The lipid droplet-associated protein ABHD5 protects the heart through proteolysis of HDAC4.,Nature Metabolism

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The lipid droplet-associated protein ABHD5 protects the heart through proteolysis of HDAC4.
Nature Metabolism ( IF 18.9 ) Pub Date : 2019-11-15 , DOI: 10.1038/s42255-019-0138-4
Zegeye H Jebessa _{1,

2,

3} , Kumar D Shanmukha _{1,

2} , Matthias Dewenter _{1,

2} , Lorenz H Lehmann _{1,

2,

3} , Chang Xu _{1,

2} , Friederike Schreiter _{1,

2} , Dominik Siede _{1,

2} , Xue-Min Gong _{1,

2} , Barbara C Worst _{1,

2,

4} , Giuseppina Federico ₅ , Sven W Sauer ₆ , Tamas Fischer ₇ , Lisa Wechselberger _{8,

9} , Oliver J Müller ₁₀ , Samuel Sossalla ₁₁ , Christoph Dieterich _{2,

3} , Patrick Most _{2,

3} , Herrmann-Josef Gröne _{5,

12} , Cedric Moro ₁₃ , Monika Oberer _{8,

9} , Guenter Haemmerle _{8,

9} , Hugo A Katus _{2,

3} , Jens Tyedmers _{1,

2} , Johannes Backs _{1,

2}

Affiliation

Institute of Experimental Cardiology, University of Heidelberg, Heidelberg, Germany.
DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Heidelberg, Germany.
Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
Pediatric Glioma Research Group, Hopp Children's Cancer Center Heidelberg (KiTZ) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.
Department of General Pediatrics, Division of Inborn Metabolic Diseases, University Children's Hospital, Heidelberg, Germany.
John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia.
Institute of Molecular Biosciences, University of Graz, Graz, Austria.
BioTechMed-Graz, Graz, Austria.
Department of Internal Medicine III, University of Kiel, Kiel, Germany.
Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany.
Institute for Pathology and Nephropathology, University Hospital Marburg, Marburg, Germany.
INSERM, UMR1048, Obesity Research Laboratory, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France.

Catecholamines stimulate the first step of lipolysis by PKA-dependent release of the lipid droplet-associated protein ABHD5 from perilipin to co-activate the lipase ATGL. Here, we unmask a yet unrecognized proteolytic and cardioprotective function of ABHD5. ABHD5 acts in vivo and in vitro as a serine protease cleaving HDAC4. Through the production of an N-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 of HDAC4-NT does not protect from intra-cardiomyocyte lipid accumulation but strikingly from 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 from 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 treat cardiometabolic disease.

中文翻译：

脂滴相关蛋白 ABHD5 通过 HDAC4 的蛋白水解保护心脏。

儿茶酚胺通过 PKA 依赖性从 perilipin 释放脂滴相关蛋白 ABHD5 来刺激脂肪分解的第一步，以共同激活脂肪酶 ATGL。在这里，我们揭示了 ABHD5 尚未被识别的蛋白水解和心脏保护功能。ABHD5 在体内和体外作为丝氨酸蛋白酶切割 HDAC4。通过产生 HDAC4 的 N 端多肽 (HDAC4-NT)，ABHD5 抑制 MEF2 依赖性基因表达，从而控制葡萄糖处理。ABHD5 缺陷导致小鼠中性脂质贮积病。HDAC4-NT 的心脏特异性基因治疗不能防止心肌细胞内脂质积累，但能明显防止心力衰竭，从而挑战脂毒性诱导的心力衰竭的概念。ABHD5 水平在衰竭的人类心脏中降低，并且鼠转基因 ABHD5 表达可防止压力过载诱导的心力衰竭。这些发现代表了通过 HDAC4 蛋白水解将脂质与葡萄糖代谢联系起来的概念性进步，并为治疗心脏代谢疾病提供了新的转化方法。

更新日期：2019-11-17

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