Chair of Pharmacology, Section of Medicine, University of Fribourg, CH-1700 Fribourg, Switzerland.
Biomolecules. 2020 Dec 18;10(12):1692. doi: 10.3390/biom10121692.
It is estimated that over 1.5 billion people suffer from various forms of chronic liver disease worldwide. The emerging prevalence of metabolic syndromes and alcohol misuse, along with the lack of disease-modifying agents for the therapy of many severe liver conditions predicts that chronic liver disease will continue to be a major problem in the future. Better understanding of the underlying pathogenetic mechanisms and identification of potential therapeutic targets remains a priority. Herein, we explored the potential role of the 3-mercaptopyruvate sulfurtransferase/hydrogen sulfide (HS) system in the regulation of the endoplasmic reticulum (ER) stress and of its downstream processes in the immortalized hepatic cell line HepG2 in vitro. ER stress suppressed endogenous HS levels and pharmacological supplementation of HS with sodium hydrogen sulfide (NaHS) mitigated many aspects of ER stress, culminating in improved cellular bioenergetics and prevention of autophagic arrest, thereby switching cells' fate towards survival. Genetic silencing of 3-MST or pharmacological inhibition of the key enzymes involved in hepatocyte HS biosynthesis exacerbated many readouts related to ER-stress or its downstream functional responses. Our findings implicate the 3-MST/HS system in the intracellular network that governs proteostasis and ER-stress adaptability in hepatocytes and reinforce the therapeutic potential of pharmacological HS supplementation.
据估计，全世界有超过 15 亿人患有各种形式的慢性肝病。代谢综合征和酒精滥用的流行率不断上升，而许多严重肝脏疾病的治疗方法缺乏疾病修饰剂，这预示着慢性肝病将在未来继续成为一个主要问题。更好地了解潜在的发病机制和确定潜在的治疗靶点仍然是当务之急。在此，我们探讨了 3-巯基丙酮酸硫转移酶/硫化氢（HS）系统在体外永生化肝细胞系 HepG2 中调节内质网（ER）应激及其下游过程中的潜在作用。内质网应激抑制内源性 HS 水平，用硫氢化钠（NaHS）进行 HS 的药理补充减轻了 ER 应激的许多方面，最终改善了细胞的生物能量学并防止自噬停滞，从而使细胞的命运转向存活。3-MST 的基因沉默或参与肝细胞 HS 生物合成的关键酶的药理抑制加剧了与 ER 应激或其下游功能反应相关的许多指标。我们的研究结果表明，3-MST/HS 系统参与了在肝细胞中调节蛋白质稳态和 ER 应激适应性的细胞内网络，并加强了药理 HS 补充的治疗潜力。
