Growth differentiation factor 15 ameliorates nonalcoholic steatohepatitis and related metabolic disorders in mice.
Growth differentiation factor 15 ameliorates nonalcoholic steatohepatitis and related metabolic disorders in mice.
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DOI：
10.1038/s41598-018-25098-0
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发表时间：
2018-05-01
影响因子：
4.6
通讯作者：
Lee MS
中科院分区：
文献类型：
--
作者：
Kim KH;Kim SH;Han DH;Jo YS;Lee YH;Lee MS
生长分化因子15（GDF 15）是一种内分泌激素，属于TGFβ超家族成员。已经报道GDF 15施用或GDF 15过表达具有抗肥胖和抗糖尿病作用。虽然非酒精性脂肪性肝病（NAFLD）/非酒精性脂肪性肝炎（NASH）经常与肥胖和胰岛素抵抗相关，但内源性GDF 15的功能作用和GDF 15过表达在NASH和相关代谢恶化中的治疗效果尚未评估。在这里，我们发现NASH动物模型和患有NASH的人类受试者的肝脏中GDF 15表达增加。GDF 15的高表达是由于饮食诱导的肝内质网（ER）应激。Gdf 15敲除小鼠表现出加重的NASH表型，如脂肪变性增加、肝脏炎症、纤维化、肝损伤和代谢恶化。此外，GDF 15直接抑制肝星状细胞（体外）和小鼠肝脏（体内）中纤维化相关基因和骨桥蛋白（OPN）（NASH相关纤维化的促成因素）的表达。最后，我们发现GDF 15转基因小鼠表现出NASH表型的减弱和代谢恶化。因此，我们的研究结果表明，内源性GDF 15的诱导是一种代偿机制，以防止NASH的进展，GDF 15可能是一个有吸引力的治疗NASH和NASH相关的代谢恶化的治疗候选人。
Growth differentiation factor 15 (GDF15) is an endocrine hormone belonging to the TGFβ superfamily member. GDF15 administration or GDF15 overexpression has been reported to have anti-obesity and anti-diabetic effects. Although non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) is frequently associated with obesity and insulin resistance, the functional role of endogenous GDF15 and therapeutic effect of GDF15 overexpression in NASH and related metabolic deterioration have not been evaluated. Here, we found that GDF15 expression was increased in the livers of NASH animal models and human subjects with NASH. Elevated expression of GDF15 was due to diet-induced hepatic endoplasmic reticulum (ER) stress. Gdf15-knockout mice exhibited aggravated NASH phenotypes such as increased steatosis, hepatic inflammation, fibrosis, liver injury, and metabolic deterioration. Furthermore, GDF15 directly suppressed expression of fibrosis-related genes and osteopontin (OPN), contributing factors for NASH-related fibrosis, in hepatic stellate cells in vitro and in the liver of mice in vivo. Finally, we found that GDF15-transgenic mice showed attenuation of NASH phenotypes and metabolic deterioration. Therefore, our results suggest that induction of endogenous GDF15 is a compensatory mechanism to protect against the progression of NASH and that GDF15 could be an attractive therapeutic candidate for treatment of NASH and NASH-related metabolic deterioration.
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