<b>Obesity enables NLRP3 activation and induces myocardial fibrosis </b><b>via hyperacetylation of HADHa</b>

<p>Obesity increases the risk of myocardial fibrosis, a pathological change in most heart diseases, but the mechanism has not been fully elucidated. Here, we found that mice with high-fat diet (HFD)-induced obesity had more severe myocardial fibrosis than control mice under normal and ischemia/reperfusion (I/R) conditions, which could be alleviated by neutralizing antibodies against interleukin (IL)-1β and IL-18, downstream products of the nucleotide-binding oligomerization-like receptor protein 3 (NLRP3) inflammasome, and the NLRP3 inhibitor MCC950. Mechanistically, mitochondrial hyperacetylation in obese mouse hearts recruited apoptosis-associated speck-like protein containing a CARD (ASC) to mitochondria and thus facilitated NLRP3 inflammasome assembly. Acetylation of K255 on hydroxyl-CoA dehydrogenase alpha subunit (HADHa) was identified to trigger the mitochondrial localization of ASC. Blockade of HADHa-K255 acetylation downregulated mitochondrial ASC, suppressed the NLRP3 inflammasome and attenuated post-I/R myocardial fibrosis in obese mouse hearts. In obese human patients, the extent of myocardial fibrosis according to T1 MRI was positively correlated with the plasma levels of IL-1β and IL-18, supporting the connection of NLRP3 inflammation to obesity-induced myocardial fibrosis. In conclusion, our study demonstrates that the heart is susceptible to fibrosis under obesity through hyperacetylated HADHa mediated activation of the NLRP3 inflammasome.</p><p><br></p><p><b>Keywords</b>: Obesity; Myocardial fibrosis; NLRP3 inflammasome; Acetylation; HADHa.</p><p><br></p><p><b>Article highlights:</b></p><p><b>Why did we undertake this study?</b></p><p>l Obesity increases the risk of myocardial fibrosis while the mechanism is not fully understood.</p><p><b>What is the specific question(s) we wanted to answer?</b></p><p>l How does obesity contribute to myocardial fibrosis?</p><p><b>What did we find?</b></p><p>l Obesity exacerbates myocardial fibrosis through NLRP3 inflammasome.</p><p>l Obesity promotes assembly of the NLRP3 inflammasome via mitochondrial hyperacetylation.</p><p>l Acetylation of HADHa-K255 recruits ASC to mitochondria, which facilitates NLRP3 inflammasome assembly and aggravates myocardial fibrosis.</p><p><b>What are the implications of our findings?</b></p><p>l This study may provide new potential therapeutic strategy for myocardial fibrosis in obese patients.</p>