Modulation of hepatocyte sialylation drives spontaneous fatty liver disease and inflammation.

Circulatory protein glycosylation is a biomarker of multiple disease and inflammatory states and has been applied in the clinic for liver dysfunction, heart disease and diabetes. With the notable exception of antibodies, the liver produces most of the circulatory glycoproteins, including the acute phase proteins released as a function of the inflammatory response. Among these proteins is β-galactoside α2,6-sialyltransferase (ST6Gal1), an enzyme required for α2,6-linked sialylation of glycoproteins. Here, we describe a hepatocyte-specific conditional knockout of ST6Gal1 (H-cKO) using albumin promoter-driven Cre-lox recombination. We confirm the loss of circulatory glycoprotein α2,6 sialylation and note no obvious dysfunction or pathology in young H-cKO mice, yet these mice show robust changes in plasma glycoprotein fucosylation, branching and the abundance of bisecting GlcNAc and marked changes in a number of metabolic pathways. As H-cKO mice aged, they spontaneously developed fatty liver disease characterized by the buildup of fat droplets in the liver, inflammatory cytokine production and a shift in liver leukocyte phenotype away from anti-inflammatory Kupffer cells and towards proinflammatory M1 macrophages. These findings connect hepatocyte and circulatory glycoprotein sialylation to the regulation of metabolism and inflammation, potentially identifying the glycome as a new target for liver-driven disease.