Table 2.
Adipokine hormones, cytokines, growth factors and other mediators that play important role in non-alcoholic fatty liver disease pathology
| Mediator/pathway | Observation /proposed mechanism | Ref. |
| Adiponectin | Shown to have anti-inflammatory and antifibrotic activity, serum levels were found to be decreased in NAFLD and NASH patients. Plasma adiponectin in NAFLD is related to hepatic insulin resistance and hepatic lipid content - not to liver disease severity | [127] |
| Ghrelin | Serum levels were found to be diminished in NAFLD and NASH patients - no correlation with histological grade. Ghrelin administration attenuated oxidative stress, inflammation and apoptosis in high fat diet induced NAFLD animal model | [128,129] |
| Leptin | Leptin levels are generally known to be higher in the sera of NASH patients, except for a subgroup; serum levels were shown to negatively correlate with AST/ALT levels. The livers of leptin-deficient mice were found to be unusually sensitive to LPS-induced injury. Recombinant leptin therapy was in clinical trial in patients with NASH and low leptin levels - no results were posted | [128] and ClinicalTrials.gov Identifier: NCT00596934 |
| Resistin | Serum levels were shown to be significantly higher in patients with NAFLD and NASH | [130] |
| Small bowel bacterial overgrowth (SIBO) | Increased gut permeability and tight junction alterations in NAFLD. Higher prevalence of small intestinal bacterial overgrowth in NAFLD patients - correlated with the severity of liver steatosis | [131] |
| Toll-like receptor-4 (TLR4) | Both the TLR4 (endotoxin-receptor) protein and RNA levels were found to be elevated in liver in NASH | [132] |
| Nuclear factor-κB (NF-κB) | Increased activation of NF-κB was found in NASH | [132] |
| Tumor necrosis factor-α (TNF-α) | Key mediator of inflammation, serum levels are elevated in NASH. TNF-α expression in adipose tissue is upregulated in several models of obesity. In patients, TNF-α levels were shown to be higher in obese than in lean individuals, and were correlated with insulin resistance | [133] |
| Interleukin-6 (IL-6) | Increased plasma levels and hepatic expression was described in NASH patients. Increased hepatic IL-6 production may play an important role in NASH, insulin resistance and diabetes development | [134] |
| Transforming growth factor-β (TGF-β) | A key growth factor and a major inductor of hepatic stellate cell activation and therefore hepatic fibrosis, TGF-β signaling in hepatocytes may contribute to hepatocyte death and lipid accumulation via Smad signaling and ROS production | [135] |
| Th17 cells and IL-17 | In the livers of mice on a high fat diet and also NASH patients an increased number of hepatic Th17 cells could be detected. In mice Il-17 neutralization ameliorated LPS induced liver injury | [136] |
| Interleukin-17 exacerbates hepatic steatosis and inflammation in non-alcoholic fatty liver disease | ||
| Notch-mTOR pathway | Liver-specific ablation of Notch signaling, or its acute inhibition with a decoy Notch1 receptor, prevents hepatosteatosis by blocking mTor complex 1 (mTorc1) activity. Notch gain of function induces NAFL through constitutive activation of mTorc1 | [137] |
| Mastocyte chymase | This enzyme is important in the convertion of angiotenzin-I to angiotenzin-II and the activation of matrix metalloproteinase-9, which both are involved in the development of liver fibrosis. Chymase inhibitor prevents the nonalcoholic steatohepatitis in a hamster model | [138] |
| Galectin 3 | Galectin 3 is a β-galactoside-binding lectin with a multiple functions. It is also a receptor of advanced lipoxidation endproducts and plays important role in inflammation, fibrosis and carcinogenesis. Its role is suspected in NASH. Regression of fibrosis by galectin inhibitors in thioacetamide-induced liver disease animal model. Phase 1 Study with a Galectin inhibitor GR-MD-02 in patients with NASH and advanced fibrosis | [139,140], ClinicalTrials.gov Identifier: NCT01899859 |
| Fibroblast geowth factor -19 (FGF19) | Both the intestinal FGF19 production and the hepatic response is impaired in NAFLD patients. A decrease in fasting FGF19 levels is associated with the development of non-alcoholic fatty liver disease in obese adolescents | [141] |
A few of these molecules are therapeutic targets (e.g., galectin 3) in early phase clinical trials. NAFLD: Non-alcoholic fatty liver disease; NASH: Non-alcoholic steatohepatitis; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase.