Metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately 40% of the global population. Plasma free fatty acids (FFAs) play a central role in the development of MASLD and are mainly transported by albumin. Our previous work demonstrated that albumin knockout (Alb-/-) mice had reduced plasma FFA and hepatic triacylglycerol (TAG) and improved insulin sensitivity compared to wildtype (WT) mice. However, it remained unclear whether these phenotypes could be attributed to the loss of the albumin-FFA interaction and whether they could be reversed by restoring albumin in both sexes. In the current study, we aimed to test two hypotheses: 1) acute injections of albumin in Alb-/- mice can raise plasma FFA, increase hepatic TAG and impair insulin sensitivity; 2) there is a sex difference in the susceptibility to these acute effects of albumin. Male and female WT and Alb-/- mice (8-week-old, n = 5-6) received human serum albumin or vehicle. After 24 hours, mice were euthanized for sample collection. In both sexes of Alb-/- mice, albumin injections markedly elevated plasma FFA and blood glucose to a comparable level as their WT counterparts. In male Alb-/- mice, albumin injections increased hepatic TAG levels, which strongly correlated with plasma FFA (r = 0.78, P < 0.01). Yet, albumin injections in female Alb-/- mice failed to alter hepatic TAG. Additionally, in both WT and Alb-/- male mice, albumin injections significantly increased the plasma insulin levels and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) score (main effect of treatment, P < 0.05 and P < 0.01). In contrast, no difference was found in plasma insulin or HOMA-IR in WT and Alb-/- females after albumin administrations. There was a significant correlation between plasma FFA and HOMA-IR score in both WT and Alb-/- male mice (WT: r = 0.65, Alb-/-: r = 0.70, both P < 0.05), suggesting a detrimental effect of plasma FFA on insulin sensitivity under conditions of acute albumin administration. No significant correlations were detected in either genotype of female mice. Overall, these results indicated that acute injections of albumin could rapidly increase the levels of plasma FFA and its delivery to the liver, promoting hepatic lipid accumulation and impairing insulin signaling. In particular, males are more susceptible to these acute metabolic disturbances. The findings significantly enhance our understanding of sex-specific responses to acute modulation of plasma FFA trafficking. The novel discovery may help explain the role of plasma FFA transport in the development of insulin resistance, hepatic steatosis, and ultimately MASLD. Funding sources: McKinley Educational Initiative This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Zhang et al. (Fri,) studied this question.