Non-alcoholic fatty liver disease and type 2 diabetes mellitus: The liver disease of our age?

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.