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α-Ketoglutarate Promotes Hepatic Steatosis by Enhancing Cidec Stability via Lactylation–Ubiquitination Crosstalk

(AKG), a key tricarboxylic acid cycle intermediate, is widely consumed as a dietary supplement by healthy individuals for its perceived anti-aging and performance-enhancing benefits. While its antidiabetic and anti-obesity effects have been reported under pathological conditions, the safety profile and mechanisms of long-term AKG intake in healthy animals remain largely unexplored. Here, we demonstrate that long-term AKG intake via food or drinking water markedly elevates hepatic triglyceride levels and induces steatosis in healthy mice by suppressing adipose triglyceride lipase (Atgl) activity. The lipid-droplet-associated protein, cell death-inducing DNA fragmentation factor 45-like effector C (Cidec), is an inhibitor of Atgl. We find that AKG stabilizes Cidec by attenuating tripartite-motif protein 21-mediated ubiquitination.

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