Liver-Derived S100A6 Propels b-Cell Dysfunction in NAFLD

Abstract

Nonalcoholic fatty liver disease (NAFLD) is an independent predictor of systemic insulin resistance and type 2 diabetes mellitus (T2DM). However, converse correlates between excess liver fat content and b-cell function remain equivo-cal. Specifically, how the accumulation of liver fat conse-quent to the enhanced de novo lipogenesis (DNL) leads to pancreatic b-cell failure and eventually to T2DM is elusive. Here, we have identified that low-molecular-weight cal-cium-binding protein S100A6, or calcyclin, inhibits glucose-stimulated insulin secretion (GSIS) from b cells through activation of the receptor for the advanced glycation end products and diminution of mitochondrial respiration. Serum S100A6 level is elevated both in human patients with NAFLD and in a high-fat diet–induced mouse model of NAFLD. Although serum S100A6 levels are negatively asso-ciated with b-cell insulin secretory capacity in human pa-tients, depletion of hepatic S100A6 improves GSIS and glycemia in mice, suggesting that S100A6 contributes to the pathophysiology of diabetes in NAFLD. Moreover, tran-scriptional induction of hepatic S100A6 is driven by the potent regulator of DNL, carbohydrate response element-binding protein (ChREBP), and ectopic expression of ChREBP in the liver suppresses GSIS in a S100A6-sensitive manner. Together, these data suggest elevated serum levels of S100A6 may serve as a biomarker in identifying patients with NAFLD with a heightened risk of developing b-cell dysfunction. Overall, our data implicate S100A6 as, to our knowledge, a hitherto unknown hepatokine to be activated by ChREBP and that participates in the hepato-pancreatic communication to impair insulin secretion and drive the development of T2DM in NAFLD.