Duan Na-Na, Liu Xue-Jing, Wu Jian
Dept. of Medical Microbiology, Key Laboratory of Molecular Virology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
Dept. of Medical Microbiology, Key Laboratory of Molecular Virology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Shanghai Institute of Liver Diseases, Fudan University, Shanghai 200032, China.
Life Sci. 2017 May 1;176:42-53. doi: 10.1016/j.lfs.2017.03.012. Epub 2017 Mar 18.
Activation of hepatic stellate cells (HSCs) plays a pivotal role at the center of the fibrogenic progression in nonalcoholic steatohepatitis (NASH). However, it is poorly understood that how various molecules interact within HSCs during the progression of NASH to fibrosis. The aim of the present study is to delineate how inflammasome molecules, hedgehog signaling and autophagy provoke HSC activation using palmitic acid (PA) as a major insult.
Inflammasome activation, hedgehog signaling activity and autophagy in PA-exposed HSCs were determined to investigate their role in activation of human and rodent HSC lines or primary HSCs.
PA treatment elicited HSC activation reflected by increased mRNA levels of transforming growth factor-β1, connective tissue growth factor, tissue inhibitor of metalloproteinase-1 and procollagen type I (α1). In addition, expression levels of NOD-like receptor protein 3 (NLRP3) and hedgehog signaling transcription factor Gli-1 were increased in PA-exposed HSCs. It's evident that PA treatment resulted in increased production of light chain 3-II and autophagosomes, as well as enhanced autophagy flux reflected by transduction of an adeno-associated viral vector. Whereas, reduced autophagy, which is often seen in the late stage of NASH, provoked inflammasome activation. Moreover, suppressing the Hh signaling pathway by LDE225 blocked production of light chain 3-II and autophagy flux.
Saturated fatty acids, such as PA, stimulate HSC activation through inflammasomes and hedgehog signaling. Meanwhile, compromised autophagy may facilitate HSC activation, implicating valuable candidates for pharmacologic intervention against the progression of fibrogenesis in NASH.
肝星状细胞（HSCs）的激活在非酒精性脂肪性肝炎（NASH）纤维化进展过程中起着关键作用。然而，在NASH向纤维化进展过程中，各种分子如何在肝星状细胞内相互作用却鲜为人知。本研究的目的是利用棕榈酸（PA）作为主要损伤因素，阐明炎性小体分子、刺猬信号通路和自噬如何引发肝星状细胞激活。
测定PA处理的肝星状细胞中的炎性小体激活、刺猬信号通路活性和自噬，以研究它们在人及啮齿动物肝星状细胞系或原代肝星状细胞激活中的作用。
PA处理引发肝星状细胞激活，表现为转化生长因子-β1、结缔组织生长因子、金属蛋白酶组织抑制剂-1和I型前胶原（α1）的mRNA水平升高。此外，PA处理的肝星状细胞中NOD样受体蛋白3（NLRP3）和刺猬信号转录因子Gli-1的表达水平增加。显然，PA处理导致轻链3-II和自噬体的产生增加，以及腺相关病毒载体转导所反映的自噬通量增强。然而，在NASH晚期常见的自噬减少会引发炎性小体激活。此外，LDE225抑制刺猬信号通路可阻断轻链3-II的产生和自噬通量。
饱和脂肪酸如PA通过炎性小体和刺猬信号通路刺激肝星状细胞激活。同时，自噬受损可能促进肝星状细胞激活，这为针对NASH纤维化进展的药物干预提供了有价值的候选靶点。
