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

SUBMITTER: Su S 

PROVIDER: S-EPMC11542008 | biostudies-literature | 2024 Nov

REPOSITORIES: biostudies-literature