The lipid-droplet-associated protein ABHD5 protects the heart through proteolysis of HDAC4

被引：44

作者：

Jebessa, Zegeye H. ^{[1
,2
,3
]}

Shanmukha, Kumar D. ^{[1
,2
]}

Dewenter, Matthias ^{[1
,2
]}

Lehmann, Lorenz H. ^{[1
,2
,3
]}

Xu, Chang ^{[1
,2
]}

Schreiter, Friederike ^{[1
,2
]}

Siede, Dominik ^{[1
,2
]}

Gong, Xue-Min ^{[1
,2
]}

Worst, Barbara C. ^{[1
,2
,12
,13
]}

Federico, Giuseppina ^{[4
]}

Sauer, Sven W. ^{[5
]}

Fischer, Tamas ^{[6
]}

Wechselberger, Lisa ^{[7
,8
]}

Mueller, Oliver J. ^{[9
]}

Sossalla, Samuel ^{[10
]}

Dieterich, Christoph ^{[2
,3
]}

Most, Patrick ^{[2
,3
]}

Groene, Herrmann-Josef ^{[4
,14
]}

Moro, Cedric ^{[11
]}

Oberer, Monika ^{[7
,8
]}

Haemmerle, Guenter ^{[7
,8
]}

Katus, Hugo A. ^{[2
,3
]}

Tyedmers, Jens ^{[1
,2
]}

Backs, Johannes ^{[1
,2
]}

机构：

[1] Heidelberg Univ, Inst Expt Cardiol, Heidelberg, Germany

[2] DZHK German Ctr Cardiovasc Res, Partner Site Heidelberg Mannheim, Heidelberg, Germany

[3] Heidelberg Univ, Dept Cardiol, Heidelberg, Germany

[4] German Canc Res Ctr, Dept Cellular & Mol Pathol, Heidelberg, Germany

[5] Univ Childrens Hosp, Dept Gen Pediat, Div Inborn Metab Dis, Heidelberg, Germany

[6] Australian Natl Univ, John Curtin Sch Med Res, Canberra, ACT, Australia

[7] Karl Franzens Univ Graz, Inst Mol Biosci, Graz, Austria

[8] BioTechMed Graz, Graz, Austria

[9] Univ Kiel, Dept Internal Med 3, Kiel, Germany

[10] Univ Hosp Regensburg, Dept Internal Med 2, Regensburg, Germany

[11] Inst Metab & Cardiovasc Dis, Obes Res Lab, UMR1048, INSERM, Toulouse, France

[12] Hopp Childrens Canc Ctr Heidelberg KiTZ, Pediat Glioma Res Grp, Heidelberg, Germany

[13] German Canc Res Ctr, Heidelberg, Germany

[14] Univ Hosp Marburg, Inst Pathol & Nephropathol, Marburg, Germany

来源：

NATURE METABOLISM | 2019年 / 1卷 / 11期

基金：

奥地利科学基金会;

关键词：

CARDIAC GENE-TRANSFER; KINASE-II; SWISS-MODEL; LIPOLYSIS; CGI-58; MICE; GENERATION; CATABOLISM; ADULT;

D O I：

10.1038/s42255-019-0138-4

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Catecholamines stimulate the first step of lipolysis through protein kinase A (PKA)-dependent release of the lipid-droplet-associated protein abhydrolase domain containing 5 (ABHD5) from perilipin to coactivate the lipase adipose triglyceride lipase (ATGL). Here, we unmask a proteolytic and cardioprotective function of ABHD5. ABHD5 acts in vivo and in vitro as a serine protease that cleaves histone deacetylase 4 (HDAC4). Through the production of an amino-terminal polypeptide of HDAC4 (HDAC4-NT), ABHD5 inhibits MEF2-dependent gene expression and thereby controls glucose handling. ABHD5 deficiency leads to neutral-lipid storage disease in mice. Cardiac-specific gene therapy using the gene encoding HDAC4-NT does not protect against intracardiomyocyte lipid accumulation, but strikingly protects against heart failure, thereby challenging the concept of lipotoxicity-induced heart failure. ABHD5 levels are reduced in failing human hearts, and murine transgenic ABHD5 expression protects against pressure-overload-induced heart failure. These findings represent a conceptual advance by connecting lipid with glucose metabolism through HDAC4 proteolysis, and enable new translational approaches to treating cardiometabolic disease.

引用

页码：1157 / +

页数：18

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