Arduini Alessandro, Serviddio Gaetano, Tormos Ana M, Monsalve Maria, Sastre Juan
Department of Physiology, School of Pharmacy, University of Valencia, Valencia, Spain.
Front Biosci (Elite Ed). 2012 Jan 1;4(6):2233-52. doi: 10.2741/539.
Cholestatic liver diseases are characterized by blockade of bile flow from the liver to the intestine, and accumulation of hydrophobic bile acids in the liver and plasma. As a consequence an inflammatory response evolves associated with increased apoptosis, oxidative stress, and eventually fibrosis. Cholestasis is associated with profound metabolic changes, alterations in the mitochondrial function, decreased fatty acid oxidation, and increased glycolisis. Mitochondria play a central role in the development of this liver disease because they mediate death receptor signaling - triggered by inflammatory cytokines or bile acids - and contribute to oxidative damage, metabolic disorder, and onset of fibrosis. During the pathogenesis of biliary cirrhosis mitochondria's need for renewal is hampered by a blunted mitochondrial biogenesis. Lack of stimulation of mitochondrial renewal helps to explain mitochondrial impairment in long-term cholestasis. The marked depletion of mitochondrial DNA and occurrence of mitochondrial DNA deletions are probably relevant contributors to the progression of this severe disease. All these findings certainly support the consideration of long-term cholestasis as a secondary mitochondrial hepatopathy.
胆汁淤积性肝病的特征是胆汁从肝脏流向肠道的过程受阻，疏水性胆汁酸在肝脏和血浆中蓄积。结果，炎症反应随之发生，伴有细胞凋亡增加、氧化应激，最终导致纤维化。胆汁淤积与深刻的代谢变化、线粒体功能改变、脂肪酸氧化减少和糖酵解增加有关。线粒体在这种肝病的发展中起核心作用，因为它们介导由炎性细胞因子或胆汁酸触发的死亡受体信号传导，并导致氧化损伤、代谢紊乱和纤维化的发生。在胆汁性肝硬化的发病过程中，线粒体的更新需求因线粒体生物发生减弱而受到阻碍。缺乏对线粒体更新的刺激有助于解释长期胆汁淤积中线粒体的损伤。线粒体DNA的显著消耗和线粒体DNA缺失的发生可能是这种严重疾病进展的相关因素。所有这些发现无疑支持将长期胆汁淤积视为继发性线粒体肝病。
