Metabolic liver disease of obesity and role of adipose tissue in the pathogenesis of nonalcoholic fatty liver disease

Table 3 Serum factors in obesity and potential mechanisms of NASH

Factors	Increase in obesity	Source: tissue/cells	Basis of increased levels	Role in development of NASH
FFA[199]	41%	Diet Adipose tissue: (adipocytes) visceral/subcutaneous	-Over nutrition -Unopposed peripheral lipolytic activity secondary to IR	-Lipotoxicity -Induce JNK dependent hepatocytes apoptosis -Cause Bax translocation to hepatocyte lysosomes leading to lysosomal degradation and release of cathepsin B -Enhance expression of apoptosis effectors(TNF-α and Fas) -Generation of ROS at ETC of mitochondria -Increase in hepatic lipid peroxidation
TNF-α[152]	28%	Liver: Kupffer cells/macrophages/HSC/hepatocytes Adipose tissue: macrophages in matrix/adipocytes	-Chronic inflammation in adipose tissue with macrophage infiltration -LPS/endotoxins from small bowel overgrowth -Viral infection -Ethanol -Reactive oxygen species	-Receptor mediated mitochondrial injury with release of ROS and caspases -Induction of lipid peroxidation and cell necrosis (intermediation of ceramide) -TNF-α R1 activation leads to Fas induced apoptosis -Causes release of other cytotoxic cytokines(IL-6, TGF-β) from activated Kupffer cells
IL-6[152]	46%	Blood: monocytes/endothelial cells Adipose tissue: subcutaneous/omental Liver: Kupffer cells/HSC/macrophages	-TNF-α mediated activation of Kupffer cells -Pro-inflammatory cytokines release by cells (macrophages) in adipose tissue	-Mediates synthesis of acute phase proteins by hepatocytes -Activates HSC to cause fibrosis and up regulate various genes involved
Leptin[111,112]	4 .2 to 5.8 times	Adipose tissue: mature adipocyte/few matrix cells Liver: activated HSC	-Increased mass of adipose tissue -Chronic inflammatory mediators in adipose tissue -Leptin resistance	-Regulates hepatic fibrosis by activation of HSC(induction of α2 collagen gene) and modulation of Kupffer cell function -Protects HSC from apoptosis and enhances their regeneration -Up regulates profibrogenic TGF-β synthesis
Resistin[161,162]	Non significant	Adipose tissue: visceral/subcutaneous (adipocytes) Blood: monocytes Liver: Kupffer cells	-IL-6 and TNF-α release inadipose tissue secondary to inflammation -Chronic liver injury	-NF-κB mediated activation of HSC and release of pro-inflammatory(MCP, IL-8, TNF-α) and fibrogenic(TGF-β, leptin) cytokines
IL-8[200]	33%	Inflammatory cells in adipose tissue,liver and blood	-Pro-inflammatory cytokines	-Mediates inflammatory response in NASH
PAI-1[201]	3.5 times	Liver: (activated HSC) Adipose tissue: visceral/omental (matrix and adipocytes)	-Locally produced TGF-β and TNF-α	-Inhibits the activation of fibrinolytic plasmin during fibrogenesis
Angiotensinogen[172]	14%	Liver: hepatocytes Adipose tissue: visceral/subcutaneous (adipocytes)	-Hyperinsulinemia of IR -FFA	-Activates HSC to secrete TGF-β to cause fibrosis

FFA: Free fatty acids; JNK: Janus N kinase; ROS: Reactive oxygen species; ETC: Electron transport chain; TNF-α: Tumor necrosis factor-α; HSC: Hepatic stellate cells; IL: Interleukin; TGF-β: Transforming growth factor-β; MCP: Monocyte chemoattractant protein; NF-κB: Nuclear factor-kappa B; PAI-1: Plasminogen activator inhibitor-1; IR: Insulin resistance.