Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, China; Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, China; Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, China.
Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, China; Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, China; Scientific Center, Shandong Provincial Hospital Affiliated to Shandong University, China.
Biochem Biophys Res Commun. 2018 Apr 6;498(3):693-699. doi: 10.1016/j.bbrc.2018.03.048. Epub 2018 Mar 16.
Increasing prevalence of non-alcoholic fatty liver disease (NAFLD) worldwide has necessitated a more thorough understanding of it and expanded the scope of research in this field. Women are more resistant to NAFLD than men despite equal exposure to major risk factors, such as obesity or hyperlipidemia. Female resistance is hormone-dependent, as evidenced by the sharp increase in NAFLD incidence in post-menopausal women who do not take hormone replacement therapy. Here, we found that the estrogen-responsive pituitary hormone prolactin (PRL), through specific PRL receptor (PRLR), down-regulates hepatic triglyceride (TG) accumulation. PRL was demonstrated to significantly down-regulate hepatic TG accumulation in female mice and protect male mice from liver steatosis induced by high-fat diet. Interestingly, Ad-shPRLR injected mice, whose hepatic PRLR abundance was effectively decreased at the protein levels, exhibited significantly aggravated liver steatosis. PRL could decrease the expression of stearoyl-coenzyme A desaturase 1 (SCD1), the rate-limiting enzyme in the biosynthesis of monounsaturated fatty acids, in animal models and multiple hepatic cell lines. Following knockdown of PRLR, the changes to PRL-triggered SCD1 expression disappeared. Thus, PRL acted as a previously unrecognized master regulator of liver TG metabolism, indicating that modification of PRL via PRLR might serve as a potential therapeutic target for NAFLD.
全球范围内非酒精性脂肪性肝病（NAFLD）的患病率不断上升，这就需要我们更深入地了解这种疾病，并扩大该领域的研究范围。尽管女性与男性面临着同样的主要风险因素，如肥胖或高血脂，但她们比男性更能抵抗 NAFLD。女性的这种抵抗力是依赖于激素的，这可以从绝经后不接受激素替代疗法的女性中 NAFLD 发病率的急剧上升得到证明。在这里，我们发现雌激素反应性垂体激素催乳素（PRL）通过特定的 PRL 受体（PRLR），下调肝甘油三酯（TG）的积累。研究表明，PRL 可显著下调雌性小鼠的肝 TG 积累，并防止雄性小鼠因高脂肪饮食引起的肝脂肪变性。有趣的是，Ad-shPRLR 注射小鼠，其肝 PRLR 丰度在蛋白水平上被有效降低，表现出明显加重的肝脂肪变性。PRL 可以降低动物模型和多种肝细胞系中硬脂酰辅酶 A 去饱和酶 1（SCD1）的表达，SCD1 是单不饱和脂肪酸生物合成中的限速酶。在敲低 PRLR 后，PRL 触发的 SCD1 表达变化消失了。因此，PRL 作为肝 TG 代谢的一个以前未被识别的主调控因子发挥作用，这表明通过 PRLR 修饰 PRL 可能成为 NAFLD 的潜在治疗靶点。
