Background

The incidence of nonalcoholic fatty liver disease (NAFLD) is increasing rapidly worldwide in parallel to the global obesity epidemic. NAFLD encompasses a range of liver pathologies and most often originates from metabolically driven accumulation of fat in the liver, or nonalcoholic fatty liver (NAFL). In a subset of people with NAFL, the disease can progress to nonalcoholic steatohepatitis (NASH), which is a more severe form of liver disease characterized by hepatocyte injury, inflammation and fibrosis. Significant progress has been made over the past decade in our understanding of NASH pathogenesis, yet there are still gaps in our mechanistic understanding of the precise metabolic triggers for disease worsening.

Scope of the Review

The transition from NAFL to NASH likely involves a complex constellation of multiple factors, both intrinsic and extrinsic to the liver. This review will focus on the early metabolic events in the establishment of NAFL and initial stages of NASH. We will discuss the association of NAFL with obesity as well as the role of adipose tissue in disease progression and will highlight early metabolic drivers implicated in the pathological transition from hepatic fat accumulation to steatohepatitis.

Conclusions

The close association of NAFL with features of the metabolic syndrome highlight plausible mechanistic roles for adipose tissue health and release of lipotoxic lipids, hepatic de novo lipogenesis (DNL) and disruption of the intestinal barrier in not only the initial establishment of hepatic steatosis, but also in mediating progression of the disease. Human genetic variants linked to NASH risk to date are heavily biased towards genes involved in regulation of lipid metabolism, providing compelling support for the hypothesis that NASH is fundamentally a metabolic disease.

中文翻译：

---

非酒精性脂肪肝的代谢驱动因素

 背景

随着全球肥胖流行，非酒精性脂肪肝（NAFLD）的发病率在全球范围内迅速增加。 NAFLD 涵盖一系列肝脏病理学，最常起源于代谢驱动的肝脏脂肪堆积，或非酒精性脂肪肝 (NAFL)。在一部分 NAFL 患者中，该疾病可能会发展为非酒精性脂肪性肝炎 (NASH)，这是一种更严重的肝病，其特征是肝细胞损伤、炎症和纤维化。过去十年，我们对 NASH 发病机制的理解取得了重大进展，但我们对疾病恶化的精确代谢触发因素的机制理解仍然存在差距。

 审查范围

从 NAFL 到 NASH 的转变可能涉及一系列复杂的因素，包括肝脏的内在因素和外在因素。本综述将重点关注 NAFL 形成过程中的早期代谢事件和 NASH 的初始阶段。我们将讨论 NAFL 与肥胖的关系以及脂肪组织在疾病进展中的作用，并将重点关注从肝脏脂肪堆积到脂肪性肝炎病理转变中涉及的早期代谢驱动因素。

 结论

NAFL 与代谢综合征特征的密切关联凸显了脂肪组织健康和脂毒性脂质释放、肝脏从头脂肪生成 (DNL) 和肠道屏障破坏的合理机制作用，不仅在肝脂肪变性的最初建立中，而且在介导疾病的进展。迄今为止，与 NASH 风险相关的人类遗传变异严重偏向于参与脂质代谢调节的基因，这为 NASH 从根本上是一种代谢疾病的假设提供了令人信服的支持。