L-Selectin (CD62L) drives development and progression of non-alcoholic steatohepatitis (NASH) in mouse and man

Question:

Non-alcoholic steatohepatitis (NASH) is the third most common reason for liver transplantation and one of the fastest growing medical problems. The significance of infiltrating lymphocytes in NASH development remains unclear. This study investigates the role of the cell adhesion molecule L-Selectin (CD62L) in human serum of patients with steatosis and in two different mouse steatohepatitis models.

Methods:

Expression levels of soluble L-Selectin (sL-Selectin) were analysed in serum of patients with acute and chronic liver diseases. Hepatic expression of L-selectin was measured in livers of patient with different stages of steatosis and NASH. Furthermore, constitutive L-Selectin-/- mice were fed MCD-diet (methionine and choline deficient) for 4 weeks or HF-diet (high fat) for 24 weeks.

Results:

Patients with non-alcoholic fatty liver disease and acute liver injury display increased serum levels of sL-Selectin. Interestingly serum levels also increase in patients after treating ulcerative colitis (UC) with Entyvio® but not in patients with UC per se. Hepatic expression of L-Selectin is significantly higher in patients with steatosis and increases dramatically in NASH patients. Coherent with the human data, MCD (4 weeks) and HFD (24 weeks) treatment of L-Selectin-/- mice showed a less invasive phenotype in steatosis development compared to WT controls. This attenuated disease pathogenesis was reflected by maintenance of an intact liver architecture and less fatty liver degeneration. Furthermore, L-Selectin-/- animals displayed a dampened manifestation of the metabolic syndrome with a decreased liver:body weight ratio, an improved insulin resistance and decreased levels of cholesterol and triglycerides in both mouse steatohepatitis models. The amelioration of steatohepatitis was further reflected by lower serum transaminases and pro-inflammatory cytokines in L-Selectin-/- mice. Consistent with the less invasive phenotype, L-Selectin-/- animals showed an increased anti-oxidative stress response by elevated expression of Nrf2 and HO-1 and an enhanced hepatic immune cell infiltration of TReg cells. Those changes finally resulted in a protection of L-Selectin-/- mice from fibrosis progression with less collagen accumulation compared to WT controls.

Conclusion:

L-Selectin is increased in patients with fatty liver disease. To analyse the underlying mechanisms, we could show that L-Selectin deficiency in mice leads to a protection against diet induced steatohepatitis. Therefore, the blockade of the interaction of L-Selectin with its endothelial receptor MAdCAM-1 provides a novel target for therapeutic interventions during NASH development.