To define the pathophysiology of metabolic dysfunction-associated steatotic liver disease (MASLD) and identify therapeutic options, it is crucial to understand the sources of hepatic fat accumulation. In patients with MASLD, it is estimated that hepatic triglycerides are primarily derived from adipose tissue as free fatty acids (~59%), followed by de novo lipogenesis (~26%) and diet (~15%). However, in 2012, through a series of radiolabelled tracer experiments in mice, van der Veen and colleagues reported for the first time in vivo that hepatic phosphatidylcholines (PCs; a major lipid component of cell membranes and lipoproteins) accounted for a staggering 65% of the hepatic triglyceride pool, challenging the existing understanding of adipose tissue free fatty acids as the primary provider of liver triglycerides, at least in mice. Specifically, the researchers found that high-density lipoprotein (HDL) PCs could account for approximately 50% of the hepatic PC pool and that one-third of the hepatic triglyceride pool could derive from HDL–PC, a finding that was reported as unexpected.

The study was elegantly performed, using a combination of wild-type and knockout mouse models, along with primary mouse hepatocytes, to provide multiple layers of evidence supporting the results. Despite the robustness and importance of the findings, the study has been largely overlooked by the liver research community. Motivated by these unexpected results, and the lack of studies on the HDL lipidome in humans across the MASLD spectrum, part of my PhD was dedicated to filling this knowledge gap.

为了定义代谢功能障碍相关脂肪性肝病 （MASLD） 的病理生理学并确定治疗选择，了解肝脏脂肪堆积的来源至关重要。在 MALD 患者中，据估计肝甘油三酯主要以游离脂肪酸 （~59%） 的形式来自脂肪组织，其次是新发脂肪生成 （~26%） 和饮食 （~15%）。然而，在 2012 年，通过在小鼠身上进行一系列放射性标记的示踪剂实验，van der Veen 及其同事首次在体内报告了肝磷脂酰胆碱（PC;细胞膜和脂蛋白的主要脂质成分）占肝脏甘油三酯库的 65%，挑战了脂肪组织游离脂肪酸作为肝脏甘油三酯主要提供者的现有理解， 至少在小鼠中是这样。具体来说，研究人员发现高密度脂蛋白 （HDL） PC 可以占肝脏 PC 库的大约 50%，而肝脏甘油三酯库的三分之一可能来自 HDL-PC，这一发现被报告为出乎意料的。

该研究巧妙地进行了，使用了野生型和基因敲除小鼠模型的组合，以及原代小鼠肝细胞，以提供多层证据来支持结果。尽管这些发现具有稳健性和重要性，但该研究在很大程度上被肝脏研究界所忽视。受到这些意想不到的结果的激励，以及缺乏对整个 MASLD 谱系中人类 HDL 脂质组的研究，我的博士学位的一部分致力于填补这一知识空白。