Figure 1.

Hypothesis explaining the progression of NAFLD/NASH. Overnutrition or inactivity leads to adipocyte hypertrophy and dysfunction, which are linked to chronic inflammation and insulin resistance through the recruitment and activation of immune cells such as macrophages and T-cells. Excess fat intake and obesity lead to hyperglycemia, hyperlipidemia, and the oversecretion of adipocytokines and the chemokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and monocyte chemoattractant protein (MCP)-1/C-C chemokine ligand 2 (CCL2). These factors further contribute to the development of systemic insulin resistance and hepatic steatosis. The latter causes hepatic inflammation and induces NASH and even cirrhosis. Hepatic inflammation involves the recruitment of macrophages/Kupffer cells and an M1-dominant phenotypic shift in macrophages in the liver, activating hepatic stellate cells and finally leading to liver fibrosis.