Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver condition in developed countries. NAFLD involves a spectrum of liver diseases that range from simple steatosis to its progressive form, non-alcoholic steatohepatitis (NASH). We have developed an advanced discovery platform with the primary aim of identifying liver-secreted proteins, that are regulated in NASH and that impact systemic metabolism.
C57BL/6 mice were fed one of two NASH-inducing diets (1. high-fat, high-cholesterol, high-fructose; 2. methionine choline deficient), followed by hepatocyte isolation and proteomic assessment of liver-secreted proteins. This screen identifies arylsulfatase A (ARSA) as a novel hepatokine that is upregulated in NASH and type 2 diabetes.
Chronic injections of ARSA recombinant protein and AAV-mediated hepatic ARSA overexpression improve glycaemic control in pre-diabetic and type 2 diabetic db/db mice, without affecting insulin secretion. Mechanistically, hepatic ARSA reduces sulfatide content and increases lysophosphatidylcholine (LPC) accumulation within cell surface 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 glycaemic 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 novel regulator of liver to muscle communication and potential therapeutic target for type 2 diabetes.