Modulation of hepatocyte sialylation drives spontaneous fatty liver disease and inflammation

Abstract

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.

Suppression of age-related salivary gland autoimmunity by glycosylation-dependent galectin-1-driven immune inhibitory circuits

“…Interestingly, an agedependent autoimmune phenotype was also observed in mice lacking other endogenous lectins including Siglec-G, a sialic acidbinding lectin, deficiency of which led to elevated autoantibody levels and mild glomerulonephritis (53), and Gal3, absence of which led to a lupus-like disease by promoting spontaneous germinal center formation and autoantibody production (54). Furthermore, loss of liver α2,6-sialyltransferase (ST6Gal1), an enzyme required for α2,6-linked sialylation which prevents Gal1 binding, elicits fatty liver disease characterized by age-dependent buildup of fatty acid droplets and a proinflammatory phenotype involving polarization of M1-type macrophages (55). Altogether, these observations suggest a broader role of endogenous glycan-binding proteins and their glycosylated ligands in supporting immune tolerance in the context of immunological senescence.…”

Macrophage maturation from blood monocytes is altered in people with HIV, and is linked to serum lipid profiles and activation indices: A model for studying atherogenic mechanisms

“…We have also highlighted a number of other selected genes that may drive changes within atherosclerotic plaques in PWH (see Highlighted Genes, Fig 5). For example, the gene for ST6 β-galactoside α-2,6-sialyltransferase1 (ST6GAL1) is associated with increased fat droplet formation, inflammatory cytokine expression and promotion of a pro-inflammatory M1 macrophage phenotype in mouse models [52]. Pituitary Tumor-Transforming gene 1 (PTTG1) was also significantly correlated with lipid levels in PWH and regulates myeloid cell differentiation [53].…”

ST6GAL1 and α2-6 Sialylation Regulates IL-6 Expression and Secretion in Chronic Obstructive Pulmonary Disease

“…For example, increased cigarette smoke exposure was shown to alter sialylation of the fallopian tubes potentially through ST6GAL1 in ectopic pregnancy ( 40 ). In addition, changes in protein sialylation were shown to contribute to fatty liver deposition and various inflammatory responses ( 45 ). Our findings demonstrate that loss of ST6GAL1 or exposure to cigarette smoke leads to decreased sialylation ( Figures 1 , 2 ) and increased IL-6 expression/secretion in bronchial epithelial cells ( Figures 3 , 4 ).…”

“…BACE1 expression has been shown to affect the sialylation of soluble/cell surface glycoproteins through cleavage of ST6GAL1 ( 52 ) suggesting that the soluble form of the ST6GAL1 still has activity when released [others have shown that ST6GAL1 has activity in a secreted/soluble form ( 53 )]. Additionally, secreted/circulating ST6GAL1 has been associated with inflammation ( 45 , 54 , 55 ). Here, we show that inhibition of BACE1 reduced ST6GAL1 secretion and α2-6 sialylation and resulted in augmented IL-6 secretion in HBECs similar to that found with CSE treatment ( Figure 5 ).…”