title: Postprandial triglyceride-rich lipoproteins induce hepatic insulin resistance in HepG2 cells independently of their receptor-mediated cellular uptake.
abstract: Non-alcoholic fatty liver disease (NAFLD) is associated with hepatic insulin resistance with the molecular basis of this association being not well understood. Here we studied the effect of hepatic triglyceride accumulation induced by postprandial triglyceride-rich lipoproteins (TGRL) on hepatic insulin sensitivity in HepG2 cells. Incubation of HepG2 cells with purified TGRL particles induced hepatocellular triglyceride accumulation paralleled by diminished insulin-stimulated glycogen content and glycogen synthase activity. Accordingly, insulin-induced inhibition of glycogen synthase phosphorylation as well as insulin-induced GSK-3 and AKT phosphorylation were reduced by TGRL. The effects of TGRL were dependent on the presence of apolipoproteins and more pronounced for denser TGRL. Moreover, TGRL effects required the presence of heparan sulfate-proteoglycans on the cell membrane and lipase activity but were independent of the cellular uptake of TGRL particles by receptors of the LDL receptor family. We suggest postprandial lipemia to be an important factor in the pathogenesis of NAFLD.
authors.affiliation: Department of Internal Medicine I, Medical University of Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria.
authors.forename: Tobias
authors.initials: T
authors.lastname: Tatarczyk
authors.forename: Christian
authors.initials: C
authors.lastname: Ciardi
authors.forename: Andreas
authors.initials: A
authors.lastname: Niederwanger
authors.forename: Michael
authors.initials: M
authors.lastname: Kranebitter
authors.forename: Josef R
authors.initials: JR
authors.lastname: Patsch
authors.forename: Michael T
authors.initials: MT
authors.lastname: Pedrini
mesh_terms: D000328:Adult; D005234:Fatty Liver / Q000378:metabolism / Q000503:physiopathology; D006003:Glycogen / Q000378:metabolism; D006006:Glycogen Synthase / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D015228:Hypertriglyceridemia / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008074:Lipoproteins / Q000737:chemistry* / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D065626:Non-alcoholic Fatty Liver Disease; D019518:Postprandial Period / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism*
chemical_list: D008074:Lipoproteins; D011973:Receptors, LDL; D014280:Triglycerides; D006003:Glycogen; D006006:Glycogen Synthase; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3