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

Zegeye H. Jebessa; Kumar D. Shanmukha; Matthias Dewenter; Lorenz H. Lehmann; Chang Xu; Friederike Schreiter; Dominik Siede; Xue Min Gong; Barbara C. Worst; Giuseppina Federico; Sven W. Sauer; Tamas Fischer; Lisa Wechselberger; Oliver J. Müller; Samuel Sossalla; Christoph Dieterich; Patrick Most; Herrmann Josef Gröne; Cedric Moro; Monika Oberer; Guenter Haemmerle; Hugo A. Katus; Jens Tyedmers; Johannes Backs

doi:10.1038/s42255-019-0138-4

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

Zegeye H. Jebessa, Kumar D. Shanmukha, Matthias Dewenter, Lorenz H. Lehmann, Chang Xu, Friederike Schreiter, Dominik Siede, Xue Min Gong, Barbara C. Worst, Giuseppina Federico, Sven W. Sauer, Tamas Fischer, Lisa Wechselberger, Oliver J. Müller, Samuel Sossalla, Christoph Dieterich, Patrick Most, Herrmann Josef Gröne, Cedric Moro, Monika ObererGuenter Haemmerle, Hugo A. Katus, Jens Tyedmers, Johannes Backs^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

43 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	1157-1167
Number of pages	11
Journal	Nature Metabolism
Volume	1
Issue number	11
DOIs	https://doi.org/10.1038/s42255-019-0138-4
Publication status	Published - 1 Nov 2019

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Jebessa, Z. H., Shanmukha, K. D., Dewenter, M., Lehmann, L. H., Xu, C., Schreiter, F., Siede, D., Gong, X. M., Worst, B. C., Federico, G., Sauer, S. W., Fischer, T., Wechselberger, L., Müller, O. J., Sossalla, S., Dieterich, C., Most, P., Gröne, H. J., Moro, C., ... Backs, J. (2019). The lipid-droplet-associated protein ABHD5 protects the heart through proteolysis of HDAC4. Nature Metabolism, 1(11), 1157-1167. https://doi.org/10.1038/s42255-019-0138-4

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title = "The lipid-droplet-associated protein ABHD5 protects the heart through proteolysis of HDAC4",

abstract = "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.",

author = "Jebessa, {Zegeye H.} and Shanmukha, {Kumar D.} and Matthias Dewenter and Lehmann, {Lorenz H.} and Chang Xu and Friederike Schreiter and Dominik Siede and Gong, {Xue Min} and Worst, {Barbara C.} and Giuseppina Federico and Sauer, {Sven W.} and Tamas Fischer and Lisa Wechselberger and M{\"u}ller, {Oliver J.} and Samuel Sossalla and Christoph Dieterich and Patrick Most and Gr{\"o}ne, {Herrmann Josef} and Cedric Moro and Monika Oberer and Guenter Haemmerle and Katus, {Hugo A.} and Jens Tyedmers and Johannes Backs",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2019",

month = nov,

day = "1",

doi = "10.1038/s42255-019-0138-4",

language = "English",

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Jebessa, ZH, Shanmukha, KD, Dewenter, M, Lehmann, LH, Xu, C, Schreiter, F, Siede, D, Gong, XM, Worst, BC, Federico, G, Sauer, SW, Fischer, T, Wechselberger, L, Müller, OJ, Sossalla, S, Dieterich, C, Most, P, Gröne, HJ, Moro, C, Oberer, M, Haemmerle, G, Katus, HA, Tyedmers, J & Backs, J 2019, 'The lipid-droplet-associated protein ABHD5 protects the heart through proteolysis of HDAC4', Nature Metabolism, vol. 1, no. 11, pp. 1157-1167. https://doi.org/10.1038/s42255-019-0138-4

TY - JOUR

T1 - The lipid-droplet-associated protein ABHD5 protects the heart through proteolysis of HDAC4

AU - Jebessa, Zegeye H.

AU - Shanmukha, Kumar D.

AU - Dewenter, Matthias

AU - Lehmann, Lorenz H.

AU - Xu, Chang

AU - Schreiter, Friederike

AU - Siede, Dominik

AU - Gong, Xue Min

AU - Worst, Barbara C.

AU - Federico, Giuseppina

AU - Sauer, Sven W.

AU - Fischer, Tamas

AU - Wechselberger, Lisa

AU - Müller, Oliver J.

AU - Sossalla, Samuel

AU - Dieterich, Christoph

AU - Most, Patrick

AU - Gröne, Herrmann Josef

AU - Moro, Cedric

AU - Oberer, Monika

AU - Haemmerle, Guenter

AU - Katus, Hugo A.

AU - Tyedmers, Jens

AU - Backs, Johannes

PY - 2019/11/1

Y1 - 2019/11/1

N2 - 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.

AB - 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.

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U2 - 10.1038/s42255-019-0138-4

DO - 10.1038/s42255-019-0138-4

M3 - Article

SN - 2522-5812

VL - 1

SP - 1157

EP - 1167

JO - Nature Metabolism

JF - Nature Metabolism

IS - 11

ER -

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

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