| First Author | Su S | Year | 2024 |
| Journal | Nat Commun | Volume | 15 |
| Issue | 1 | Pages | 9602 |
| PubMed ID | 39505896 | Mgi Jnum | J:379836 |
| Mgi Id | MGI:7778844 | Doi | 10.1038/s41467-024-54031-5 |
| Citation | Su S, et al. (2024) AS160 is a lipid-responsive regulator of cardiac Ca(2+) homeostasis by controlling lysophosphatidylinositol metabolism and signaling. Nat Commun 15(1):9602 |
| abstractText | 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. |
