The enzymatic activity of histone deacetylase 4 connects regulation of lipid metabolism with diastolic heart function.

Jiale Huang (Heidelberg)1, X. Gong (Heidelberg)1, L. Schlicker (Heidelberg)2, A. de Britto Chaves Filho (Heidelberg)2, H. Paluvai (Heidelberg)1, J. Tyedmers (Heidelberg)1, A. Schulze (Heidelberg)2, J. Backs (Heidelberg)1

1Heidelberg University Medical Faculty Heidelberg, Institute of Experimental Cardiology Heidelberg, Deutschland; 2German Cancer Research Center Division of Tumor Metabolism and Microenvironment Heidelberg, Deutschland


Class II a histone deacetylase HDAC4 has a cardioprotective function in mouse models for systolic dysfunction. This function can be carried out not only by the full-length protein, but also by an N-terminal fragment thereof termed HDAC4-NT. NT is generated by cleavage through the lipid droplet associated protein abhydrolase domain containing 5 (ABHD5) and can be regulated by the interplay of additional lipid droplet associated proteins that also control lipid metabolism. Thus, regulation of lipid metabolism is interconnected with the maintenance of cardiac homeostasis during cardiac stress.

To further investigate this interplay between lipid metabolism and HDAC4 function, we employed two mouse models for aberrant lipid metabolism. The first one is a model for inherited Neutral Lipid Storage Disease - Cardiomyopathy (NLSD-CM) and consists of mice that are deficient for the enzyme that catalyzes the first step of lipolysis of triacylglycerides (TAGs), PNPLA2. These mice have been described to develop massive systolic heart failure at 12-14 weeks of age. The second one was previously described as a model for heart failure with preserved ejection fraction (HFpEF) in which the mice develop diastolic dysfunction. It combines feeding the mice with high fat diet (HFD) and application of Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) to induce hypertension, two common comorbidities in human HFpEF.

HFD + L-NAME treated mice developed diastolic dysfunction as expected. Interestingly, also PNPLA2-deficient mice developed diastolic dysfunction at 8 weeks of age when systolic heart function was still completely normal. As expected, we observed in both mouse models massive accumulation of lipid droplets in the heart as revealed by BODIPY staining. Lipidomics analysis demonstrated global metabolic remodeling in these hearts. Unexpectedly, however, we found in cardiac tissue of both models a markedly increased enzymatic activity of HDAC4. This suggests that aberrant lipid accumulations are associated with increased HDAC4 deacetylase activity through a yet unknown mechanism. To reveal whether this increased deacetylation activity contributes to the diastolic dysfunction phenotype, we subjected mice with a cardiac specific knock-out of Hdac4 as well as KI mice in which the Hdac4wt gene was replaced by an enzymatically dead point mutant, Hdac4H968Y, to HFD and L-NAME treatment. Stunningly, the absence of HDAC4 in cardiomyocytes or even just the absence of HDAC4’s enzymatic class IIa activity rescued diastolic dysfunction in both models almost completely, revealing a crucial role of HDAC4’s enzymatic activity in the development of diastolic dysfunction. Moreover, the aberrant lipid accumulations were also prevented by the absence of HDAC4 or its enzymatic activity. Thus, HDAC4, through its enzymatic function, also regulates lipid droplet biogenesis to balance lipid metabolism with cardiomyocyte function. 
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