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Costunolide reduces glycolysis-associated activation of hepatic stellate cells via inhibition of hexokinase-2.
Cellular & Molecular Biology Letters ( IF 9.2 ) Pub Date : 2019-08-14 , DOI: 10.1186/s11658-019-0179-4
Dujing Ban 1, 2 , Shangbo Hua 3 , Wen Zhang 2 , Chao Shen 2 , Xuehua Miao 2 , Wensheng Liu 2
Affiliation  

BACKGROUND Hepatic stellate cell (HSC) activation is a central event during hepatic fibrosis. Aerobic glycolysis is one of its metabolic hallmarks. Blocking glycolysis is a novel therapeutic option for liver fibrosis. This study investigated the effects of costunolide, a natural product demonstrated to have hepatoprotective effects, on HSC activation and glycolysis. METHODS Primary HSCs were isolated from rats and cultured through 5 to 6 passages. Cell viability, activation markers, and glycolytic metabolism were examined in primary HSCs using various cellular and molecular approaches. RESULTS At 30 μM, costunolide reduced the viability of HSCs and inhibited the expression of α-smooth muscle actin and collagen I, two key markers of HSC activation. It also decreased glucose uptake and consumption, and reduced the intracellular levels of lactate in HSCs. At 10 mM, the glycolysis inhibitor 2-DG had a similar impact to costunolide at 30 μM: it significantly downregulated the expression of HSC activation markers. The combination of the two compounds produced more remarkable effects. Furthermore, costunolide repressed the expression and activity of hexokinase 2 (HK2), a pivotal rate-limiting enzyme that regulates glycolysis. However, overexpression of HK2 via plasmid transfection significantly reversed the costunolide-mediated downregulation of activation markers in HSCs, indicating that suppression of HK2 was required for costunolide to inhibit glycolysis-associated HSC activation. CONCLUSIONS Our results show that costunolide can suppress HSC activation, and this is associated with inhibition of HK2, which blocks aerobic glycolysis. This suggests that costunolide is an antifibrotic candidate with potential for further development.

中文翻译:

Costunolide 通过抑制 hexokinase-2 减少与糖酵解相关的肝星状细胞活化。

背景技术肝星状细胞(HSC)活化是肝纤维化期间的中心事件。有氧糖酵解是其代谢标志之一。阻断糖酵解是肝纤维化的一种新的治疗选择。本研究调查了一种天然产物 cosunolide 对 HSC 活化和糖酵解的影响,这种天然产物被证明具有保肝作用。方法分离大鼠原代HSCs,传代5~6代。使用各种细胞和分子方法在原代 HSC 中检查细胞活力、活化标志物和糖酵解代谢。结果 在 30 μM 时,costunolide 降低了 HSC 的活力并抑制了 α-平滑肌肌动蛋白和胶原蛋白 I(HSC 活化的两个关键标志物)的表达。它还减少了葡萄糖的摄取和消耗,并降低 HSC 中的细胞内乳酸水平。在 10 mM 时,糖酵解抑制剂 2-DG 与 30 μM 时的 costunolide 具有相似的影响:它显着下调 HSC 激活标志物的表达。这两种化合物的组合产生了更显着的效果。此外,costunolide 抑制己糖激酶 2 (HK2) 的表达和活性,这是一种调节糖酵解的关键限速酶。然而,通过质粒转染的 HK2 过表达显着逆转了 HSC 中 cosunolide 介导的活化标志物下调,表明抑制 HK2 是 costunolide 抑制糖酵解相关 HSC 活化所必需的。结论 我们的结果表明,costunolide 可以抑制 HSC 活化,这与抑制有氧糖酵解的 HK2 的抑制有关。
更新日期:2019-11-01
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