GADD45β inhibits hepatic lipogenesis through the AMPK/SREBP1 pathway via reducing the ubiquitination-mediated degradation of SIRT1

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Metabolic dysfunction-associated steatotic liver disease (MASLD) is a globally increasing metabolic disorder associated with serious health complications. The molecular mechanisms linking stress-response proteins to hepatic lipogenesis in MASLD remain poorly understood. Here, we identified GADD45β as a key suppressor of de novo lipogenesis through SIRT1 stabilization. In both methionine-choline-deficient (MCD) diet-fed mice and palmitic acid (PA)-treated hepatocytes, GADD45β deficiency exacerbated lipid accumulation and upregulated lipogenic genes (SREBP1, FASN, ACC). Mechanistically, GADD45β directly bound to SIRT1 and inhibited its ubiquitination, thereby prolonging SIRT1 protein stability. Enhanced SIRT1 stability increased AMPK phosphorylation, which suppressed SREBP1-mediated transcription of lipogenic targets. Crucially, hepatic overexpression of GADD45β reversed PA-induced steatosis in vitro. Our study uncovered a GADD45β/SIRT1-/AMPK axis as a central regulator of hepatic lipogenesis, proposing GADD45β as a therapeutic target for MASLD.

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