Insulin‐dependent translocation of the small GTP‐binding protein rab3C in cardiac muscle: studies on insulin‐resistant Zucker rats

Uphues, Ingo; Chern, Yijuang; Eckel, Jürgen

doi:10.1016/0014-5793(95)01315-6

Cited by 11 publications

(10 citation statements)

References 37 publications

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“…Alterations in transporter redistribution associated with obesity have also been observed for GLUT4 in both muscle (43) and heart (44). In healthy muscles (43) and heart (45) GLUT4 is mobilized by insulin from intracellular stores to the sarcolemma, whereas in obese heart and muscles intracellular GLUT4 translocation by insulin is inhibited (43,45). In contrast, our data show that in obese rats more FAT/CD36 is located at the plasma membrane when compared with lean animals.…”

Section: Discussionsupporting

confidence: 53%

Increased Rates of Fatty Acid Uptake and Plasmalemmal Fatty Acid Transporters in Obese Zucker Rats

Luiken¹,

Arumugam²,

Dyck³

et al. 2001

Journal of Biological Chemistry

247

270

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Giant vesicles were used to study the rates of uptake of long-chain fatty acids by heart, skeletal muscle, and adipose tissue of obese and lean Zucker rats. With obesity there was an increase in vesicular fatty acid uptake of 1.8-fold in heart, muscle and adipose tissue. In some tissues only fatty acid translocase (FAT) mRNA (heart, ؉37%; adipose, ؉80%) and fatty acid-binding protein (FABPpm) mRNA (heart, ؉148%; adipose, ؉196%) were increased. At the protein level FABPpm expression was not changed in any tissues except muscle (؉14%), and FAT/CD36 protein content was altered slightly in adipose tissue (؉26%). In marked contrast, the plasma membrane FAT/CD36 protein was increased in heart (؉60%), muscle (؉80%), and adipose tissue (؉50%). The plasma membrane FABPpm was altered only in heart (؉50%) and adipose tissues (؉70%). Thus, in obesity, alterations in fatty acid transport in metabolically important tissues are not associated with changes in fatty acid transporter mRNAs or altered fatty acid transport protein expression but with their increased abundance at the plasma membrane. We speculate that in obesity fatty acid transporters are relocated from an intracellular pool to the plasma membrane in heart, muscle, and adipose tissues.Fatty acids (FA) 1 are important substrates for most mammalian tissues. Based on their hydrophobic structure it has been postulated that FA are sequestered by cells through passive diffusion across the plasma membrane (cf. Ref. 1). However, other evidence has shown that FA also traverse the plasma membrane via a protein-mediated mechanism (cf. Refs. 2 and 3). Indeed, this latter system is quantitatively more important than passive diffusion, as FA uptake can be reduced markedly by inhibitors of protein-mediated membrane transport (4 -6) and by a reactive ester of oleate (4). Thus, a number of groups began to search for FA transport proteins.Several putative fatty acid transport proteins have been identified that promote the cellular uptake of FA. These are a 43-kDa plasma membrane fatty acid-binding protein (FABPpm) (7), identical to mitochondrial aspartate aminotransferase (7-9), and an 88-kDa heavily glycosylated fatty acid translocase (FAT/CD36), the rat homologue of human CD36 (10). In addition, to these membrane-associated proteins, a soluble cytoplasmic fatty acid-binding protein (FABPc) is also important for cellular FA uptake, because in FABPc null mice there is a marked decrease of FA influx into cardiac myocytes (11). FATP1, another putative fatty acid transport protein (12, 13), correlates inversely with fatty acid transport in muscle and heart (4), and this protein appears to be a very long-chain acyl-CoA synthetase (14, 15). These observations suggest that FATP1 is unlikely to be involved directly in fatty acid translocation across the plasma membrane.To examine the regulation of transmembrane fatty acid transport, we have characterized giant vesicles (4, 16, 17), which can be prepared from metabolically important tissue such as heart (4) and skeletal muscle (16, 17) as...

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Section: Discussionsupporting

confidence: 53%

Increased Rates of Fatty Acid Uptake and Plasmalemmal Fatty Acid Transporters in Obese Zucker Rats

Luiken¹,

Arumugam²,

Dyck³

et al. 2001

Journal of Biological Chemistry

247

270

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“…Cardiac muscle expresses a variety of small GTPbinding proteins with a molecular mass between 23 000 and 29 000 M r [38]. Of the Rab family three members, Rab3C, Rab4 and Rab5 [21,39,40] have been observed in the rat heart, whereas Rab1A, Rab2, Rab6 and Rab8 were expressed below the detection level [21,39]. A low protein expression of Rab11 in cardiac muscle was observed when analysing homogenates of different tissues [41].…”

