Division of Endocrinology and Metabolism, Medanta the Medicity Hospital, Gurugram, 122001, Haryana, India.
Institute of Digestive and Hepatobiliary Sciences, Medanta-The Medicity Hospital, Gurugram, 122001, Haryana, India.
Diabetes Metab Syndr. 2020 Nov-Dec;14(6):1875-1887. doi: 10.1016/j.dsx.2020.09.026. Epub 2020 Sep 24.
The pathophysiology underlying metabolic associated fatty liver disease (MAFLD) involves a multitude of interlinked processes, including insulin resistance (IR) underlying the metabolic syndrome, lipotoxicity attributable to the accumulation of toxic lipid species, infiltration of proinflammatory cells causing hepatic injury and ultimately leading to hepatic stellate cell (HSC) activation and fibrogenesis. The proximal processes, such as IR, lipid overload and lipotoxicity are relatively well established, but the downstream molecular mechanisms, such as inflammatory processes, hepatocyte lipoapoptosis, and fibrogenesis are incompletely understood.
A literature search was performed with Medline (PubMed), Scopus and Google Scholar electronic databases till June 2020, using relevant keywords (nonalcoholic fatty liver disease; metabolic associated fatty liver disease; nonalcoholic steatohepatitis; NASH pathogenesis) to extract relevant studies describing pathogenesis of MAFLD/MASH.
Several studies have reported new concepts underlying pathophysiology of MAFLD. Activation of HSCs is the common final pathway for diverse signals from damaged hepatocytes and proinflammatory cells. Activated HSCs then secrete excess extracellular matrix (ECM) which accumulates and impairs structure and function of the liver. TAZ (a transcriptional regulator), hedgehog (HH) ligands, transforming growth factor-β (TGF-β), bone morphogenetic protein 8B (BMP8B) and osteopontin play important roles in activating these HSCs. Dysfunctional gut microbiome, dysregulated bile acid metabolism, endogenous alcohol production, and intestinal fructose handling, modify individual susceptibility to MASH.
Newer concepts of pathophysiology underlying MASH, such as TAZ/Ihh pathway, extracellular vesicles, microRNA, dysfunctional gut microbiome and intestinal fructose handling present promising targets for the development of therapeutic agents.
代谢相关性脂肪性肝病（MAFLD）的病理生理学涉及多种相互关联的过程，包括代谢综合征相关的胰岛素抵抗（IR）、毒性脂质堆积导致的脂毒性、促炎细胞浸润导致肝损伤，最终导致肝星状细胞（HSC）激活和纤维化。IR、脂质过载和脂毒性等近端过程相对较为明确，但炎症过程、肝细胞脂肪凋亡和纤维化等下游分子机制尚不完全清楚。
通过 Medline（PubMed）、Scopus 和 Google Scholar 电子数据库进行文献检索，检索时间截至 2020 年 6 月，使用相关关键词（非酒精性脂肪性肝病；代谢相关性脂肪性肝病；非酒精性脂肪性肝炎；NASH 发病机制）提取描述 MAFLD/MASH 发病机制的相关研究。
几项研究报告了 MAFLD 病理生理学的新概念。HSC 的激活是受损肝细胞和促炎细胞的各种信号的共同最终途径。活化的 HSCs 然后分泌过量的细胞外基质（ECM），这些 ECM 会积聚并损害肝脏的结构和功能。转录调节因子 TAZ、 hedgehog（HH）配体、转化生长因子-β（TGF-β）、骨形态发生蛋白 8B（BMP8B）和骨桥蛋白在激活这些 HSCs 中发挥重要作用。功能失调的肠道微生物组、胆汁酸代谢失调、内源性酒精产生和肠道果糖处理改变了个体对 MASH 的易感性。
MASH 病理生理学的新概念，如 TAZ/Ihh 通路、细胞外囊泡、microRNA、功能失调的肠道微生物组和肠道果糖处理，为治疗药物的开发提供了有希望的靶点。
