Liver-Secreted Hexosaminidase A Regulates Insulin-Like Growth Factor Signalling and Glucose Transport in Skeletal Muscle

Author:

Montgomery Magdalene K.1,Bayliss Jacqueline1,Nie Shuai2,de Nardo William1,Keenan Stacey N.1,Anari Marziyeh1,Taddese Amanuiel Z.1,Williamson Nicholas A.2,Ooi Geraldine J.3,Brown Wendy A.3,Burton Paul R.3,Gregorevic Paul14,Goodman Craig A.14,Watt Kevin I.14,Watt Matthew J.1

Affiliation:

1. 1Department of Anatomy and Physiology, School of Biomedical Sciences, Faculty of Medicine Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC 3010, Australia

2. 2Melbourne Mass Spectrometry and Proteomics Facility, Bio21 Molecular Science & Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia

3. 3Centre for Obesity Research and Education, Department of Surgery, Monash University, The Alfred Hospital, Melbourne, VIC 3004, Australia

4. 4Centre for Muscle Research, The University of Melbourne, Melbourne, VIC, Australia

Abstract

Non-alcoholic fatty liver disease (NAFLD) and impaired glycaemic control are closely linked, however, the pathophysiological mechanisms underpinning this bidirectional relationship remain unresolved. The high secretory capacity of the liver and impairments in protein secretion in NAFLD suggest that endocrine changes in the liver are likely to contribute to glycaemic defects. We identify hexosaminidase A (HEXA) as a NAFLD-induced hepatokine in both mice and humans. HEXA regulates sphingolipid metabolism, converting GM2 to GM3 gangliosides; sphingolipids that are primarily localized to cell surface lipid rafts. Using recombinant murine HEXA protein, an enzymatically inactive HEXA(R178H) mutant, or adeno-associated viral vectors to induce hepatocyte-specific overexpression of HEXA, we show that HEXA improves blood glucose control by increasing skeletal muscle glucose uptake in mouse models of insulin resistance and type 2 diabetes, with these effects being dependent on HEXA’s enzymatic action. Mechanistically, HEXA remodels muscle lipid raft ganglioside composition, thereby increasing insulin-like growth factor 1 signalling and glucose transporter 4 localization to the cell surface. Disrupting lipid rafts reverses these HEXA-mediated effects. Together, this study identifies a novel pathway for inter-tissue communication between liver and skeletal muscle in the regulation of systemic glycaemic control.

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

Cited by 1 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. Placing a Hex on Glucose Uptake;Diabetes;2023-05-19

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