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

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 () and Shuai Chen ()
Additional contact information
Shu Su: Nanjing University
Chao Quan: Nanjing University
Qiaoli Chen: Nanjing University
Ruizhen Wang: Nanjing University
Qian Du: Nanjing University
Sangsang Zhu: Nanjing University
Min Li: Nanjing University
Xinyu Yang: Nanjing University
Ping Rong: Nanjing University
Jiang Chen: Nanjing University
Yingyu Bai: Tianjin Medical University
Wen Zheng: Peking University
Weikuan Feng: Nanjing University
Minjun Liu: Nanjing University
Bingxian Xie: Nanjing University
Kunfu Ouyang: Peking University Shenzhen Hospital
Yun Stone Shi: Nanjing University
Feng Lan: Beijing Anzhen Hospital, Capital Medical University
Xiuqin Zhang: Peking University
Ruiping Xiao: Peking University
Xiongwen Chen: Tianjin Medical University
Hong-Yu Wang: Nanjing University
Shuai Chen: Nanjing University

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-54031-5

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