Adiponectin increases LPL activity via RhoA/ROCK-mediated actin remodelling in adult rat cardiomyocytes.

Cardiomyocyte substrate utilization is important in maintaining optimal cardiac function. Adiponectin has been shown to confer cardioprotective effects in part via regulating glucose and fatty acid uptake and oxidation in cardiomyocytes. Here we investigated mechanisms whereby adiponectin mediates a particular metabolic effect by focusing on lipoprotein lipase (LPL), an enzyme that increases free fatty acid availability to the heart by breakdown of chylomicrons and very-low-density lipoproteins in circulation. We used primary adult rat cardiomyocytes and demonstrate that adiponectin increased LPL translocation to the cell surface where it could be released at least partly in its active form, as evidenced by measuring basal and heparin-releasable LPL activity. Furthermore, these effects of adiponectin were mediated via remodeling of the actin cytoskeleton. We quantitatively assessed the filamentous to globular actin ratio and show that increased stress fiber formation, visualized by rhodamine-phalloidin immunofluorescence, in response to adiponectin, is achieved via stimulating Ras homolog gene family A (RhoA) activity, determined using G-LISA RhoA activation assay kit. We also demonstrate that adiponectin induces phosphorylation and inhibition of cofilin, leading to a reduction in actin treadmilling. Increased cofilin phosphorylation and stress fiber formation in response to adiponectin were prevented by inhibition of either RhoA or its downstream kinase Rho-associated protein kinase. Importantly, inhibition of cytoskeletal remodeling prevented adiponectin-stimulated plasma membrane LPL content detected by immunofluorescence and also subsequent LPL activity. In summary, we show that adiponectin mediates actin cytoskeleton remodeling to translocate LPL and allow subsequent activation.

[1]  Masahide Takahashi,et al.  Adiponectin promotes migration activities of endothelial progenitor cells via Cdc42/Rac1 , 2009, FEBS letters.

[2]  R. Eckel,et al.  Lipoprotein lipase: from gene to obesity. , 2009, American journal of physiology. Endocrinology and metabolism.

[3]  T. Kadowaki,et al.  Physiological and pathophysiological roles of adiponectin and adiponectin receptors in the integrated regulation of metabolic and cardiovascular diseases , 2008, International Journal of Obesity.

[4]  R. Evans,et al.  Metabolism of very-low-density lipoprotein and chylomicrons by streptozotocin-induced diabetic rat heart: effects of diabetes and lipoprotein preference. , 2008, American journal of physiology. Endocrinology and metabolism.

[5]  F. Wang,et al.  Acute dexamethasone-induced increase in cardiac lipoprotein lipase requires activation of both Akt and stress kinases. , 2008, American journal of physiology. Endocrinology and metabolism.

[6]  J. Shao,et al.  Adiponectin Reduces Plasma Triglyceride by Increasing VLDL Triglyceride Catabolism , 2008, Diabetes.

[7]  B. Goldstein,et al.  Adiponectin inhibits vascular endothelial growth factor-induced migration of human coronary artery endothelial cells. , 2008, Cardiovascular research.

[8]  G. Sweeney,et al.  Cardiac remodeling in obesity. , 2008, Physiological reviews.

[9]  T. Kadowaki,et al.  The physiological and pathophysiological role of adiponectin and adiponectin receptors in the peripheral tissues and CNS , 2008, FEBS letters.

[10]  P. Puthanveetil,et al.  Acute Diabetes Moderates Trafficking of Cardiac Lipoprotein Lipase Through p38 Mitogen-Activated Protein Kinase–Dependent Actin Cytoskeleton Organization , 2008, Diabetes.

[11]  T. Murohara,et al.  Potential of adiponectin as a cardioprotective agent. , 2007, Future cardiology.

[12]  Y. Liu,et al.  Total and high molecular weight but not trimeric or hexameric forms of adiponectin correlate with markers of the metabolic syndrome and liver injury in Thai subjects. , 2007, The Journal of clinical endocrinology and metabolism.

[13]  G. Lopaschuk,et al.  Cardiac Energy Metabolism in Obesity , 2007, Circulation research.

[14]  J. McNeill,et al.  Acute inhibition of Rho-kinase improves cardiac contractile function in streptozotocin-diabetic rats. , 2007, Cardiovascular research.

