Osteoprotegerin Promotes Liver Steatosis by Targeting the ERK-PPAR-γ-CD36 Pathway
Osteoprotegerin Promotes Liver Steatosis by Targeting the ERK-PPAR-γ-CD36 Pathway
复制标题
骨保护素通过靶向 ERK-PPARγ-CD36 途径促进肝脏脂肪变性
DOI：
10.2337/db18-1055
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发表时间：
2019-10-01
期刊：
影响因子：
7.7
通讯作者：
Yang, Gangyi
中科院分区：
文献类型：
--
作者：
Zhang, Cheng;Luo, Xiaohe;Yang, Gangyi
先前的横断面研究已经确定循环中的骨保护素（OPG）水平与非酒精性脂肪肝（NAFLD）相关。然而，OPG在代谢性疾病（如糖尿病和NAFLD）中的作用仍不清楚。在目前的研究中，我们证明了肝脏OPG表达下调NAFLD个体和肥胖小鼠。在OPG（-/-）小鼠肝脏和培养细胞中，OPG缺乏分别降低脂质蓄积和CD 36和过氧化物酶体增殖物激活受体-γ（PPAR-gamma）的表达，而OPG过度表达则引起相反的效应。从CD 36（-/-）小鼠分离的肝细胞中CD 36失活可阻断OPG在脂质积聚中的刺激作用。OPG过表达导致OPG（-/-）小鼠肝脏和培养细胞中细胞外信号调节激酶（ERK）磷酸化水平降低，而OPG缺乏则相反。抑制PPAR-gamma或激活ERK可阻断OPG对培养细胞CD 36表达的诱导作用。在机制上，OPG通过作用于CD 36启动子上的PPAR反应元件（PPRE）促进CD 36表达。综上所述，我们的研究表明，OPG信号通过ERK-PPAR-γ-CD 36通路促进肝脏脂肪变性。NAFLD时OPG的下调可能是机体对肥胖时肝脏脂肪过度堆积的一种代偿反应。
Previous cross-sectional studies have established that circulating osteoprotegerin (OPG) levels are associated with nonalcoholic fatty liver disease (NAFLD). However, the role of OPG in metabolic diseases, such as diabetes and NAFLD, is still unclear. In the current study, we demonstrated that hepatic OPG expression was downregulated in NAFLD individuals and in obese mice. OPG deficiency decreased lipid accumulation and expression of CD36 and peroxisome proliferator-activated receptor-gamma (PPAR-gamma) in the livers of OPG(-/-) mice and cultured cells, respectively, whereas OPG overexpression elicited the opposite effects. The stimulatory role of OPG in lipid accumulation was blocked by CD36 inactivation in hepatocytes isolated from CD36(-/-) mice. The overexpression of OPG led to a decrease in extracellular signal-regulated kinase (ERK) phosphorylation in the livers of OPG(-/-) mice and in cultured cells, while OPG deficiency resulted in the opposite effect. The inhibition of PPAR-gamma or the activation of ERK blocked the induction of CD36 expression by OPG in cultured cells. Mechanistically, OPG facilitated CD36 expression by acting on PPAR response element (PPRE) present on the CD36 promoter. Taken together, our study revealed that OPG signaling promotes liver steatosis through the ERK-PPAR-gamma-CD36 pathway. The downregulation of OPG in NAFLD might be a compensatory response of the body to dampen excess hepatic fat accumulation in obesity.