Insulin stimulates hepatic low density lipoprotein receptor-related protein 1 (LRP1) to increase postprandial lipoprotein clearance.
BACKGROUND
While the role of insulin in glucose uptake and its aberration in diabetes are well established, the effect of insulin on lipoprotein clearance in the postprandial phase is not yet fully understood. The dietary lipids are carried in chylomicron remnants (CR) which are taken up into the liver mainly via LDLR-related protein 1 (LRP1). In this study, the effect of insulin on LRP1-mediated hepatic CR uptake was investigated.


METHODS
The study was based on determining the subcellular localisation of LRP1 by subcellular fractionation and immunofluorescence microscopy and correlating those findings with the hepatic uptake of fluorescently or radioactively labelled LRP1-specific ligands and CR in hepatoma cells, primary hepatocytes and mouse models.


CONCLUSIONS
In vitro and in vivo, insulin stimulated the translocation of hepatic LRP1 from intracellular vesicles to the plasma membrane, which correlates with an increased uptake of LRP1-specific ligands. In wild-type mice, a glucose-induced insulin response increased the hepatic uptake of LRP1 ligands while in leptin-deficient obese mice (ob/ob), which are characterised by hepatic insulin resistance, insulin-inducible LRP1 ligand uptake was abolished. Finally, upon hepatic LRP1 knockdown, insulin no longer significantly enhanced CR uptake into the liver. The insulin-induced LRP1-mediated CR uptake, as demonstrated here, suggests that impaired hepatic LRP1 translocation can contribute to the postprandial lipaemia in insulin resistance.
Department of Biochemistry and Molecular Biology II: Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. laatsch@uke.uni-hamburg.de
Alexander
A
Laatsch
Martin
M
Merkel
Philippa J
PJ
Talmud
Thomas
T
Grewal
Ulrike
U
Beisiegel
Joerg
J
Heeren
D000818:Animals; D045744:Cell Line, Tumor; D053298:Chylomicron Remnants / Q000378:metabolism; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D006949:Hyperlipidemias / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D020738:Leptin / Q000172:deficiency / Q000235:genetics; D008024:Ligands; D008074:Lipoproteins / Q000378:metabolism*; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D019518:Postprandial Period; D021381:Protein Transport; D051381:Rats; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013347:Subcellular Fractions; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D053298:Chylomicron Remnants; D007328:Insulin; D020738:Leptin; D008024:Ligands; D008074:Lipoproteins; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D011973:Receptors, LDL; D011994:Recombinant Proteins; D025521:Tumor Suppressor Proteins