AI Article Synopsis
- Adiponectin is an important protein that helps protect the heart and metabolic functions, but its levels are regulated by various mechanisms, including the role of 5-InsP7, generated by the enzyme IP6K1.
- Deletion or inhibition of IP6K1 leads to increased levels of adiponectin in the body, which enhances the protection against heart injury caused by ischemia-reperfusion.
- The study suggests that targeting 5-InsP7 could be a potential strategy for increasing adiponectin levels and providing cardioprotective effects.
Article Abstract
Aims: Adiponectin is an adipocyte-derived circulating protein that exerts cardiovascular and metabolic protection. Due to the futile degradation of endogenous adiponectin and the challenges of exogenous administration, regulatory mechanisms of adiponectin biosynthesis are of significant pharmacological interest.
Methods And Results: Here, we report that 5-diphosphoinositol 1,2,3,4,6-pentakisphosphate (5-InsP7) generated by inositol hexakisphosphate kinase 1 (IP6K1) governed circulating adiponectin levels via thiol-mediated protein quality control in the secretory pathway. IP6K1 bound to adiponectin and DsbA-L and generated 5-InsP7 to stabilize adiponectin/ERp44 and DsbA-L/Ero1-Lα interactions, driving adiponectin intracellular degradation. Depleting 5-InsP7 by either IP6K1 deletion or pharmacological inhibition blocked intracellular adiponectin degradation. Whole-body and adipocyte-specific deletion of IP6K1 boosted plasma adiponectin levels, especially its high molecular weight forms, and activated AMPK-mediated protection against myocardial ischaemia-reperfusion injury. Pharmacological inhibition of 5-InsP7 biosynthesis in wild-type but not adiponectin knockout mice attenuated myocardial ischaemia-reperfusion injury.
Conclusion: Our findings revealed that 5-InsP7 is a physiological regulator of adiponectin biosynthesis that is amenable to pharmacological intervention for cardioprotection.
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|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11218692 | PMC |
| http://dx.doi.org/10.1093/cvr/cvae017 | DOI Listing |
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