The ins and outs of liver fat metabolism: The effect of phenotype and diet on risk of intrahepatic triglyceride accumulation

In health, the liver is a metabolically flexible organ that plays a key role in regulating systemic lipid and glucose concentrations. There is a constant flux of fatty acids (FAs) to the liver from multiple sources, including adipose tissue, dietary, endogenously synthesized from non-lipid precursors, intrahepatic lipid droplets and recycling of triglyceride-rich remnants. Within the liver, FAs are used for triglyceride synthesis, which can be oxidized, stored or secreted in very low-density lipoproteins into the systemic circulation. The processes of FA uptake, FA synthesis and the intracellular partitioning of FAs into storage, oxidation or secretory pathways are tightly regulated. An imbalance in these processes causes intrahepatic triglyceride to accumulate and is associated with the development of metabolic dysfunction-associated steatotic liver disease. It is well appreciated that many factors can influence intrahepatic FA partitioning, and although there is good evidence that both phenotype (e.g., sex, ethnicity and adiposity) and dietary macronutrient composition can play a role in intrahepatic triglyceride accumulation, their interaction remains poorly understood. The aim of this review is to explore how the respective pathways of FA delivery, synthesis and disposal are altered by phenotype and understand how dietary macronutrient composition might influence the partitioning of FAs in the liver in vivo, in humans.