Heparan sulfate (HS) is a highly sulfated glycosaminoglycan distributed on the cell surface. Our recent studies revealed that HS played an essential role in energy homeostasis through the regulation of insulin secretion from pancreatic β-cells and glucose sensitivity in adipose tissues. Although liver is one of the most important organs for energy homeostasis, the functions of HS in liver remain largely unknown. In the present study, we phenotyped hepatocyte-specific HS-deleted mice (cKO) to elucidate the roles of HS in hepatocytes.
Blood glucose testing showed that HS deletion in hepatocytes resulted in the lower glucose level of cKO after glucose challenge due to higher insulin sensitivity, indicating the augmented insulin signaling in cKO hepatocytes. Indeed, the phosphorylation level of Akt, which is one of the important molecules of insulin signaling, was robustly increased in cKO liver after insulin treatment. Biochemical assays indicated HS reduction led to the enhanced differentiation of hepatocytes due to attenuated TGFβ signaling which interrupts hepatocyte differentiation. These data suggests that HS in hepatocytes prevents the differentiation of hepatocytes and has a negative impact on insulin sensitivity.