The liver is a key metabolic organ that undertakes a multitude of physiological processes. It serves as an intermediary organ between exogenous (dietary) and endogenous energy supply to extrahepatic organs, with hepatocytes rapidly transitioning back and forth between the metabolic tasks of energy storage and supply. Given its pivotal role in regulating systemic lipid metabolism, perturbations in hepatic metabolism can impact on metabolic disease risk. For example, the accumulation of intra-hepatocellular triglyceride (IHTG), which likely results from an imbalance between fatty acid delivery to the liver, hepatic fatty acid synthesis and fatty acid removal (via oxidation or export as triglyceride (TG)) from the liver. Insulin is the main regulator of all these processes; insulin resistance has profound effects on liver fat metabolism. By using a combination of in vivo, ex situ and in vitro models with methodologies such as stable isotope tracers, there is the potential to gain insight into intra-hepatocellular lipid metabolism. This talk will review the insights gained from undertaking studies using these models of human liver metabolism and discuss how metabolic (e.g. adiposity) and nutritional state may alter hepatic fatty acid partitioning and influence the risk of metabolic diseases including insulin resistance, metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiovascular disease.