Liver derived S100A6 propels β cell dysfunction in NAFLD

Abstract

<p>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 β-cell function remain equivocal. Specifically, how the accumulation of liver fat consequent to the enhanced <em>de novo</em> lipogenesis (DNL) leads to pancreatic β-cell failure and eventually to T2DM is elusive. Here we have identified low-molecular-weight calcium-binding protein S100A6 or calcyclin inhibits glucose-stimulated insulin secretion (GSIS) from β-cells through activation of the receptor for the advanced glycation end product (RAGE) and diminution of mitochondrial respiration. Serum S100A6 level is elevated both in human NAFLD patients and in a high-fat diet (HFD) induced mouse model of NAFLD. While serum S100A6 levels are negatively associated with β-cell insulin secretory capacity in human patients, depletion of hepatic S100A6 improves GSIS and glycemia in mice suggesting that S100A6 contributes to the pathophysiology of diabetes in NAFLD. Moreover, transcriptional 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 NAFLD patients with a heightened risk of developing β-cell dysfunction. Overall, our data, implicate S100A6 as a hitherto unknown hepatokine to be activated by ChREBP and participates in the hepato-pancreatic communication to impair insulin secretion and drive the development of T2DM in NAFLD. </p>