Albumin Lipidomics Reveals Meaningful Compositional Changes in Advanced Cirrhosis and Its Potential to Promote Inflammation Resolution

Abstract

Albumin infusions are therapeutically used to revert hypoalbuminemia and to replace the extensively oxidized albumin molecule circulating in patients with acutely decompensated (AD) cirrhosis. Because albumin has high affinity for lipids, here we characterized the albumin lipidome in patients with AD and explored the albumin effects on the release of fatty acid (FA)-derived lipid mediators by peripheral leukocytes. Lipids and lipid mediators were measured by liquid chromatography-tandem mass spectrometry in albumin-enriched and albumin-depleted plasma fractions separated by affinity chromatography and in leukocyte incubations from 18 patients with AD and 10 healthy subjects (HS). Lipid mediators were also measured in 41 patients with AD included in an albumin therapy trial. The plasma lipidome associated with AD cirrhosis was characterized by generalized suppression of all lipid classes except FAs. In contrast to HS, albumin from patients with AD had lower content of polyunsaturated FAs (PUFAs), especially of the omega-3-PUFA docosahexaenoic acid. Consistent with this, the PUFA-derived lipid mediator landscape of albumin from patients with AD was dominated by lower content of monohydroxy FA precursors of anti-inflammatory/pro-resolving lipid mediators (i.e., 15-hydroxyeicosatetraenoic acid [15-HETE]). In addition, albumin from patients with AD was depleted in prostaglandin (PG) E2 , suggesting that this proinflammatory PG primarily travels disassociated to albumin in these patients. Incubation of leukocytes with exogenous albumin reduced PG production while inducing 15-lipoxygenase expression and 15-HETE release. Similar effects were seen under lipopolysaccharide plus N-formylmethionyl-leucyl-phenylalanine-stimulated conditions. Finally, PG levels were lower in patients with AD receiving albumin therapy, whereas 15-HETE was increased after albumin treatment compared with baseline. Conclusion: Our findings indicate that the albumin lipid composition is severely disorganized in AD cirrhosis and that administration of exogenous albumin has the potential to redirect leukocyte biosynthesis from pro-inflammatory to pro-resolving lipid mediators.