Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China.
Department of General Surgery, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China.
J Hepatol. 2018 Jun;68(6):1247-1255. doi: 10.1016/j.jhep.2018.01.035. Epub 2018 Feb 13.
BACKGROUND & AIMS: Prolactin (PRL) is a multifunctional polypeptide with effects on metabolism, however, little is known about its effect on hepatic steatosis and lipid metabolism. Herein, we aimed to assess the role of PRL in the development of non-alcoholic fatty liver disease (NAFLD).
The serum PRL levels of 456 patients with NAFLD, 403 controls without NAFLD diagnosed by ultrasound, and 85 individuals with liver histology obtained during metabolic surgery (44 female and 30 male patients with NAFLD and 11 age-matched non-NAFLD female individuals) were evaluated. The expression of the gene encoding the prolactin receptor (PRLR) and signalling molecules involved in hepatic lipid metabolism were evaluated in human liver and HepG2 cells. The effects of overexpression of PRLR or fatty acid translocase (FAT)/CD36 or knockdown of PRLR on hepatic lipid metabolism were tested in free fatty acid (FFA)-treated HepG2 cells.
Circulating PRL levels were lower in individuals with ultrasound-diagnosed NAFLD (men: 7.9 [range, 5.9-10.3] µg/L; women: 8.7 [range, 6.1-12.4] µg/L) than those with non-NAFLD (men: 9.1 [range, 6.8-13.0] µg/L, p = 0.002; women: 11.6 [range, 8.2-16.1] µg/L, p <0.001). PRL levels in patients with biopsy-proven severe hepatic steatosis were lower compared with those with mild-to-moderate hepatic steatosis in both men (8.3 [range, 5.4-9.5] µg/L vs. 9.7 [range, 7.1-12.3] µg/L, p = 0.031) and women (8.5 [range, 4.2-10.6] µg/L vs. 9.8 [range, 8.2-15.7] µg/L, p = 0.027). Furthermore, hepatic PRLR gene expression was significantly reduced in patients with NAFLD and negatively correlated with CD36 gene expression. In FFA-induced HepG2 cells, PRL treatment or PRLR overexpression significantly reduced the expression of CD36 and lipid content, effects that were abrogated after silencing of PRLR. Furthermore, overexpression of CD36 significantly reduced the PRL-mediated improvement in lipid content.
Our results reveal a novel association between the central nervous system and the liver, whereby PRL/PRLR improved hepatic lipid accumulation via the CD36 pathway.
Our clinical study suggests a negative association between prolactin (PRL)/prolactin receptor (PRLR) and the presence of non-alcoholic fatty liver disease (NAFLD). Using cell experiments, we found that PRL ameliorates hepatic steatosis via the hepatic PRLR and fatty acid translocase (FAT)/CD36, a key transporter of free fatty acid uptake in liver. Our findings suggest a novel approach to improving NAFLD using PRL and PRLR. Clinical trial number: NCT03296605.
催乳素（PRL）是一种具有代谢作用的多功能多肽，但人们对其在肝脂肪变性和脂质代谢中的作用知之甚少。在此，我们旨在评估 PRL 在非酒精性脂肪性肝病（NAFLD）发展中的作用。
评估了 456 名 NAFLD 患者、403 名经超声诊断无 NAFLD 的对照者和 85 名在代谢手术中获得的肝组织学个体（44 名女性和 30 名男性 NAFLD 患者和 11 名年龄匹配的非 NAFLD 女性个体）的血清 PRL 水平。评估了人肝和 HepG2 细胞中编码催乳素受体（PRLR）的基因和参与肝脂质代谢的信号分子的表达。在游离脂肪酸（FFA）处理的 HepG2 细胞中，测试了 PRLR 过表达或脂肪酸转运蛋白（FAT）/CD36 过表达或 PRLR 敲低对肝脂质代谢的影响。
与非 NAFLD 个体相比，经超声诊断的 NAFLD 个体（男性：7.9 [范围，5.9-10.3] µg/L；女性：8.7 [范围，6.1-12.4] µg/L）的循环 PRL 水平较低（男性：9.1 [范围，6.8-13.0] µg/L，p=0.002；女性：11.6 [范围，8.2-16.1] µg/L，p<0.001）。与轻度至中度肝脂肪变性的患者相比，活检证实严重肝脂肪变性的患者的 PRL 水平较低，男性（8.3 [范围，5.4-9.5] µg/L 与 9.7 [范围，7.1-12.3] µg/L，p=0.031）和女性（8.5 [范围，4.2-10.6] µg/L 与 9.8 [范围，8.2-15.7] µg/L，p=0.027）。此外，NAFLD 患者的肝 PRLR 基因表达显著降低，与 CD36 基因表达呈负相关。在 FFA 诱导的 HepG2 细胞中，PRL 处理或 PRLR 过表达显著降低了 CD36 的表达和脂质含量，而 PRLR 沉默后，这些作用被阻断。此外，CD36 的过表达显著降低了 PRL 介导的脂质含量的改善。
我们的研究结果揭示了中枢神经系统与肝脏之间的新关联，即 PRL/PRLR 通过 CD36 途径改善肝脏脂质堆积。
我们的临床研究表明催乳素（PRL）/催乳素受体（PRLR）与非酒精性脂肪性肝病（NAFLD）的存在呈负相关。通过细胞实验，我们发现 PRL 通过肝 PRLR 和脂肪酸转运蛋白（FAT）/CD36 改善肝脂肪变性，FAT/CD36 是肝脏中摄取游离脂肪酸的关键转运蛋白。我们的研究结果表明，使用 PRL 和 PRLR 改善 NAFLD 是一种新方法。临床试验编号：NCT03296605。
