American Diabetes Association
Browse
DB23-0264 supplementary_materials_20230803_v2-clean.docx (1.25 MB)

Obesity enables NLRP3 activation and induces myocardial fibrosis via hyperacetylation of HADHa

Download (1.25 MB)
figure
posted on 2023-08-25, 20:33 authored by Yan Deng, Xin Liu, Min Xie, Rui Zhao, Liwei Ji, Kuo Tang, Wei Yang, Wei Ou, Maodi Xie, Tao Li

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.


Keywords: Obesity; Myocardial fibrosis; NLRP3 inflammasome; Acetylation; HADHa.


Article highlights:

Why did we undertake this study?

l Obesity increases the risk of myocardial fibrosis while the mechanism is not fully understood.

What is the specific question(s) we wanted to answer?

l How does obesity contribute to myocardial fibrosis?

What did we find?

l Obesity exacerbates myocardial fibrosis through NLRP3 inflammasome.

l Obesity promotes assembly of the NLRP3 inflammasome via mitochondrial hyperacetylation.

l Acetylation of HADHa-K255 recruits ASC to mitochondria, which facilitates NLRP3 inflammasome assembly and aggravates myocardial fibrosis.

What are the implications of our findings?

l This study may provide new potential therapeutic strategy for myocardial fibrosis in obese patients.

Funding

Key Research and Development Program of Sichuan Province x 2022YFS0132 2022YFS0198

Ministry of Science and Technology of the People's Republic of China > National Natural Science Foundation of China 81970715

Natural Science Foundation of Sichuan Province 2023NSFSC1633

Yunnan Provincial Cardiovascular Disease Clinical Medical Center Project x 2022YFKY078

History

Usage metrics

    Diabetes

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC