Nontriglyceride hepatic lipotoxicity: the new paradigm for the pathogenesis of NASH.
Nontriglyceride hepatic lipotoxicity: the new paradigm for the pathogenesis of NASH.
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DOI：
10.1007/s11894-009-0083-6
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发表时间：
2010-02-01
影响因子：
--
通讯作者：
Neuschwander-Tetri, Brent A
中科院分区：
文献类型：
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作者：
Neuschwander-Tetri, Brent A
脂滴积聚和氧化应激曾被认为在非酒精性脂肪性肝炎（NASH）的发病机制中起重要作用，但实际上可能代表了平行的副现象。新出现的数据指出，非甘油三酯脂毒性和肝细胞损伤和细胞凋亡的复杂机制是目前公认的NASH疾病表型的主要贡献者。虽然肝脏脂毒性的特定介质尚未确定，但动物研究和人类最新数据的大量证据表明，肝脏中的游离脂肪酸可作为导致肝损伤的非甘油三酯脂毒性代谢物形成的底物。甘油三酯在液滴中的积累实际上可能是保护性的，因此针对脂肪积累作为唯一终点的治疗努力可能被误导。本文综述了支持非甘油三酯脂肪酸代谢产物在引起NASH中的作用以及脂肪和肌肉胰岛素抵抗如何导致肝脏脂毒性的新证据。
Lipid droplet accumulation and oxidant stress, once thought to play essential roles in the pathogenesis of nonalcoholic steatohepatitis (NASH), may actually represent parallel epiphenomena. Emerging data now point to nontriglyceride lipotoxicity and complex mechanisms of hepatocyte injury and apoptosis as the major contributors to the disease phenotype currently recognized as NASH. Although specific mediators of hepatic lipotoxicity have not been identified with certainty, abundant evidence from animal studies and recent data in humans indicate that free fatty acids in the liver can serve as substrates for formation of nontriglyceride lipotoxic metabolites that cause liver injury. The accumulation of triglyceride in droplets may actually be protective, and thus therapeutic efforts directed at fat accumulation as a sole endpoint may be misguided. This review examines the new evidence supporting the role of nontriglyceride fatty acid metabolites in causing NASH and how adipose and muscle insulin resistance contribute to hepatic lipotoxicity.