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

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.

Intestinal PPARδ protects against diet-induced obesity, insulin resistance and dyslipidemia.

Peroxisome proliferator-activated receptor δ (PPARδ) is a ligand-activated transcription factor that has an important role in lipid metabolism. Activation of PPARδ stimulates fatty acid oxidation in adipose tissue and skeletal muscle and improves dyslipidemia in mice and humans. PPARδ is highly expressed in the intestinal tract but its physiological function in this organ is not known. Using mice with an intestinal epithelial cell-specific deletion of PPARδ, we show that intestinal PPARδ protects against diet-induced obesity, insulin resistance and dyslipidemia. Furthermore, absence of intestinal PPARδ abolished the ability of PPARδ agonist GW501516 to increase plasma levels of HDL-cholesterol. Together, our findings show that intestinal PPARδ is important in maintaining metabolic homeostasis and suggest that intestinal-specific activation of PPARδ could be a therapeutic approach for treatment of the metabolic syndrome and dyslipidemia, while avoiding systemic toxicity.