title: Discoidal HDL and apoA-I-derived peptides improve glucose uptake in skeletal muscle.
abstract: Lipid-free apoA-I and mature spherical HDL have been shown to induce glucose uptake in skeletal muscle. To exploit apoA-I and HDL states for diabetes therapy, further understanding of interaction between muscle and apoA-I is required. This study has examined whether nascent discoidal HDL, in which apoA-I attains a different conformation from mature HDL and lipid-free states, could induce muscle glucose uptake and whether a specific domain of apoA-I can mediate this effect. Using L6 myotubes stimulated with synthetic reconstituted discoidal HDL (rHDL), we show a glucose uptake effect comparable to insulin. Increased plasma membrane GLUT4 levels in ex vivo rHDL-stimulated myofibers from HA-GLUT4-GFP transgenic mice support this observation. rHDL increased phosphorylation of AMP kinase (AMPK) and acetyl-coA carboxylase (ACC) but not Akt. A survey of domain-specific peptides of apoA-I showed that the lipid-free C-terminal 190-243 fragment increases plasma membrane GLUT4, promotes glucose uptake, and activates AMPK signaling but not Akt. This may be explained by changes in α-helical content of 190-243 fragment versus full-length lipid-free apoA-I as assessed by circular dichroism spectroscopy. Discoidal HDL and the 190-243 peptide of apoA-I are potent agonists of glucose uptake in skeletal muscle, and the C-terminal α-helical content of apoA-I may be an important determinant of this effect.
authors.affiliation: Department of Experimental Medical Science, Lund University, S-221 84 Lund, Sweden.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Dalla-Riva
authors.forename: Karin G
authors.initials: KG
authors.lastname: Stenkula
authors.forename: Jitka
authors.initials: J
authors.lastname: Petrlova
authors.forename: Jens O
authors.initials: JO
authors.lastname: Lagerstedt
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D016632:Apolipoprotein A-I / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008076:Cholesterol, HDL / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D007328:Insulin; D010455:Peptides; D000263:Adenylate Kinase; D000103:Acetyl-CoA Carboxylase; D005947:Glucose