ApoA-I Milano stimulates lipolysis in adipose cells independently of cAMP/PKA activation.
ApoA-I, the main protein component of HDL, is suggested to be involved in metabolic homeostasis. We examined the effects of Milano, a naturally occurring ApoA-I variant, about which little mechanistic information is available. Remarkably, high-fat-fed mice treated with Milano displayed a rapid weight loss greater than ApoA-I WT treated mice, and a significantly reduced adipose tissue mass, without an inflammatory response. Further, lipolysis in adipose cells isolated from mice treated with either WT or Milano was increased. In primary rat adipose cells, Milano stimulated cholesterol efflux and increased glycerol release, independently of β-adrenergic stimulation and phosphorylation of hormone sensitive lipase (Ser563) and perilipin (Ser522). Stimulation with Milano had a significantly greater effect on glycerol release compared with WT but similar effect on cholesterol efflux. Pharmacological inhibition or siRNA silencing of ABCA1 did not diminish Milano-stimulated lipolysis, although binding to the cell surface was decreased, as analyzed by fluorescence microscopy. Interestingly, methyl-β-cyclodextrin, a well-described cholesterol acceptor, dose-dependently stimulated lipolysis. Together, these results suggest that decreased fat mass and increased lipolysis following Milano treatment in vivo is partly explained by a novel mechanism at the adipose cell level comprising stimulation of lipolysis independently of the canonical cAMP/protein kinase A signaling pathway.
Medical Protein Science, Lund University, 221 84 Lund, Sweden Glucose Transport and Protein Trafficking, Lund University, 221 84 Lund, Sweden.
Maria
M
Lindahl
Medical Protein Science, Lund University, 221 84 Lund, Sweden.
Jitka
J
Petrlova
Medical Protein Science, Lund University, 221 84 Lund, Sweden.
Jonathan
J
Dalla-Riva
Glucose Transport and Protein Trafficking, Lund University, 221 84 Lund, Sweden.
Sebastian
S
Wasserstrom
Cellular Biomechanics, Lund University, 221 84 Lund, Sweden.
Catarina
C
Rippe
Medical Protein Science, Lund University, 221 84 Lund, Sweden.
Joan
J
Domingo-Espin
Glucose Transport and Protein Trafficking, Lund University, 221 84 Lund, Sweden.
Dorota
D
Kotowska
Medical Protein Science, Lund University, 221 84 Lund, Sweden.
Ewa
E
Krupinska
Protein Phosphorylation, Lund University, 221 84 Lund, Sweden.
Christine
C
Berggreen
Molecular Endocrinology, Department of Experimental Medical Science, Biomedical Center, Lund University, 221 84 Lund, Sweden.
Helena A
HA
Jones
Cellular Biomechanics, Lund University, 221 84 Lund, Sweden.
Karl
K
Swärd
Medical Protein Science, Lund University, 221 84 Lund, Sweden.
Jens O
JO
Lagerstedt
Protein Phosphorylation, Lund University, 221 84 Lund, Sweden.
Olga
O
Göransson
Glucose Transport and Protein Trafficking, Lund University, 221 84 Lund, Sweden karin.stenkula@med.lu.se.
Karin G
KG
Stenkula
D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism*; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D016632:Apolipoprotein A-I / Q000494:pharmacology*; D002784:Cholesterol / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D008066:Lipolysis / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
D016632:Apolipoprotein A-I; C080631:apolipoprotein A-I Milano; D002784:Cholesterol; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases
adenosine 3′,5′-cyclic monophosphate; adipose tissue; apolipoprotein A-I; cholesterol; diabetes; obesity; protein kinase A