title: 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 HSCs 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 diacylglycerol acyltransferase (DGAT)1 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-smooth muscle actin, in rat HSCs, but not in mouse HSCs. Compared with mouse HSCs, 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 preexisting TAGs and REs in HSCs. Furthermore a large change in TAG levels has modest effect on rat HSC activation.
authors.affiliation: Departments of Biochemistry and Cell Biology Faculty of Veterinary Medicine and Institute of Biomembranes, Utrecht University, 3584 CM Utrecht, The Netherlands.
authors.forename: Maidina
authors.initials: M
authors.lastname: Tuohetahuntila
authors.affiliation: Departments of Biochemistry and Cell Biology Faculty of Veterinary Medicine and Institute of Biomembranes, Utrecht University, 3584 CM Utrecht, The Netherlands.
authors.forename: Martijn R
authors.initials: MR
authors.lastname: Molenaar
authors.affiliation: Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine and Institute of Biomembranes, Utrecht University, 3584 CM Utrecht, The Netherlands.
authors.forename: Bart
authors.initials: B
authors.lastname: Spee
authors.affiliation: Departments of Biochemistry and Cell Biology Faculty of Veterinary Medicine and Institute of Biomembranes, Utrecht University, 3584 CM Utrecht, The Netherlands.
authors.forename: Jos F
authors.initials: JF
authors.lastname: Brouwers
authors.affiliation: Departments of Biochemistry and Cell Biology Faculty of Veterinary Medicine and Institute of Biomembranes, Utrecht University, 3584 CM Utrecht, The Netherlands.
authors.forename: Martin
authors.initials: M
authors.lastname: Houweling
authors.affiliation: Departments of Biochemistry and Cell Biology Faculty of Veterinary Medicine and Institute of Biomembranes, Utrecht University, 3584 CM Utrecht, The Netherlands.
authors.forename: Arie B
authors.initials: AB
authors.lastname: Vaandrager
authors.affiliation: Departments of Biochemistry and Cell Biology Faculty of Veterinary Medicine and Institute of Biomembranes, Utrecht University, 3584 CM Utrecht, The Netherlands J.B.Helms@uu.nl.
authors.forename: J Bernd
authors.initials: JB
authors.lastname: Helms
mesh_terms: D000818:Animals; D002788:Cholesterol Esters / Q000235:genetics / Q000378:metabolism; D051048:Diacylglycerol O-Acyltransferase / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005231:Fatty Acids, Unsaturated / Q000096:biosynthesis; D055166:Hepatic Stellate Cells / Q000378:metabolism* / Q000473:pathology; D008049:Lipase / Q000235:genetics*; D066292:Lipid Droplets / Q000378:metabolism; D050155:Lipogenesis / Q000235:genetics; D008066:Lipolysis / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D010671:Phenylurea Compounds / Q000008:administration & dosage; D051381:Rats; D014280:Triglycerides / Q000096:biosynthesis* / Q000235:genetics; D000217:Acyltransferases
chemical_list: D002788:Cholesterol Esters; D051048:Diacylglycerol O-Acyltransferase; D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D008049:Lipase; D010671:Phenylurea Compounds; D014280:Triglycerides; C585749:atglistatin; C494883:Dgat1 protein, rat; C571275:PNPLA2 protein, rat; D000217:Acyltransferases
keywords: adipose triglyceride lipase; diacylglycerol acyltransferase 1; heavy isotope labeling; lipase; lipid droplets; lipidomics; lipolysis and fatty acid metabolism; retinyl esters; triacylglycerol pools; vitamin A