The prevalence of metabolic dysfunction-associated steatohepatitis (MASH) is increasing at an alarming rate in Australia and world-wide. MASH is characterized by hepatic steatosis, inflammation and hepatocyte ballooning, along with at least one co-existing cardiometabolic risk factor. MASH is further associated with the development of life-threatening diseases, including fibrosis, cirrhosis and liver cancer. To date, only one therapy has been FDA-approved for MASH and liver fibrosis, and novel strategies are urgently needed. In addition, the frequent coexistence of MASH and type 2 diabetes has further intensified interest in devising comprehensive therapies to tackle both diseases simultaneously.
We have recently identified Hexosaminidase A (HEXA) as a novel MASH-regulated hepatokine (i.e., liver-secreted protein) in both mice and humans (1) and have shown that increasing circulating levels of HEXA offers therapeutic benefits for metabolic dysfunction-associated liver disease (MASLD) (2) and type 2 diabetes (1). HEXA is a lysosomal protein that removes the terminal N-acetyl-galactosamine from GM2 gangliosides, producing GM3 gangliosides, which are components of the plasma membrane and are localized to lipid rafts.
In addition, our pilot data suggest that HEXA recombinant protein therapy in obese mice with hepatic steatosis reduces expression of proteins associated with inflammation and fibrosis, highlighting the potential for HEXA as a novel therapy for MASH and liver fibrosis.
Taking advantage of the MUP-uPA mouse model, including both wild-type (WT) mice with mild MASH and MUP-uPA mice with severe MASH and F2 fibrosis, we show that bi-weekly treatment with a long-lasting FC-HEXA analogue improves features of MASLD, including hepatocyte ballooning, in mice with mild MASH (i.e. WT mice) when compared to mice treated with IgG FC alone. Furthermore, we observed significantly enhanced glucose disposal into peripheral tissues, and overall improvements in glycaemic control. In contrast, FC-HEXA treatment did not ameliorate any pathological features of MASH or liver fibrosis in MUP-uPA mice with severe MASH and liver fibrosis.
Together, these outcomes suggest that while FC-HEXA treatment may offer therapeutic benefits in mild MASH and insulin resistance, it is ineffective against severe MASH and liver fibrosis.