Nonalcoholic fatty liver disease (NAFLD) is a common complication of obesity that encompasses a spectrum of liver disorders, including nonalcoholic fatty liver and the more progressive nonalcoholic steatohepatisis (NASH), which is histologically defined by steatosis, lobular inflammation, and hepatocyte ballooning. NAFLD is associated with insulin resistance, dyslipidemia and an increased risk of type 2 diabetes and coronary heart disease, and progression to NASH increases the risk of fibrosis, cirrhosis, hepatic decompensation, and liver-related mortality. Notably, there is a paucity of pharmacotherapies available for the treatment of NAFLD and related co-morbidities.
This presentation will outline our team’s efforts to elucidate the complement of proteins secreted by the human liver in progressive NAFLD and how this information has been used to understand inter-tissue communication and identify novel pathways to improve insulin sensitivity and glycemic control. Our studies identified 3333 secreted proteins from human liver, of which 9.8% were classically secreted and 3.2% were differentially regulated in human NASH. Hexosaminidase A and Arylsulfatase A were shown to be upregulated in NASH and unexpectedly, these proteins were shown in cell culture and pre-clinical mouse studies to enhance glycemic control via liver to skeletal muscle communication and induction of distinct signalling pathways. In addition, proteins contained within small extracellular vesicles were shown to induce positive effects on blood glucose control by signaling to skeletal muscle to enhance glucose effectiveness and the pancreas to increase glucose-stimulated insulin secretion. Together, these results identify liver secreted proteins as regulators of skeletal muscle metabolism and harnessing this signalling may unlock new therapeutic options for impaired glycemic control.