The role of Annexin A6 in hepatic lipid and glucose homeostasis

Abstract

Annexin A6 (AnxA6) is a Ca2+ and phospholipid binding protein that acts as a scaffolding protein and regulates cholesterol transport along endo- and exocytic pathways. The aim of this study was to examine the role of AnxA6 in hepatic lipid and glucose homeostasis. Alterations in lipid and glucose handling are implicated in diabetes, fatty liver disease and the metabolic syndrome. Thus, the identification of potential mediators of metabolic processes could be important for increasing understanding of these diseases. To examine the role of AnxA6 in a metabolic context, C57BL/6 mice lacking AnxA6 (AnxA6 KO) were fed a high fat diet (HFD) to induce an obese and insulin resistant phenotype. HFD feeding revealed that AnxA6 KO mice were less susceptible to diet induced obesity, despite consuming more food. An oral glucose tolerance test showed similar glucose disposal in WT and AnxA6 KO mice. However, a pyruvate tolerance test resulted in sustained hyperglycaemia in AnxA6 KO mice, without concomitant defects in insulin release or signalling. In fact, insulin signalling was enhanced in livers of AnxA6 KO mice. Aberrant hepatic glucose handling was underscored by the presence of increased glycogen accumulation in livers from AnxA6 KO mice, and glycogen in autophagic vesicles. Lipid profiling revealed increased lipolysis and increased high density lipoprotein in AnxA6 KO mice. AnxA6 KO mice had reduced hepatic steatosis, and a reduction in lipid droplet (LD) accumulation was observed in cells with AnxA6 knockdown. Conversely, cultured hepatocytes overexpressing AnxA6 had increased LD accumulation. Thus, loss of AnxA6 alters both lipid and glucose homeostasis, and the complex phenotype observed may be a result of impaired metabolic fuel switching (known as metabolic flexibility). This study constitutes the first major metabolic characterisation of the AnxA6 KO mice, with the data presented here indicative of a role for AnxA6 in metabolism and energy balance.