ATGL and DGAT1 are involved in the turnover of newly synthesized triacylglycerols in hepatic stellate cells

Abstract

Hepatic stellate cell (HSC) activation is a critical step in the development of chronic liver disease. During activation, HSCs lose their lipid droplets (LDs) containing triacylglycerol (TAG), cholesteryl esters (CEs) and retinyl esters (REs). Here we aimed to investigate which enzymes are involved in LD turnover in HSC during activation in vitro. Targeted deletion of the Atgl gene in mice HSCs had little effect on the decrease of the overall TAG, CE and RE levels during activation. However, ATGL-deficient HSCs specifically accumulated TAG species enriched in PUFAs and degraded new TAG species more slowly. TAG synthesis and levels of PUFA-TAGs were lowered by the DGAT1 inhibitor T863. The lipase inhibitor Atglistatin increased the levels of TAG in both wt and ATGL-deficient mouse HSCs. Both Atglistatin and T863 inhibited the induction of activation marker α-SMA in rat HSCs, but not in mouse HSCs. Compared to mouse, rat HSCs have a higher turnover of new TAGs and Atglistatin and the DGAT1 inhibitor T863 were more effective. Our data suggest that ATGL preferentially degrades newly synthesized TAGs, synthesized by DGAT1, and is less involved in the breakdown of pre-existing TAGs and retinyl esters in HSCs. Furthermore a large change in TAG levels has modest effect on rat HSC activation.