Tardelli Matteo, Moreno-Viedma Veronica, Zeyda Maximilian, Itariu Bianca K, Langer Felix B, Prager Gerhard, Stulnig Thomas M
Christian Doppler-Laboratory for Cardio-Metabolic Immunotherapy and Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
Department of Surgery, Division of General Surgery, Medical University of Vienna, Vienna, Austria.
J Gastroenterol Hepatol. 2017 Jan;32(1):253-260. doi: 10.1111/jgh.13415.
Obesity is a major risk factor for liver fibrosis and tightly associated with low levels of adiponectin. Adiponectin has antifibrogenic activity protecting from liver fibrosis, which is mainly driven by activated hepatic stellate cells (HSC). Aquaporins are transmembrane proteins that allow the movement of water and, in case of aquaglyceroporins (AQPs), of glycerol that is needed in quiescent HSC for lipogenesis. Expression of various AQPs in liver is altered by obesity; however, the mechanisms through which obesity influences HSCs activation and AQPs expression remain unclear. This study aimed to identify obesity-associated factors that are related to HSC AQPs expression activation and lipid storage.
Correlations between serum adipokine levels and hepatic AQPs gene expression were analyzed from a cohort of obese patients. AQP and fibrotic gene expression was determined in a HSC line (LX2) and in a hepatocyte cell line (HepG2) after stimulation with adiponectin using quantitative real-time polymerase chain reaction.
We found that serum adiponectin significantly correlated with liver AQP3, AQP7, AQP9 gene expressions. In vitro, adiponectin induced upregulation of AQP3 gene and AQP3 protein expression in human HSCs, but not in hepatocytes, while AQP7, AQP9 remained undetectable. Accordingly, HSC stimulated with adiponectin increased glycerol uptake, lipogenic gene expression, and lipid storage while downregulating activation/fibrosis markers.
These findings demonstrate that adiponectin is a potent inhibitor of HSC activation and induces AQPs expression. Thus, low serum levels of adiponectin could be a mechanism how obesity affects the functional state of HSC, thereby contributing to obesity-associated liver fibrosis.
肥胖是肝纤维化的主要危险因素，且与脂联素水平降低密切相关。脂联素具有抗纤维化活性，可保护肝脏免受纤维化影响，这主要由活化的肝星状细胞（HSC）驱动。水通道蛋白是跨膜蛋白，可允许水移动，而对于水甘油通道蛋白（AQP），还可允许甘油移动，静止的HSC进行脂肪生成需要甘油。肥胖会改变肝脏中各种AQP的表达；然而，肥胖影响HSC活化和AQP表达的机制仍不清楚。本研究旨在确定与HSC AQP表达活化和脂质储存相关的肥胖相关因素。
分析一组肥胖患者血清脂肪因子水平与肝脏AQP基因表达之间的相关性。使用定量实时聚合酶链反应，在脂联素刺激后，测定HSC系（LX2）和肝细胞系（HepG2）中AQP和纤维化基因的表达。
我们发现血清脂联素与肝脏AQP3、AQP7、AQP9基因表达显著相关。在体外，脂联素可诱导人HSC中AQP3基因上调和AQP3蛋白表达增加，但在肝细胞中无此作用，而AQP7、AQP9仍无法检测到。因此，用脂联素刺激的HSC增加了甘油摄取、脂肪生成基因表达和脂质储存，同时下调了活化/纤维化标志物。
这些发现表明脂联素是HSC活化的有效抑制剂，并诱导AQP表达。因此，血清脂联素水平低可能是肥胖影响HSC功能状态的一种机制，从而导致肥胖相关的肝纤维化。
