Deep proteomic profiling unveils arylsulfatase A as a non-alcoholic steatohepatitis inducible hepatokine and regulator of glycemic control

Magdalene K Montgomery; Jacqueline Bayliss; Shuai Nie; William De Nardo; Stacey N Keenan; Paula M Miotto; Hamzeh Karimkhanloo; Cheng Huang; Ralf B Schittenhelm; Anthony S Don; Andrew Ryan; Nicholas A Williamson; Geraldine J Ooi; Wendy A Brown; Paul R Burton; Benjamin L Parker; Matthew J Watt

doi:10.1038/s41467-022-28889-2

Deep proteomic profiling unveils arylsulfatase A as a non-alcoholic steatohepatitis inducible hepatokine and regulator of glycemic control

Nat Commun. 2022 Mar 10;13(1):1259. doi: 10.1038/s41467-022-28889-2.

Authors

Magdalene K Montgomery¹, Jacqueline Bayliss², Shuai Nie³, William De Nardo², Stacey N Keenan², Paula M Miotto², Hamzeh Karimkhanloo^{2

4}, Cheng Huang⁵, Ralf B Schittenhelm⁵, Anthony S Don⁶, Andrew Ryan⁷, Nicholas A Williamson³, Geraldine J Ooi⁸, Wendy A Brown⁸, Paul R Burton⁸, Benjamin L Parker², Matthew J Watt⁹

Affiliations

¹ Department of Anatomy and Physiology, School of Biomedical Sciences, Faculty of Medicine Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, 3010, Australia. magdalene.montgomery@unimelb.edu.au.
² Department of Anatomy and Physiology, School of Biomedical Sciences, Faculty of Medicine Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, 3010, Australia.
³ Melbourne Mass Spectrometry and Proteomics Facility, Bio21 Molecular Science & Biotechnology Institute, The University of Melbourne, Melbourne, VIC, 3010, Australia.
⁴ Metabolism, Diabetes and Obesity Program, Monash Biomedicine Discovery Institute, and Department of Physiology, Monash University, Melbourne, VIC, 3800, Australia.
⁵ Proteomics & Metabolomics Facility, Monash University, Melbourne, VIC, 3800, Australia.
⁶ School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2050, Australia.
⁷ TissuPath, Mount Waverley, VIC, 3149, Australia.
⁸ Centre for Obesity Research and Education, Department of Surgery, Monash University, Melbourne, VIC, 3004, Australia.
⁹ Department of Anatomy and Physiology, School of Biomedical Sciences, Faculty of Medicine Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, 3010, Australia. matt.watt@unimelb.edu.au.

Abstract

Non-alcoholic steatohepatitis (NASH) and type 2 diabetes are closely linked, yet the pathophysiological mechanisms underpinning this bidirectional relationship remain unresolved. Using proteomic approaches, we interrogate hepatocyte protein secretion in two models of murine NASH to understand how liver-derived factors modulate lipid metabolism and insulin sensitivity in peripheral tissues. We reveal striking hepatokine remodelling that is associated with insulin resistance and maladaptive lipid metabolism, and identify arylsulfatase A (ARSA) as a hepatokine that is upregulated in NASH and type 2 diabetes. Mechanistically, hepatic ARSA reduces sulfatide content and increases lysophosphatidylcholine (LPC) accumulation within lipid rafts and suppresses LPC secretion from the liver, thereby lowering circulating LPC and lysophosphatidic acid (LPA) levels. Reduced LPA is linked to improvements in skeletal muscle insulin sensitivity and systemic glycemic control. Hepatic silencing of Arsa or inactivation of ARSA's enzymatic activity reverses these effects. Together, this study provides a unique resource describing global changes in hepatokine secretion in NASH, and identifies ARSA as a regulator of liver to muscle communication and as a potential therapeutic target for type 2 diabetes.

MeSH terms

Animals
Cerebroside-Sulfatase* / metabolism
Diabetes Mellitus, Type 2* / metabolism
Glycemic Control
Insulin Resistance*
Liver / metabolism
Mice
Non-alcoholic Fatty Liver Disease* / metabolism
Proteomics

Substances

Cerebroside-Sulfatase