Excessive free fatty acids sensing in pituitary lactotrophs elicits liver steatosis by decreasing prolactin levels

Background & Aims: It has been known that overnutrition-associated elevation of serum free fatty acids (FFA) exerts toxic effects on hepatic lipid metabolism. Pituitary is the central endocrine gland with effects on lipid metabolism. However, it is not clear whether the pituitary responds to FFA toxicity. Herein, we aimed to investigate the role of FFA sensing in the pituitary, thus regulating hepatic lipid metabolism.
Methods: A cohort including 328 biopsy-proven subjects were analyzed to investigate the association between pituitary hormones and NAFLD. Dynamic diets intervention and stereotactic FFA injection targeted to mice pituitary were performed. Lipid uptake assays and silencing-viruses transfection were used to assess the role of FFA sensing in lactotrophs. Fluorescence analysis was used to assess localization of SSO delivery system (TRH-PEG-LP-SSO) in pituitary. Virus injection in pituitary and pituitary-targeted delivery system was developed to investigate the therapeutic effects on fatty liver.
Results: Elevated levels of FFA increased the risk of NAFLD (OR 1.645, p < 0.05), which was mediated by decreased PRL levels with a mediation effect of 29.1% (p < 0.05). Moreover, elevation of FFA contributed to decreased serum PRL levels, thus promoted liver steatosis in vivo. Mechanic studies showed that increased CD36 expression in lactotrophs enhanced FFA sensing and uptake, thus inhibited the synthesis of PRL. Importantly, silencing of pituitary CD36 by stereotactic virus injection, as well as by the targeted drug delivery system of TRH-PEG-LP-SSO, could efficiently elevate PRL levels and alleviate liver steatosis.
Conclusions: Excessive FFA sensing in pituitary lactotrophs plays new roles in liver steatosis by decreasing PRL expression. Targeted inhibition of FFA sensing in pituitary may be a potential therapeutic target for liver steatosis.