Department of Community Medicine, Faculty of Medicine, "Iuliu Hațieganu" University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania.
5th Department-Internal Medicine, 1st Medical Clinic, Faculty of Medicine, "Iuliu Hațieganu" University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania.
Medicina (Kaunas). 2022 May 6;58(5):641. doi: 10.3390/medicina58050641.
Nonalcoholic fatty liver disease (NAFLD) is a new challenge in modern medicine, due to its high prevalence in the world. The pathogenesis of NAFLD is a complex dysmetabolic process, following the "multiple-hit" hypothesis that involves hepatocytes excessive accumulation of triglycerides, insulin resistance (IR), increased oxidative stress, chronic low-grade inflammatory response and lipotoxicity. In this review, we provide an overview of the interrelation of these processes, the link between systemic and local inflammation and the role of dysfunctional adipose tissue (AT) in the NAFLD development. Multiple extrahepatic triggers of the pathophysiological mechanisms of NAFLD are described: nutritional deficiency or malnutrition, unhealthy food intake, the dysfunction of the liver-gut axis, the involvement of the mesenteric adipose tissue, the role of adipokines such as adiponectin, of food intake hormone, the leptin and leptin resistance (LR) and adipose tissue's hormone, the resistin. In addition, a wide range of intrahepatic players are involved: oxidative stress, fatty acid oxidation, endoplasmic reticulum stress, mitochondrial dysfunction, resident macrophages (Kupffer cells), neutrophils, dendritic cells (DCs), B and T lymphocytes contributing to the potential evolution of NAFLD to nonalcoholic steatohepatitis (NASH). This interdependent approach to complex dysmetabolic imbalance in NAFLD, integrating relevant studies, could contribute to a better clarification of pathogenesis and consequently the development of new personalized treatments, targeting de novo lipogenesis, chronic inflammation and fibrosis. Further studies are needed to focus not only on treatment, but also on prevention strategy in NAFLD.
非酒精性脂肪性肝病（NAFLD）是现代医学面临的新挑战，其在全球的高发病率是其主要原因。NAFLD 的发病机制是一个复杂的代谢紊乱过程，遵循“多次打击”假说，涉及肝细胞内甘油三酯过度堆积、胰岛素抵抗（IR）、氧化应激增加、慢性低度炎症反应和脂毒性。在本综述中，我们概述了这些过程之间的相互关系、全身和局部炎症之间的联系以及功能失调的脂肪组织（AT）在 NAFLD 发展中的作用。描述了 NAFLD 病理生理机制的多种肝外触发因素：营养缺乏或营养不良、不健康的饮食摄入、肝肠轴功能障碍、肠系膜脂肪组织的参与、脂联素等脂肪因子的作用、摄食激素、瘦素和瘦素抵抗（LR）以及脂肪组织激素、抵抗素。此外，还涉及广泛的肝内参与者：氧化应激、脂肪酸氧化、内质网应激、线粒体功能障碍、固有巨噬细胞（Kupffer 细胞）、中性粒细胞、树突状细胞（DC）、B 和 T 淋巴细胞，有助于 NAFLD 向非酒精性脂肪性肝炎（NASH）的潜在进展。这种对 NAFLD 复杂代谢失衡的相互依赖方法，整合了相关研究，可以更好地阐明发病机制，并因此开发针对从头脂肪生成、慢性炎症和纤维化的新的个性化治疗方法。需要进一步的研究不仅要关注治疗，还要关注 NAFLD 的预防策略。
