This is a collaborative project between

Molecular and Microbiology Department, College of Science,George Mason University, Fairfax, VA

Translational Reseach Institute, Inova Hospital, VA

Published in: Aliment Pharmacol Ther. 2008 Mar 1;27(5):412-21

Nonalcoholic fatty liver disease (NAFLD) is considered as the hepatic manifestation of metabolic syndrome along with insulin resistance, type 2 diabetes, dyslipidemia and obesity [Collantes et al., 2006; Clark JM et al., 2006]. An imbalance in circulating levels of various adipokines may participate in the development of both progressive and non-progressive forms of NAFLD (Baranova, Lutchman, Musso). An interplay between adipokines and pro-inflammatory cytokines produced both by the peripheral blood mononuclear cells (PBMC) and infiltrating lymphocytes and macrophages embedded with white adipose tissue adds another layer of the complexity to the pathogenesis of NAFLD [Tilg H et al., 2006].

In this study we attempted to profile three most important adipokines (adiponectin, resistin, visfatin) and three common pro-inflammatory cytokines (TNF-alpha, IL-6, IL-8) in the sera of the same cohort of patients matched by their BMIs and HOMA scores and different in histological presentation of their liver biopsies.

Some of our results confirmed findings of other investigators. For example, our results showed clearly that hypoadiponectemia negatively correlates with HOMA and HOMA related parameters as previously reported. Lower levels of adiponectin were found in NASH group, in comparison with any other BMI-matched morbidly obese group. No significant association between NAFLD progression and resistin levels were found.

TNF-a levels in simple steatosis patients were much higher than in normal donors and significantly increased with the progression of simple steatosis to NASH. Interestingly, TNF-a levels were lower in obese subgroup compared to normal controls, indicative of the hepatoprotection that lower than normal levels of TNF-a exert on the liver in obesity. Our observations corroborate findings of Satapathy et al resulted from the treatment of 18 patients with histologically proven NASH with a TNF-alpha inhibitor pentoxifylline as a sole medication (Satapathy et al., 2004). Pentoxifylline treatment resulted in the significant reduction of serum TNF-a levels accompanied by normalization of both ALT and AST and improvement of the insulin resistance index. Similar findings were reported in other studies (Adams et al., 2004). Our study adds confidence to the TNF-a suppressive approaches in NAFLD management, pointing at the potential of pentoxyfylline in the prevention of NAFLD in morbidly obese subjects.

The role of IL-6 in the pathogenesis of NASH is far from clear due to the lack of the systematic observations. In our patients cohort serum levels of IL-6 were risen from Control I subgroup to SS subgroup, then demonstrated sharp and significant drop in the NASH patients in comparison to SS patients. Such pattern can be explained by failure of the IL-6 and/or visfatin-dependent hepatoprotection associated with onset of overt NASH. In our NASH cohort the levels of IL-6 were found to be independent from the levels of other soluble molecules participating in the development of NASH (not shown). In NAFLD patients, IL-6 behavior depends only on HOMA score (P < 0.032) and IL-8 (P < 0.0027) levels, but not on TNF-alpha levels.

Visfatin levels profiles in various patient groups analyzed closely resembled these of IL-6 indicative of their possible co-regulation. Visfatin serum levels were significantly higher in each of the subgroup of obese patients when these groups were compared to normal donors (Control II), while in NASH patients these levels were lower than in Obese Controls (Control I) and in Simple Steatosis. To our knowledge, this is the first clinical observation pointing at involvement of the visfatin in NAFLD pathogenesis.

An analysis of the association between the presence of liver fibrosis and the adipokine and cytokine serum levels revealed the significant influence of TNF-alpha only (p < 0.0004). Further analysis of the TNF-alpha related fibrogenesis in the human NASH livers is necessary.

Supplementary Table. Adipokines and pro-inflammatory cytokines in serum of morbidly obese patients with and without NAFLD: Descriptive parameters and results of the group comparison by non-parametric Mann Whitney tests.