EHD2-mediated restriction of caveolar dynamics regulates cellular fatty acid uptake

被引：37

作者：

Matthaeus, Claudia ^{[1
]}

Lahmann, Ines ^{[2
]}

Kunz, Severine ^{[3
]}

Jonas, Wenke ^{[4
,5
]}

Melo, Arthur Alves ^{[1
]}

Lehmann, Martin ^{[6
,7
]}

Larsson, Elin ^{[8
]}

Lundmark, Richard ^{[8
]}

Kern, Matthias ^{[9
]}

Blueher, Matthias ^{[9
]}

Olschowski, Hannah ^{[10
]}

Kompa, Julian ^{[10
]}

Bruegger, Britta ^{[10
]}

Mueller, Dominik N. ^{[11
,12
]}

Haucke, Volker ^{[6
,7
,13
]}

Schuermann, Annette ^{[4
,5
]}

Birchmeier, Carmen ^{[2
]}

Daumke, Oliver ^{[1
,13
]}

机构：

[1] Max Delbruck Ctr Mol Med, Crystallog, D-13125 Berlin, Germany

[2] Max Delbruck Ctr Mol Med, Signal Transduct Dev Biol, D-13125 Berlin, Germany

[3] Max Delbruck Ctr Mol Med, Electron Microscopy Core Facil, D-13125 Berlin, Germany

[4] German Inst Human Nutr Potsdam Rehbrucke, Expt Diabetol, D-14558 Nuthetal, Germany

[5] German Ctr Diabet Res, Dept Expt Diabetol, D-85764 Munich, Germany

[6] Leibniz Forschungsinst Mol Pharmakol, Dept Mol Pharmacol & Cell Biol, D-13125 Berlin, Germany

[7] Leibniz Forschungsinst Mol Pharmakol, Imaging Core Facil, D-13125 Berlin, Germany

[8] Umea Univ, Integrat Med Biol, S-90187 Umea, Sweden

[9] Univ Leipzig, Dept Med, D-04103 Leipzig, Germany

[10] Heidelberg Univ, Biochem Ctr, D-69120 Heidelberg, Germany

[11] Charite, Expt & Clin Res Ctr, D-13125 Berlin, Germany

[12] Max Delbruck Ctr Mol Med, Expt & Clin Res Ctr, D-13125 Berlin, Germany

[13] Free Univ Berlin, Inst Chem & Biochem, D-14195 Berlin, Germany

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2020年 / 117卷 / 13期

关键词：

EHD2; ATPase; caveolae; fatty acid uptake; lipid metabolism; obesity; PLASMA-MEMBRANE; INTRACELLULAR TRAFFICKING; METABOLIC HOMEOSTASIS; STRUCTURAL INSIGHTS; ADIPOSE-TISSUE; PROTEINS; OBESITY; CAVIN; LOCALIZATION; ARCHITECTURE;

D O I：

10.1073/pnas.1918415117

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Eps15-homology domain containing protein 2 (EHD2) is a dynamin-related ATPase located at the neck of caveolae, but its physiological function has remained unclear. Here, we found that global genetic ablation of EHD2 in mice leads to increased lipid droplet size in fat tissue. This organismic phenotype was paralleled at the cellular level by increased fatty acid uptake via a caveolae- and CD36-dependent pathway that also involves dynamin. Concomitantly, elevated numbers of detached caveolae were found in brown and white adipose tissue lacking EHD2, and increased caveolar mobility in mouse embryonic fibroblasts. EHD2 expression itself was down-regulated in the visceral fat of two obese mouse models and obese patients. Our data suggest that EHD2 controls a cell-autonomous, caveolae-dependent fatty acid uptake pathway and imply that low EHD2 expression levels are linked to obesity.

引用

页码：7471 / 7481

页数：11

共 55 条

[1] Vectorial proteomics reveal targeting, phosphorylation and specific fragmentation of polymerase I and transcript release factor (PTRF) at the surface of caveolae in human adipocytes [J].

