Noureddin Mazen, Sanyal Arun J
Director, Fatty Liver Program and Associate Professor of Clinical Medicine, Division of Digestive and Liver Diseases, Comprehensive Transplant Program, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Professor of Medicine, Physiology and Molecular Pathology, Division of Gastroenterology, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
Curr Hepatol Rep. 2018 Dec;17(4):350-360. doi: 10.1007/s11901-018-0425-7. Epub 2018 Oct 31.
Advancing our understanding of the mechanisms that underlie NASH pathogenesis.
Recent findings on NASH pathogenesis have expanded our understanding of its complexity including: (1) there are multiple parallel hits that lead to NASH; (2) the microbiota play an important role in pathogenesis, with bacterial species recently shown to accurately differentiate between NAFL and NASH patients; (3) the main drivers of liver cell injury are lipotoxicity caused by free fatty acids (FFAs) and their derivatives combined with mitochondrial dysfunction; (4) decreased endoplasmic reticulum (ER) efficiency with increased demand for protein synthesis/folding/repair results in ER stress, protracted unfolded protein response, and apoptosis; (5) upregulated proteins involved in multiple pathways including JNK, CHOP, PERK, BH3-only proteins, and caspases result in mitochondrial dysfunction and apoptosis; and (6) subtypes of NASH in which these pathophysiological pathways vary may require patient subtype identification to choose effective therapy.
Recent pathogenesis studies may lead to important therapeutic advances, already seen in patients treated with ACC, ASK1 and SCD1 inhibitors and FXR agonists. Further advancing our understanding of mechanisms underlying NASH pathogenesis and the complex interplay between them will be crucial for developing effective therapies.
加深我们对非酒精性脂肪性肝炎（NASH）发病机制的理解。
关于NASH发病机制的最新发现扩展了我们对其复杂性的认识，包括：（1）存在多个导致NASH的平行打击因素；（2）微生物群在发病机制中起重要作用，最近有细菌种类被证明能准确区分非酒精性脂肪性肝病（NAFL）和NASH患者；（3）肝细胞损伤的主要驱动因素是游离脂肪酸（FFA）及其衍生物引起的脂毒性，以及线粒体功能障碍；（4）内质网（ER）效率降低，蛋白质合成/折叠/修复需求增加，导致内质网应激、持续的未折叠蛋白反应和细胞凋亡；（5）参与多种途径的蛋白质上调，包括JNK、CHOP、PERK、仅含BH3结构域的蛋白质和半胱天冬酶，导致线粒体功能障碍和细胞凋亡；（6）这些病理生理途径不同的NASH亚型可能需要识别患者亚型以选择有效的治疗方法。
最近的发病机制研究可能会带来重要的治疗进展，这在接受ACC、ASK1和SCD1抑制剂以及FXR激动剂治疗的患者中已经有所体现。进一步加深我们对NASH发病机制及其之间复杂相互作用的理解，对于开发有效的治疗方法至关重要。
