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

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.