Abstract
Annexin A6 (AnxA6) controls cholesterol and membrane transport in endo- and exocytosis, and modulates triglyceride accumulation and storage. In addition, AnxA6 acts as a scaffolding protein for negative regulators of growth factor receptors and their effector pathways in many different cell types. Here we investigated the role of AnxA6 in the regulation of whole body lipid metabolism and insulin-regulated glucose homeostasis. Therefore, wildtype (WT) and AnxA6-knockout (KO) mice were fed a high-fat diet (HFD) for 17 weeks. During the course of HFD feeding, AnxA6-KO mice gained less weight compared to controls, which correlated with reduced adiposity. Systemic triglyceride and cholesterol levels of HFD-fed control and AnxA6-KO mice were comparable, with slightly elevated high density lipoprotein (HDL) and reduced triglyceride-rich lipoprotein (TRL) levels in AnxA6-KO mice. AnxA6-KO mice displayed a trend towards improved insulin sensitivity in oral glucose and insulin tolerance tests (OGTT, ITT), which correlated with increased insulin-inducible phosphorylation of protein kinase B (Akt) and ribosomal protein S6 kinase (S6) in liver extracts. However, HFD-fed AnxA6-KO mice failed to downregulate hepatic gluconeogenesis, despite similar insulin levels and insulin signaling activity, as well as expression profiles of insulin-sensitive transcription factors to controls. In addition, increased glycogen storage in livers of HFD- and chow-fed AnxA6-KO animals was observed. Together with an inability to reduce glucose production upon insulin exposure in AnxA6-depleted HuH7 hepatocytes, this implicates AnxA6 contributing to the fine-tuning of hepatic glucose metabolism with potential consequences for the systemic control of glucose in health and disease.
Highlights
The liver is the central organ for many vital metabolic functions, including lipid and glucose homeostasis
Annexin A6 (AnxA6)-KO mice gained less weight compared to controls during the high-fat diet (HFD) feeding period, which correlated with reduced white adipose tissue mass
Rabbit anti-insulin receptor β antibody was from Upstate, rabbit anti-low density lipoprotein receptor-related protein 1 antibody was from Epitomics, rabbit anti-apolipoprotein E antibody was from Acris, and goat anti-LDLR antibody was from R&D Systems
Summary
The liver is the central organ for many vital metabolic functions, including lipid and glucose homeostasis. Regulatory proteins that control delivery of proteins and lipids to specific cellular destinations, enabling localized assembly and disassembly of multifactorial protein complexes in a spatiotemporal manner, are increasingly emerging as important control devices for liver function in health and disease [5,6,7,8] This complex transport machinery includes Rab GTPases and soluble NSF attachment protein receptor proteins (SNAREs), as well as many others scaffolding and targeting proteins [5,6,7,8]. Loss of AnxA7 was linked to abnormal insulin secretion [24]; these findings were challenged by others [25]
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