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

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

doi:10.1038/s41467-022-28889-2

Magdalene K Montgomery, Cheng Huang + Show 15 more

Open Access

https://doi.org/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 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.

Highlights

Non-alcoholic steatohepatitis (NASH) and type 2 diabetes are closely linked, yet the pathophysiological mechanisms underpinning this bidirectional relationship remain unresolved
We have developed a unique resource describing global changes in hepatokine secretion in murine NASH, which provides a deeper appreciation of potential endocrine circuits in NASH and identification of putative therapeutic targets for related comorbidities, in particular impaired glycemic control
arylsulfatase A (ARSA) was identified as a liver-secreted protein that is increased in Nonalcoholic fatty liver disease (NAFLD)/NASH and type 2 diabetes in humans

Summary

Introduction

Non-alcoholic steatohepatitis (NASH) and type 2 diabetes are closely linked, yet the pathophysiological mechanisms underpinning this bidirectional relationship remain unresolved. 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. NASH increases in parallel with obesity and type 2 diabetes mellitus (T2D), with prevalence estimated at 57–64% in obesity and 37% in T2D, an incidence that dramatically exceeds the 3–5% observed in the general population[2,4] Despite these strong associations, the factors linking NASH with these metabolic diseases are incompletely understood. We identify ARSA as a NASH-inducible hepatokine and powerful modulator of hepatic sulfatide and lysophospholipid metabolism, skeletal muscle insulin action, and whole-body glycemic control

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