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.