Abstract
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.
Highlights
ApoA-I, the main protein component of HDL, is suggested to be involved in metabolic homeostasis
Anti-hormone sensitive lipase (HSL) pSer563, anti-HSL pSer565 antibodies (Cell Signaling Technologies) and anti-HSL antibodies were kindly provided by Cecilia Holm (Lund University, Sweden); anti-perilipin and anti-perilipin pSer522 antibodies were from Valia Science; antiadipose triglyceride lipase, anti-ABCA1, and anti-ApoA-I antibodies were from Abcam; anti-caveolin-1 and -2, anti-pPKA consensus antibodies were obtained from Cell Signaling Technologies; and anti-actin antibodies were from Sigma
Apolipoproteins are well known for promoting cholesterol efflux from the vascular wall but have been shown to promote cholesterol efflux in adipose cell models [43, 44]
Summary
ApoA-I, the main protein component of HDL, is suggested to be involved in metabolic homeostasis. Methyl-cyclodextrin, a well-described cholesterol acceptor, dosedependently 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.—Lindahl, M., J. The lipid droplet-associated cholesterol pool increases further by redistribution of cholesterol from the plasma membrane pool [10] This rearrangement could contribute to adipose cell dysfunction associated with obesity [11], one of the main risk factors for insulin resistance and metabolic diseases including type 2 diabetes and cardiovascular complications [12].
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