This is a collaborative project between
Molecular and Microbiology Department, College of Science,George Mason University, Fairfax, VA
Translational Reseach Institute, Inova Hospital, VA
This study was published in: Obesity Surgery 2009 Mar 12.
Background and Aims: The role of visceral obesity in the development of non-alcoholic fatty liver disease (NAFLD), and its progressive type, non-alcoholic steatohepatitis (NASH), is partially due to cytokines and adipokines produced by the white adipose tissue. Our aim was to assess the association of hepatic fibrosis and NASH by evaluating the intrinsic differences in the inflammatory cytokine signaling in the visceral adipose tissue.
Methods: We used targeted microarrays representing human genes involved in the inflammatory and fibrogenic reactions to profile visceral adipose samples of 15 well-matched NASH patients with and without fibrosis. Additionally, visceral adipose samples were subjected to Real Time PCR profiling of 84 inflammations related genes.
Results: Eight genes (CCL2, CCL4, CCL18, CCR1, IL10RB, IL15RA and LTB) were differentially expressed in NASH with fibrosis. Additionally, an overlapping but distinct list of four differentially expressed genes were found in NASH with type-II diabetes (DM) (IL8, BLR1, IL2RA, CD40LG, IL1RN, IL15RA and CCL4) as compared to NASH without DM.
An expression of CCL2 encoding MCP1 in adipose has been associated with liver fibrosis. The higher levels of CCL2 production by macrophages embedded in adipose tissue as compared to pro-inflammatory M1 macrophages are generally thought to play a role in the development of insulin resistance. However, in this study the comparison of CCL2 mRNA levels were shown to be related to fibrosis rather than to diabetes. Interestingly, in NASH patients with fibrosis, the levels of RNAs were increased both for CCL2 as well as its receptor which could cause a local increase in pro-inflammatory signaling. Additionally, excessive CLL2 produced by adipose may be delivered to the liver by portal vein and exert a direct fibrogenic effect.
We also registered exclusive over-expression of mRNA for CD40 ligand (CD40LG) in the in the diabetic patients with NASH and fibrosis. In fact, the expression level of CD40 ligand mRNA was below the detection threshold in all other groups (Supplementary Table 1), including NASH patients who had diabetes but not fibrosis. CD40LG has been previously implicated in the pathogenesis of metabolic syndrome in relation to heart disease and diabetes and also shown to induce apoptosis in hepatocytes and biliary epithelial cells as well as stimulating NF- k B signaling. Our findings support further investigation into the possibility of the using soluble CD40LG as a component for the predictive diagnostic of the fibrosis patients with NASH.
Conclusions: Inflammatory cytokines are differentially expressed in the adipose tissue of NASH with fibrosis, as well in NASH with DM. These findings points at the interaction of adipose inflammatory cytokines, DM and hepatic fibrosis in NASH.