Section: Discussionmentioning

confidence: 99%

Rab11 is associated with GLUT4-containing vesicles and redistributes in response to insulin

et al. 2000

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Homeostasis of blood glucose by insulin involves the rapid and large stimulation of glucose uptake by muscle and adipose tissue. This important action of the hormone is based on the translocation of the glucose transporter isoform GLUT4 from an intracellular pool to the cell surface [1,2]. A major aspect of this process that is still to be defined is that of the downstream signalling from the insulin receptor to the GLUT4 compartment and how these signals trigger recruitment of the GLUT4-containing vesicles to the plasma membrane. To explain these processes, several laboratories have isolated the intracellular vesicles containing GLUT4 and characterized their protein composition [3±9]. In addition to GLUT4, three major companion proteins have been identified in GLUT4-containing vesicles including an insulin-reg- Diabetologia (2000) Abstract Aims/hypothesis. To identify a GTPase of 24 000 M r which we recently found to co-localize with GLUT4 in cardiac muscle. Methods. A 24 000 M r -GTP-binding fraction was purified from pig heart by a three-step chromatographic procedure, followed by two-dimensional electrophoresis and electrospray ionization-mass spectrometry. Subcellular distribution of the GTPase was assessed by western blotting. Co-localization with GLUT4 was assessed by continuous sucrose density gradient fractionation and immunoadsorption of GLUT4-containing vesicles.Results. The Rab11 protein was identified as a major component of the GTP-binding fraction and its expression in rat cardiac muscle was confirmed. In vivo insulin treatment resulted in the recruitment of Rab11 from the microsomal fraction to the plasma membrane. Subcellular fractionation indicated two immunoreactive GLUT4 pools. Most of the intracellular pool of Rab11 overlapped with the high-density GLUT4 pool and most of the transferrin receptor pool. The Rab11 protein also co-sedimented with the low-density, non-endosomal GLUT4 pool and substantially increased in this fraction after insulin treatment. It was specifically present in GLUT4-containing vesicles and insulin increased its abundance in these vesicles 2.2-fold relative to the amount of GLUT4. These vesicles also containend Rab4 and Akt-2, the latter being only associated after insulin stimulation. Insulin was unable to alter the cellular localization of Rab11 in insulin-resistant obese Zucker rats. Conclusion/interpretation. These results support the hypothesis that at least two GTPases of the Rab family participate in GLUT4-vesicle trafficking. We suggest that Rab11 is involved in the endosomal recycling, sorting and exocytotic movement of the glucose transporter.

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“…The few studies to date addressing the presence of rab proteins in the heart have revealed the presence of rab1, -3, -4, -5, -6 and -11 [119,120,128]. While rab1 and -6 are involved in antegrade and retrograde vesicular trafficking between the endoplasmic reticulum and Golgi stacks [78,89], rab3, -4, -5 and -11 are candidates for regulating GLUT4 recycling.…”

Section: Glut4 and Insulinmentioning

confidence: 98%

“…While rab1 and -6 are involved in antegrade and retrograde vesicular trafficking between the endoplasmic reticulum and Golgi stacks [78,89], rab3, -4, -5 and -11 are candidates for regulating GLUT4 recycling. rab3 and -4 translocate to the plasma membrane of cardiac myocytes in response to insulin [120]. rab4, but not rab3, has been detected in immunopurified GLUT4-containing intracellular vesicles obtained from rat heart [120].…”

Section: Glut4 and Insulinmentioning

confidence: 98%

Regulation of cardiac long-chain fatty acid and glucose uptake by translocation of substrate transporters

Luiken

Coort

Koonen

et al. 2004

Pflugers Arch - Eur J Physiol

152

103

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Cardiac uptake of long-chain fatty acids (FA) is mediated predominantly by two membrane-associated proteins, the 43-kDa plasma membrane fatty acid-binding protein (FABPpm) and the 88-kDa fatty acid translocase/CD36 (FAT/CD36). While FABPpm is present constitutively in the sarcolemma, FAT/CD36 is recycled between an intracellular membrane compartment and the sarcolemma. Since the amount of sarcolemmal FAT/CD36 is a major determinant of cellular FA uptake, understanding of the regulation of its recycling is likely to provide new insights into altering substrate preference of the heart. FAT/CD36 recycling displays a remarkable similarity with that of the two glucose transporters (GLUT) in the heart, GLUT1 and GLUT4. Translocation of all three transporters is induced by insulin and by contraction, which stimuli activate distinct signalling cascades. The insulin pathway involves phosphatidylinositol-3 kinase (PI3K) whilst the contraction pathway is dependent on AMP-activated protein kinase (AMPK). For the identification of additional protein components involved in the regulation of FAT/CD36 recycling, valuable lessons can be learned from GLUT1 and GLUT4 recycling. Especially GLUT4 recycling is an intensively studied process in which a number of signalling proteins, both upstream and downstream from PI3 K and AMPK, have been identified, as well as proteins that are part of the translocation machinery involving Rab GTPases and soluble N-ethylmaleimide attachment protein receptors (SNAREs). Comparison of the magnitude of the effects of insulin and contraction on substrate uptake and on transporter appearance in the sarcolemma have revealed that FAT/CD36 recycling resembles GLUT1 recycling more closely than that of GLUT4. This pinpoints the recycling compartment and excludes a pre-endosomal storage compartment as the intracellular storage site for FAT/CD36. Further research will probably establish whether FAT/CD36 translocation is (partly) coupled to that of one or both GLUTs or, alternatively, whether it is a distinct process that also can be induced independently of GLUT1 or GLUT4 movement. In the latter case, a unique set of proteins would be dedicated to FAT/CD36 recycling, which would then provide an attractive target for manipulating cardiac substrate preference.

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Insulin‐dependent translocation of the small GTP‐binding protein rab3C in cardiac muscle: studies on insulin‐resistant Zucker rats

Cited by 11 publications

References 37 publications

Increased Rates of Fatty Acid Uptake and Plasmalemmal Fatty Acid Transporters in Obese Zucker Rats

Increased Rates of Fatty Acid Uptake and Plasmalemmal Fatty Acid Transporters in Obese Zucker Rats

Rab11 is associated with GLUT4-containing vesicles and redistributes in response to insulin

Regulation of cardiac long-chain fatty acid and glucose uptake by translocation of substrate transporters

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