[15]  M. Eguchi,et al.  Globular and full-length forms of adiponectin mediate specific changes in glucose and fatty acid uptake and metabolism in cardiomyocytes. , 2007, Cardiovascular research.

[16]  J. Cooper,et al.  Actin filament severing by cofilin. , 2007, Journal of molecular biology.

[17]  I. Goldberg,et al.  Cardiac Metabolism and Mechanics are Altered by Genetic Loss of Lipoprotein Triglyceride Lipolysis , 2006, Cardiovascular Drugs and Therapy.

[18]  G. Sweeney,et al.  Mechanisms regulating energy metabolism by adiponectin in obesity and diabetes. , 2006, Biochemical Society transactions.

[19]  J. Hartwig,et al.  Cell surface actin remodeling , 2006, Journal of Cell Science.

[20]  M. Eguchi,et al.  Distinct effects of short- and long-term leptin treatment on glucose and fatty acid uptake and metabolism in HL-1 cardiomyocytes. , 2006, Metabolism: clinical and experimental.

[21]  R. Palanivel,et al.  Hyperglycemia- and hyperinsulinemia-induced alteration of adiponectin receptor expression and adiponectin effects in L6 myoblasts. , 2005, Journal of molecular endocrinology.

[22]  R. Piñeiro,et al.  Adiponectin is synthesized and secreted by human and murine cardiomyocytes , 2005, FEBS letters.

[23]  H. Mabuchi,et al.  Relationship of Lipoprotein Lipase and Hepatic Triacylglycerol Lipase Activity to Serum Adiponectin Levels in Japanese Hyperlipidemic Men , 2005, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[24]  Sanjoy Ghosh,et al.  Lysophosphatidic acid-mediated augmentation of cardiomyocyte lipoprotein lipase involves actin cytoskeleton reorganization. , 2005, American journal of physiology. Heart and circulatory physiology.

[25]  J. Schneider,et al.  Decreased plasma lipoprotein lipase in hypoadiponectinemia: an association independent of systemic inflammation and insulin resistance. , 2004, Diabetes care.

[26]  G. Lopaschuk,et al.  gAd-globular Head Domain of Adiponectin Increases Fatty Acid Oxidation in Newborn Rabbit Hearts* , 2004, Journal of Biological Chemistry.

[27]  Y. Taura,et al.  Overexpression of lipoprotein lipase improves insulin resistance induced by a high-fat diet in transgenic rabbits , 2004, Diabetologia.

[28]  R. Zechner,et al.  Cardiac-specific Knock-out of Lipoprotein Lipase Alters Plasma Lipoprotein Triglyceride Metabolism and Cardiac Gene Expression* , 2004, Journal of Biological Chemistry.

[29]  Ary L Goldberger,et al.  Diurnal and ultradian dynamics of serum adiponectin in healthy men: comparison with leptin, circulating soluble leptin receptor, and cortisol patterns. , 2003, The Journal of clinical endocrinology and metabolism.

[30]  D. Ramji,et al.  Lipoprotein lipase: structure, function, regulation, and role in disease , 2002, Journal of Molecular Medicine.

[31]  Mark Stamnes,et al.  Regulating the actin cytoskeleton during vesicular transport. , 2002, Current opinion in cell biology.

[32]  M. Matsuda,et al.  Diet-induced insulin resistance in mice lacking adiponectin/ACRP30 , 2002, Nature Medicine.

[33]  A. Xu,et al.  Hydroxylation and Glycosylation of the Four Conserved Lysine Residues in the Collagenous Domain of Adiponectin , 2002, The Journal of Biological Chemistry.

[34]  D. Severson,et al.  Altered metabolism causes cardiac dysfunction in perfused hearts from diabetic (db/db) mice. , 2000, American journal of physiology. Endocrinology and metabolism.

[35]  J. Schaper,et al.  The role of the cytoskeleton in heart failure. , 2000, Cardiovascular research.

[36]  R. Zechner,et al.  Induced mutant mouse lines that express lipoprotein lipase in cardiac muscle, but not in skeletal muscle and adipose tissue, have normal plasma triglyceride and high-density lipoprotein-cholesterol levels. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[37]  B. Wolffenbuttel,et al.  Post-heparin plasma lipoprotein lipase, but not hepatic lipase activity, is related to plasma adiponectin in type 2 diabetic patients and healthy subjects. , 2005, Clinical laboratory.