Objective

Long-term glucocorticoids (GCs) therapy usually causes many metabolic side effects, including fatty liver. However, the molecular mechanisms remain poorly understood. Herein, we explored the molecular basis of GCs in the development of fatty liver.

Methods

C57BL/6 male mice were injected with Dexamethasone (DEX) while mouse primary hepatocytes (MPHs), HepG2 and Hep1-6 cells were cultured in the presence of DEX. Genes expression in liver tissues and hepatocytes were assessed by quantitative real-time PCR and western blotting, respectively. To explore whether Periostin is involved in the development of GCs-induced fatty liver, wild-type and Periostin knockout mice were treated with DEX or vehicle control. Luciferase reporter and chromatin immunoprecipitation assays were used to determine the regulatory roles of GCs on Periostin expression.

Results

We show that treatment of dexamethasone (DEX), a synthetic analog of GCs, led to the accumulation of triglycerides in the livers of mice, but not in cultured hepatocytes, suggesting that GCs may promote liver steatosis through integrative organ crosstalk mediated by systemic factors. We further found that DEX upregulated the expression levels of Periostin in white adipose tissues, which in turn promoted liver steatosis. Administration of a Periostin-neutralizing antibody or genetic ablation of Periostin largely attenuated DEX-induced hepatic steatosis in mice.

Conclusions

Our findings provided a novel insight that GCs could promote liver steatosis through integrative organ crosstalk mediated by white fat-secreted Periostin. These results establish Periostin as an endocrine factor with therapeutic potential for the treatment of GCs-associated fatty liver.

中文翻译：

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脂肪细胞来源的骨膜素介导小鼠糖皮质激素诱导的肝脂肪变性。

客观的

长期糖皮质激素（GCs）治疗通常会引起许多代谢性副作用，包括脂肪肝。但是，分子机制仍然知之甚少。在这里，我们探讨了GCs在脂肪肝发展中的分子基础。

方法

给C57BL / 6雄性小鼠注射地塞米松（DEX），同时在DEX存在下培养小鼠原代肝细胞（MPHs），HepG2和Hep1-6细胞。分别通过定量实时PCR和蛋白质印迹法评估肝组织和肝细胞中的基因表达。为了探索Periostin是否参与GC诱导的脂肪肝的发生，用DEX或媒介物对照治疗了野生型和Periostin基因敲除小鼠。使用萤光素酶报告基因和染色质免疫沉淀测定来确定GC对Periostin表达的调节作用。

结果

我们显示，地塞米松（DEX）（一种GC的合成类似物）的治疗导致小鼠肝脏中甘油三酸酯的积累，但未在培养的肝细胞中积累，这表明GC可能通过系统性因素介导的整合器官串扰促进肝脏脂肪变性。我们进一步发现，DEX上调了白色脂肪组织中骨膜素的表达水平，进而促进了肝脂肪变性。骨膜素中和抗体的施用或骨膜素的基因消融在很大程度上减轻了DEX诱导的小鼠肝脂肪变性。

结论

我们的发现提供了一种新颖的见解，认为气相色谱可以通过白脂分泌的骨膜素介导的整合器官串扰促进肝脏脂肪变性。这些结果将骨膜素确定为具有治疗GCs相关性脂肪肝的治疗潜力的内分泌因子。