AS160 is a Lipid-responsive Regulator of Cardiac Ca Homeostasis by Controlling Lysophosphatidylinositol Metabolism and Signaling

Overview

Journal Nat Commun

Specialty Biology

Date 2024 Nov 6

PMID 39505896

Authors

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

Affiliations

Soon will be listed here.

Abstract

The obese heart undergoes metabolic remodeling and exhibits impaired calcium (Ca) 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 Ca 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 Ca that subsequently impairs cardiac contractility. Mechanistically, Rab8a downstream of AS160 interacts with DDHD1 to increase lysophosphatidylinositol metabolism and signaling that leads to Ca 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 Ca homeostasis in obese heart, and have therapeutic implications to combat obesity cardiomyopathy.

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