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 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 and Matthew J. Watt ()
Additional contact information
Magdalene K. Montgomery: School of Biomedical Sciences, Faculty of Medicine Dentistry and Health Sciences, University of Melbourne
Jacqueline Bayliss: School of Biomedical Sciences, Faculty of Medicine Dentistry and Health Sciences, University of Melbourne
Shuai Nie: Melbourne Mass Spectrometry and Proteomics Facility, Bio21 Molecular Science & Biotechnology Institute, The University of Melbourne
William Nardo: School of Biomedical Sciences, Faculty of Medicine Dentistry and Health Sciences, University of Melbourne
Stacey N. Keenan: School of Biomedical Sciences, Faculty of Medicine Dentistry and Health Sciences, University of Melbourne
Paula M. Miotto: School of Biomedical Sciences, Faculty of Medicine Dentistry and Health Sciences, University of Melbourne
Hamzeh Karimkhanloo: School of Biomedical Sciences, Faculty of Medicine Dentistry and Health Sciences, University of Melbourne
Cheng Huang: Proteomics & Metabolomics Facility, Monash University
Ralf B. Schittenhelm: Proteomics & Metabolomics Facility, Monash University
Anthony S. Don: School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney
Andrew Ryan: TissuPath
Nicholas A. Williamson: Melbourne Mass Spectrometry and Proteomics Facility, Bio21 Molecular Science & Biotechnology Institute, The University of Melbourne
Geraldine J. Ooi: Centre for Obesity Research and Education, Department of Surgery, Monash University
Wendy A. Brown: Centre for Obesity Research and Education, Department of Surgery, Monash University
Paul R. Burton: Centre for Obesity Research and Education, Department of Surgery, Monash University
Benjamin L. Parker: School of Biomedical Sciences, Faculty of Medicine Dentistry and Health Sciences, University of Melbourne
Matthew J. Watt: School of Biomedical Sciences, Faculty of Medicine Dentistry and Health Sciences, University of Melbourne

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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.

Date: 2022
References: View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-022-28889-2 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28889-2

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-28889-2

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().