Aboulaich, N ;

Vainonen, JP ;

Strålfors, P ;

Vener, AV .

BIOCHEMICAL JOURNAL, 2004, 383 :237-248

[2] Proteomic analysis of proteins associated with lipid droplets of basal and lipolytically stimulated 3T3-L1 adipocytes [J].

Brasaemle, DL ;

Dolios, G ;

Shapiro, L ;

Wang, R .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (45) :46835-46842

[3] Caveolin-1 Expression and Cavin Stability Regulate Caveolae Dynamics in Adipocyte Lipid Store Fluctuation [J].

Briand, Nolwenn ;

Prado, Cecilia ;

Mabilleau, Guillaume ;

Lasnier, Francoise ;

Le Liepvre, Xavier ;

Covington, Jeffrey D. ;

Ravussin, Eric ;

Le Lay, Soazig ;

Dugail, Isabelle .

DIABETES, 2014, 63 (12) :4032-4044

[4] Caveolae: One Function or Many? [J].

Cheng, Jade P. X. ;

Nichols, Benjamin J. .

TRENDS IN CELL BIOLOGY, 2016, 26 (03) :177-189

[5] Architectural and mechanistic insights into an EHD ATPase involved in membrane remodelling [J].

Daumke, Oliver ;

Lundmark, Richard ;

Vallis, Yvonne ;

Martens, Sascha ;

Butler, P. Jonathan G. ;

McMahon, Harvey T. .

NATURE, 2007, 449 (7164) :923-U15

[6] Pleiotropic Effects of Cavin-1 Deficiency on Lipid Metabolism [J].

Ding, Shi-Ying ;

Lee, Mi-Jeong ;

Summer, Ross ;

Liu, Libin ;

Fried, Susan K. ;

Pilch, Paul F. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2014, 289 (12) :8473-8483

[7] Loss of caveolae, vascular dysfunction, and pulmonary defects in caveolin-1 gene-disrupted mice [J].

Drab, M ;

Verkade, P ;

Elger, M ;

Kasper, M ;

Lohn, M ;

Lauterbach, B ;

Menne, J ;

Lindschau, C ;

Mende, F ;

Luft, FC ;

Schedl, A ;

Haller, H ;

Kurzchalia, TV .

SCIENCE, 2001, 293 (5539) :2449-2452

[8] De novo lipogenesis in human fat and liver is linked to ChREBP-β and metabolic health [J].

Eissing, Leah ;

Scherer, Thomas ;

Toedter, Klaus ;

Knippschild, Uwe ;

Greve, Jan Willem ;

Buurman, Wim A. ;

Pinnschmidt, Hans O. ;

Rensen, Sander S. ;

Wolf, Anna M. ;

Bartelt, Alexander ;

Heeren, Joerg ;

Buettner, Christoph ;

Scheja, Ludger .

NATURE COMMUNICATIONS, 2013, 4

[9] Importance of the carboxyl terminus of FAT/CD36 for plasma membrane localization and function in long-chain fatty acid uptake [J].

Eyre, Nicholas S. ;

Cleland, Leslie G. ;

Tandon, Narendra N. ;

Mayrhofer, Graham .

JOURNAL OF LIPID RESEARCH, 2007, 48 (03) :528-542

[10] Bone Morphogenetic Protein 2 (BMP2) may Contribute to Partition of Energy Storage into Visceral and Subcutaneous Fat Depots [J].

Guiu-Jurado, Esther ;

Unthan, Mark ;

Boehler, Nina ;

Kern, Matthias ;

Landgraf, Kathrin ;

Dietrich, Arne ;

Schleinitz, Dorit ;

Ruschke, Karen ;

Kloeting, Nora ;

Fasshauer, Mathias ;

Toenjes, Anke ;

Stumvoll, Michael ;

Koerner, Antje ;

Kovacs, Peter ;

Blueher, Matthias .

OBESITY, 2016, 24 (10) :2092-2100

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