AS160 is a lipid-responsive regulator of cardiac Ca2+ homeostasis by controlling lysophosphatidylinositol metabolism and signaling.

The obese heart undergoes metabolic remodeling and exhibits impaired calcium (Ca2+) homeostasis, which are two critical assaults leading to cardiac dysfunction. The molecular mechanisms underlying these alterations in obese heart are not well understood. Here, we show that the Rab-GTPase activating protein AS160 is a lipid-responsive regulator of Ca2+ homeostasis through governing lysophosphatidylinositol metabolism and signaling. Palmitic acid/high fat diet inhibits AS160 activity through phosphorylation by NEK6, which consequently activates its downstream target Rab8a. Inactivation of AS160 in cardiomyocytes elevates cytosolic Ca2+ that subsequently impairs cardiac contractility. Mechanistically, Rab8a downstream of AS160 interacts with DDHD1 to increase lysophosphatidylinositol metabolism and signaling that leads to Ca2+ release from sarcoplasmic reticulum. Inactivation of NEK6 prevents inhibition of AS160 by palmitic acid/high fat diet, and alleviates cardiac dysfunction in high fat diet-fed mice. Together, our findings reveal a regulatory mechanism governing metabolic remodeling and Ca2+ homeostasis in obese heart, and have therapeutic implications to combat obesity cardiomyopathy. © 2024. The Author(s).

Citation

Shu Su, Chao Quan, Qiaoli Chen, Ruizhen Wang, Qian Du, Sangsang Zhu, Min Li, Xinyu Yang, Ping Rong, Jiang Chen, Yingyu Bai, Wen Zheng, Weikuan Feng, Minjun Liu, Bingxian Xie, Kunfu Ouyang, Yun Stone Shi, Feng Lan, Xiuqin Zhang, Ruiping Xiao, Xiongwen Chen, Hong-Yu Wang, Shuai Chen. AS160 is a lipid-responsive regulator of cardiac Ca2+ homeostasis by controlling lysophosphatidylinositol metabolism and signaling. Nature communications. 2024 Nov 06;15(1):9602

Mesh Tags

Substances

PMID: 39505896

search → result