Obesity Enables NLRP3 Activation and Induces Myocardial Fibrosis via Hyperacetylation of HADHa

Author:

Deng Yan12ORCID,Liu Xin12ORCID,Xie Min123,Zhao Rui24,Ji Liwei12,Tang Kuo12,Yang Wei12,Ou Wei12,Xie Maodi12,Li Tao12ORCID

Affiliation:

1. 1Department of Anesthesiology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China

2. 2Laboratory of Mitochondria and Metabolism, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China

3. 3Department of Anesthesiology, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, China

4. 4Division of Gastrointestinal Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China

Abstract

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–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 α 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. Article Highlights

Funder

Natural Science Foundation of Sichuan Province

National Natural Science Foundation of China

Yunnan Provincial Cardiovascular Disease Clinical Medical Center Project

Key Research and Development Program of Sichuan Province

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

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