Hyaluronidase-1 (Hyal1) is a lysosomal hyaluronidase that intracellularly hydrolyzes hyaluronan (HA). Studies have demonstrated the critical role of Hyal1 in the development of diabetes-induced endothelium dysfunction. However, whether it plays a role in the development of glucose intolerance and obesity remains unclear. We treated Hyal1 whole-body knockout (Hyal1 KO) mice and liver specific overexpression (OE) of Hyal1 mice with a low-fat diet (LFD) or high-fat diet (HFD), Hyal1 KO mice gained similar body weight but developed glucose intolerance compared to littermate wildtype (WT) mice on HFD, the latter is primarily contributed by an increase in gluconeogenesis in the Hyal1 KO liver. In contrast, Hepatic OE of Hyal1 suppressed gluconeogenesis. However, the change in gluconeogenesis is unlikely mediated by digestion of extracellular HA by Hyal1 in the liver as albumin-driven expression of a more potent hyaluronidase Ph20 had no effect on glucose tolerance nor gluconeogenesis from pyruvate. Liver metabolites in the gluconeogenesis pathway were significantly increased by HFD, whereas this was significantly attenuated in hepatic Hyal1-OE mice. Glucose transportersGLUT1 and GLUT2 were not affected by Hyal1 OE. Hyal1 deletion does not affect overall gene expression, as revealed by mRNA-sequencing of liver. However, ATP generation measured by OCR before and after inhibiting ATPase is decreased in hepatocytes OE of Hyal1, which likely contributes to the reduced energy-consuming gluconeogenesis process in Hyal1 overexpressing hepatocytes. In summary, Hyal1 regulates gluconeogenesis independent of changes in extracellular HA content, gene expression, or glucose transporter abundance in hepatocytes. Reduced gluconeogenesis is likely due to the reprogramming of intracellular metabolism and a reduction in ATP production through a remain-to-understand lysosome to mitochondria crosstalk.


X.Chen: None. Y.Zhu: None.


U.S. Department of Agriculture-Agricultural Research Service (3092-51000-062)

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