<b>Excessive free fatty acids sensing in pituitary lactotrophs elicits steatotic liver disease by decreasing prolactin levels</b>

Pituitary is the central endocrine gland with effects on metabolic dysfunction-associated steatotic liver disease (MASLD). However, it’s not clear whether the pituitary responds to free fatty acids (FFAs) toxicity, thus dysregulating hepatic lipid metabolism. Here, we demonstrated that elevated FFAs levels increased the risk of MASLD mediating by decreased prolactin (PRL) levels in a liver biospecimen-based cohort. Moreover, overloaded FFAs decreased serum PRL levels thus promoted liver steatosis both in mice with dynamic diets intervention and stereotactic pituitary FFAs injection. Mechanic studies showed that increased CD36 expression in pituitary lactotrophs inhibited the synthesis of PRL by enhancing FFAs sensing through lipid uptake assays and virus transfection analysis. Importantly, silencing of pituitary CD36 by stereotactic virus injection, as well as by a pituitary-targeted drug delivery system of TRH-PEG-LP-SSO, efficiently elevated PRL levels and alleviated liver steatosis. Targeted inhibition of pituitary FFAs sensing may be a potential therapeutic target for liver steatosis.</p