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

<b>Background &amp; Aims:</b> 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.<b>Methods:</b> 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.<b>Results:</b> Elevated levels of FFA increased the risk of NAFLD (OR 1.645, <i>p</i> &lt; 0.05), which was mediated by decreased PRL levels with a mediation effect of 29.1% (<i>p</i> &lt; 0.05). Moreover, elevation of FFA contributed to decreased serum PRL levels, thus promoted liver steatosis <i>in vivo</i>. 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.<b>Conclusions:</b> 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.

**研究背景与研究目的：** 目前已知，营养过剩相关的血清游离脂肪酸（free fatty acids, FFA）会对肝脏脂质代谢产生毒性作用。垂体作为中枢内分泌腺体，参与脂质代谢调控，但目前尚不清楚垂体是否会响应游离脂肪酸的毒性作用。本研究旨在探究垂体感知游离脂肪酸的作用及其对肝脏脂质代谢的调控机制。
**研究方法：** 本研究纳入328例经活检证实的受试者，分析垂体激素与非酒精性脂肪性肝病（non-alcoholic fatty liver disease, NAFLD）之间的关联。对小鼠实施动态饮食干预，并向其垂体进行立体定位注射游离脂肪酸。通过脂质摄取实验及沉默病毒转染，评估催乳素细胞（lactotrophs）感知游离脂肪酸的功能。采用荧光分析技术，检测TRH-PEG-LP-SSO靶向递送系统在垂体中的定位分布。构建垂体病毒注射模型及垂体靶向递送系统，以探究其对脂肪肝的治疗效果。
**研究结果：** 血清游离脂肪酸水平升高会增加非酒精性脂肪性肝病的发病风险（优势比OR=1.645，P<0.05），该作用可通过催乳素（prolactin, PRL）水平降低介导，中介效应占比为29.1%（P<0.05）。此外，体内实验证实，游离脂肪酸水平升高可降低血清催乳素水平，进而促进肝脏脂肪变性。机制研究显示，催乳素细胞中CD36表达上调可增强其对游离脂肪酸的感知与摄取能力，进而抑制催乳素的合成。值得注意的是，通过垂体立体定位病毒注射或TRH-PEG-LP-SSO靶向递送系统沉默垂体CD36的表达，可有效升高血清催乳素水平并减轻肝脏脂肪变性。
**研究结论：** 垂体催乳素细胞对游离脂肪酸的过度感知可通过下调催乳素的表达，在肝脏脂肪变性进程中发挥全新的调控作用。靶向抑制垂体对游离脂肪酸的感知，有望成为治疗肝脏脂肪变性的潜在靶点。