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

MK Montgomery; J Bayliss; S Nie; W De Nardo; SN Keenan; PM Miotto; H Karimkhanloo; C Huang; RB Schittenhelm; AS Don; A Ryan; NA Williamson; GJ Ooi; WA Brown; PR Burton; BL Parker; MJ Watt

Journal article

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

MK Montgomery, J Bayliss, S Nie, W De Nardo, SN Keenan, PM Miotto, H Karimkhanloo, C Huang, RB Schittenhelm, AS Don, A Ryan, NA Williamson, GJ Ooi, WA Brown, PR Burton, BL Parker, MJ Watt

Nature Communications | Published : 2022

DOI: 10.1038/s41467-022-28889-2

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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 lysophosphatidylc..

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University of Melbourne Researchers

Magda Montgomery Author

Jacqueline Bayliss Author

Stacey Keenan Author

Nicholas Williamson Author

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Grants

Awarded by Diabetes Australia Research Trust

Funding Acknowledgements

These studies were supported by funding from the National Health and Medical Research Foundation of Australia (APP1098972, M.J.W.; APP1162511, M.J.W.) and the Diabetes Australia Research Trust (Y17G-WATM, M.J.W.). M.J.W. and M.K.M. are supported by Research Fellowships from the NHMRC (APP1077703, M.J.W.; APP1143224, M.K.M.). P.M.M. was supported by a Canadian NSERC Post-doctoral fellowship (PDF-516731-2018). Figure 8 was created with BioRender.com.