L-Selectin/CD62L Is a Key Driver of Non-Alcoholic Steatohepatitis in Mice and Men

Abstract

CD62L (L-Selectin) dependent lymphocyte infiltration is known to induce inflammatory bowel disease (IBD), while its function in the liver, especially in non-alcoholic steatohepatitis (NASH), remains unclear. We here investigated the functional role of CD62L in NASH in humans as well as in two mouse models of steatohepatitis. Hepatic expression of a soluble form of CD62L (sCD62L) was measured in patients with steatosis and NASH. Furthermore, CD62L−/− mice were fed with a methionine and choline deficient (MCD) diet for 4 weeks or with a high fat diet (HFD) for 24 weeks. Patients with NASH displayed increased serum levels of sCD62L. Hepatic CD62L expression was higher in patients with steatosis and increased dramatically in NASH patients. Interestingly, compared to wild type (WT) mice, MCD and HFD-treated CD62L−/− mice were protected from diet-induced steatohepatitis. This was reflected by less fat accumulation in hepatocytes and a dampened manifestation of the metabolic syndrome with an improved insulin resistance and decreased cholesterol and triglyceride levels. Consistent with ameliorated disease, CD62L−/− animals exhibited an enhanced hepatic infiltration of Treg cells and a strong activation of an anti-oxidative stress response. Those changes finally resulted in less fibrosis in CD62L−/− mice. Additionally, this effect could be reproduced in a therapeutic setting by administrating an anti-CD62L blocking antibody. CD62L expression in humans and mice correlates with disease activity of steatohepatitis. CD62L knockout and anti-CD62L-treated mice are protected from diet-induced steatohepatitis suggesting that CD62L is a promising target for therapeutic interventions in NASH.

Treatment of Fatty Liver Disease: The Present and the Future

“…Drescher et al in their study established that CD62L was detected at a higher level in patients with NASH compared to control subjects. The CD62L messenger ribonucleic acid (mRNA) was expressed at a higher level in patients with NASH when compared to patients with simple steatosis [ 19 ]. Flow cytometry also showed a significant increase in the CD62L levels in the intrahepatic immune cells in patients with NASH when compared to control subjects.…”

“…Flow cytometry also showed a significant increase in the CD62L levels in the intrahepatic immune cells in patients with NASH when compared to control subjects. On performing an experimental study on mice, Drescher et al found that CD62L deficient mice had less pronounced metabolic syndrome, lower fat content both visceral and subcutaneous, and developed a lower grade of NAFLD with lesser ballooning degeneration and lower serum transaminases compared to wild type mice [ 19 ]. His study also demonstrated that there is a reduction in the level of inflammatory cell infiltration in CD62L deficient mice when compared to wild-type mice (WT mice).…”

“…His study also demonstrated that there is a reduction in the level of inflammatory cell infiltration in CD62L deficient mice when compared to wild-type mice (WT mice). The anti-inflammatory properties of CD62L deficiency were further consolidated by an increased level of regulatory T cell and lower levels of pro-inflammatory cytokines in CD62L deficient mice [ 19 ].…”

“…The production of reactive oxygen species is a key driver in the development of NASH. CD62 deficient mice were found to produce significantly lower levels of (reactive oxygen species) ROS compared to wild-type mice thereby strengthening the role of CD62L in the development of NASH [ 19 ]. Fibrosis in the liver was noticeably lower in CD62L deficient mice.…”

“…Fibrosis in the liver was noticeably lower in CD62L deficient mice. This can be demonstrated by the less severe activation of stellate cells and lower collagen deposition [ 19 ]. CD62L is therefore a potential target in NAFLD/NASH treatment either via gene knockout therapy or with the development of CD62L blocking antibodies.…”