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 (Ca 2+ ) 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 2+ 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 2+ that subsequently impairs cardiac contractility. Mechanistically, Rab8a downstream of AS160 interacts with DDHD1 to increase lysophosphatidylinositol metabolism and signaling that leads to Ca 2+ 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 2+ homeostasis in obese heart, and have therapeutic implications to combat obesity cardiomyopathy. How obesity causes cardiac dysfunction is not fully understood. Here, the authors show that a high fat diet inhibits the activity of RabGAP AS160 in the heart, causing pathological metabolic remodeling and altering calcium signaling.