Max Planck Institute for Metabolism Research, Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), Cologne, 50931, Germany.
Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), Germany; Max Planck Institute for Biology of Ageing, Cologne, 50931, Germany.
Mol Metab. 2018 Nov;17:122-133. doi: 10.1016/j.molmet.2018.08.010. Epub 2018 Sep 5.
The current obesity pandemic represents a major health burden, given that it predisposes to the development of numerous obesity-associated disorders. The obesity-derived adipokines not only impair systemic insulin action but also increase the incidence of hepatocellular carcinoma (HCC), a highly prevalent cancer with poor prognosis. Thus, worldwide incidences of HCC are expected to further increase, and defining the molecular as well as cellular mechanisms will allow for establishing new potential treatment options. The adipose tissue of obese individuals increases circulating leptin and interleukin-6 (IL-6) levels, which both share similar signaling capacities such as Signal Transducer and Activator of Transcription 3 (STAT3) and Phosphoinositide 3-kinase (PI3K)/Akt activation. While mouse models with deficient IL-6 signaling show an ameliorated but not absent Diethylnitrosamine (DEN)-induced HCC development, the morbid obesity in mice with mutant leptin signaling complicates the dissection of hepatic leptin receptor (LEPR) and IL-6 signaling in HCC development. Here we have investigated the function of compensating hepatic LEPR expression in HCC development of IL-6Rα-deficient mice.
We generated and characterized a mouse model of hepatic LEPR deficiency that was intercrossed with IL-6Rα-deficient mice. Cohorts of single and double knockout mice were subjected to the DEN-HCC model to ascertain liver cancer development and characterize metabolic alterations.
We demonstrate that both high-fat diet (HFD)-induced obesity and IL-6Rα deficiency induce hepatic Lepr expression. Consistently, double knockout mice show a further reduction in tumor burden in DEN-induced HCC when compared to control and single LepR/IL-6Rα knock out mice, whereas metabolism remained largely unaltered between the genotypes.
Our findings reveal a compensatory role for hepatic LEPR in HCC development of IL-6Rα-deficient mice and suggest hepatocyte-specific leptin signaling as promoter of HCC under obese conditions.
当前的肥胖流行是一个主要的健康负担，因为它易导致许多与肥胖相关的疾病的发生。肥胖相关的脂肪因子不仅损害全身胰岛素作用，而且增加肝细胞癌（HCC）的发生率，HCC 是一种具有较差预后的高发癌症。因此，预计全球 HCC 的发病率将进一步增加，确定分子和细胞机制将为建立新的潜在治疗选择提供依据。肥胖个体的脂肪组织增加了循环瘦素和白细胞介素-6（IL-6）的水平，这两者都具有相似的信号转导能力，如信号转导和转录激活因子 3（STAT3）和磷酸肌醇 3-激酶（PI3K）/ Akt 激活。虽然缺乏 IL-6 信号的小鼠模型显示出 DEN 诱导的 HCC 发展得到改善，但突变型瘦素信号的肥胖小鼠使肝瘦素受体（LEPR）和 IL-6 信号在 HCC 发展中的解析复杂化。在这里，我们研究了补偿性肝 LEPR 表达在 IL-6Rα缺陷型小鼠 HCC 发展中的功能。
我们生成并鉴定了一种肝 LEPR 缺陷型小鼠模型，该模型与 IL-6Rα缺陷型小鼠进行了杂交。单和双敲除小鼠的队列被用于 DEN-HCC 模型以确定肝癌的发展并描述代谢改变。
我们证明高脂肪饮食（HFD）诱导的肥胖和 IL-6Rα缺乏均诱导肝 Lepr 表达。一致地，与对照和单 LepR/IL-6Rα敲除小鼠相比，双敲除小鼠在 DEN 诱导的 HCC 中肿瘤负担进一步降低，而基因型之间的代谢仍基本未改变。
我们的研究结果揭示了肝 LEPR 在 IL-6Rα缺陷型小鼠 HCC 发展中的代偿作用，并表明肥胖条件下肝特异性瘦素信号作为 HCC 的促进因子。
