4.8 Article

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

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NATURE COMMUNICATIONS
卷 13, 期 1, 页码 -

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NATURE PORTFOLIO
DOI: 10.1038/s41467-022-28889-2

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  1. National Health and Medical Research Foundation of Australia [APP1098972, APP1162511]
  2. Diabetes Australia Research Trust [Y17G-WATM]
  3. NHMRC [APP1077703, APP1143224]
  4. Canadian NSERC [PDF-516731-2018]

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Non-alcoholic steatohepatitis (NASH) and type 2 diabetes are closely linked, and this study identifies arylsulfatase A (ARSA) as a regulator that improves muscle insulin sensitivity and systemic glucose control by inhibiting liver secretion of lysophosphatidylcholine and lysophosphatidic acid.
Non-alcoholic steatohepatitis (NASH) and type 2 diabetes are closely linked, but the connecting pathophysiological mechanisms are incompletely understood. Here the authors identify arylsulfatase A as a NASH-induced hepatokine that inhibits hepatic lysophosphatidylcholine and lysophosphatidic acid secretion, and improves muscle insulin action and systemic glucose homeostasis. 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.

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