Fatty liver protein improves glycaemic control via muscle insulin sensitivity

Tuesday, 22 Mar 2022

Australian researchers have identified a novel protein secreted from a fatty liver called arylsulfatase A (ARSA) that improves muscle insulin sensitivity and may be a potential treatment for type 2 diabetes.

A team at Melbourne University have shown that ARSA is a non-alcoholic steatohepatitis (NASH) -inducible hepatokine and powerful modulator of hepatic sulfatide and lysophospholipid metabolism, skeletal muscle insulin action, and whole-body glycaemic control.

They also demonstrated that increasing ARSA – either in the liver through gene therapy, or in the blood through protein therapy (injections of ARSA protein) – may be a viable strategy for the treatment of insulin resistance and thus type 2 diabetes.

The findings, published in Nature Communications, are based on experiments in animal models by Dr Magda Montgomery and Professor Matt Watt in the School of Biomedical Sciences.

They investigated hepatocyte protein secretion in two models of murine NASH to understand how liver-derived factors modulate lipid metabolism and insulin sensitivity in peripheral tissues.

The results revealed ‘striking’ hepatokine remodelling that was associated with insulin resistance and maladaptive lipid metabolism, and identified ARSA as a hepatokine that is upregulated in NASH and type 2 diabetes, they said.

“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,” they wrote.

“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.

“Altogether, these findings strongly point towards the existence of ARSA-mediated regulation of hepatic LPC and LPA secretion in driving a previously unappreciated liver–muscle endocrine axis in the regulation of insulin action and systemic glycemic control,” they concluded.

The authors noted that ARSA protein and gene therapy has previously been shown to be a safe therapeutic approach for metachromatic leukodystrophy in humans, and they said further studies are warranted to assess the potential for ARSA as a therapeutic strategy for the treatment of type 2 diabetes.

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