Liver-Derived S100A6 Propels β-Cell Dysfunction in NAFLD

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 equivocal. Specifically, how the accumulation of liver fat consequent 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 calcium-binding protein S100A6, or calcyclin, inhibits glucosestimulated 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 associated with b-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 elementbinding 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 hepatopancreatic communication to impair insulin secretion and drive the development of T2DMin NAFLD.

Automated summary

Nonalcoholic fatty liver disease (NAFLD) is associated with insulin resistance and type 2 diabetes mellitus (T2DM). This study found that S100A6 protein inhibits insulin secretion from pancreatic β cells by activating RAGE and reducing mitochondrial respiration. Elevated levels of S100A6 were observed in both NAFLD patients and a high-fat diet-induced mouse model. Depletion of S100A6 improved insulin secretion and blood glucose levels in mice. Hepatic S100A6 expression is regulated by ChREBP, which suppresses insulin secretion in a S100A6-sensitive manner. Elevated serum levels of S100A6 may serve as a biomarker for identifying NAFLD patients at risk of b-cell dysfunction.