RBP1, which contributes to retinol uptake into cells and retinyl ester synthesis, accountsfor the differences. We further show that the retinyl ester-containing lipid droplets in HSCs are affectedin Dgat1-null mice, being fewer in number but, on average, larger than in wild type (WT) HSCs. Finally,we demonstrate that DGAT1 affects experimentally induced HSC activation in vivo but that this effect isindependent of altered retinoic acid availability or effects on gene expression.Conclusions: Our studies establish that DGAT1 has a role in hepatic retinoid storage and metabolism, butthis does not involve direct actions of DGAT1 in retinyl ester synthesis.