Fetuin‐b Mediates Lipid Overload‐Induced Hepatic Lipid Accumulation in Large Yellow Croaker ( <scp> <i>Larimichthys crocea</i> </scp> )

Fetuin-b is a nutritionally regulated hepatokine that critically influences hepatic lipid content. However, the precise mechanism by which it regulates lipid content remains elusive. Here, our experiments found that lipid overload conditions can upregulate the expression of large yellow croaker fetuin-b through activating the transcription factor C/EBPα. Moreover, under lipid overload conditions, overexpression of fetuin-b in vitro elevated hepatic triglyceride (TG) content, whereas knockdown of fetuin-b in vivo reduced TG content in hepatocytes. Mechanistically, fetuin-b elevated hepatic TG content by upregulating genes involved in lipogenesis, lipid intake, and lipid droplets (LDs) synthesis, while repressing those in fatty acid oxidation. Concurrently, fetuin-b might promote LDs expansion by inhibiting the ubiquitination of Plin2. Collectively, our findings reveal that nutritional lipid overload upregulates fetuin-b to drive hepatic lipid accumulation, providing a potential therapeutic target for diet-induced hepatic steatosis.