Figure 1: Contributing factors and molecular targets in NAFLD & NASH. Insulin resistance is an important factor in the pathology of non-alcoholic fatty liver disease (NAFLD) and elevated insulin levels play a crucial role in disease manifestation and progression. Insulin enhances the transcription of sterol regulatory element-binding protein 1c (SREBP-1c) and liver X receptor (LXR), which upregulate the three key glycolytic enzymes L-type pyruvate kinase (L-PK), acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). These enzymes catalyse conversion of carbohydrates to triglycerides. SREBP-1c additionally causes malonyl-Co-A production, which inhibits carnitine palmitoyl transferase-1 (CPT-1), the pivotal enzyme for the transport of fatty acids through the inner mitochondrial membrane to the mitochondrial matrix, where their metabolism by β-oxidation takes place. When high glucose levels occur, carbohydrate response element binding protein (ChREBP) is upregulated, which further promotes conversion of carbohydrates to triglycerides. The transcription factor forkhead box protein O1 (FOXO1) induces phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) which are usually induced by glucagon and repressed by insulin. Both enzymes are involved in hepatic gluconeogenesis, and therefore, insulin resistance leads to a loss of gluconeogenesis inhibition, thus elevating plasma glucose levels. FOXO 1 additionally induces cluster of differentiation (CD)-36, which recognizes long-chain fatty-acid (LCFAs) and mediates their transport through membrane barriers into cellular compartments. Lipoprotein lipase (LPL) which hydrolyses triglycerides to free fatty acids and glycerol is also upregulated by FOXO1 further increasing the amount of free fatty acids. Another FOXO1 target gene is pyruvate dehydrogenase kinase 4 (PDK4), an inhibitor of glucose oxidation to acetyl-CoA leading to further glucose accumulation. The peptide hormone adiponectin also seems to be crucially involved in the pathogenesis of NAFLD and is downregulated in affected patients. It improves insulin sensitivity and promotes β-oxidation, reduces gluconeogenesis and has anti-inflammatory properties by inhibiting tumor necrosis factor-α (TNF-α). When free fatty acids are elevated, mitochondrial β-oxidation can be overburdened leading to further hepatic accumulation and steatosis. As compensatory effect peroxisomal β-oxidation and microsomal omega-oxidation are activated and cause oxidative stress. Impaired very low density lipoprotein (VLDL) synthesis and transport by apolipoprotein (APO)-B expression, which is essential for triglyceride accumulation into VLDL, may also contribute to hepatic fat accumulation. Insulin is also involved in this context, because in postprandial state insulin targets APO-B and leads to VLDL degradation. The progression of NAFLD to non-alcoholic steatohepatitis (NASH) is mainly caused by hepatic inflammation. Inflammation is triggered by alterations in gut microbiota leading to release of endotoxins by gram negative bacteria and reactive oxygen species (ROS). ROS are produced as a result of dysfunctional mitochondria, by CYP enzymes in lipid peroxidation, or by iron, which increases the steady state concentration of oxygen radical intermediates. Hepatic inflammation activates hepatic stellate cells (HSCs) leading to fibrotic remodelling and, terminally, cirrhosis. PPARα can counteract the disease by inducing CPT-1 and CD36, thus improving the transport of fatty acids into mitochondrial matrix. Furthermore, PPARα upregulates enzymes that mediate β-oxidation, decreases de novo lipogenesis and inhibits NF-κB signalling by increasing the transcription of the Inhibitor of κB (IκB). However, PPARα also promotes hydrolysis of lipoproteins by inducing LPL expression and LPL inhibitor APO CIII repression which increases free fatty acid levels. PPARγ also induces CD36 promoting fatty acid uptake into mitochondria and increases adiponectin levels that improve insulin sensitivity. Furthermore, PPARγ can reduce ROS formation and oxidative stress by repression of the NADPH oxidase enzyme and TNF-α. On the other hand, PPARγ activation promotes adipocyte differentiation, fatty acid biosynthesis and LPL expression, which enhance fatty acid formation. PPARδ can influence lipid metabolism, but mainly in skeletal muscle (not depicted). The receptor induces the expression of FOXO1, which has negative and positive effects on NAFLD. On one hand, flux of fatty acids into mitochondria is improved by CD36, but on the other hand glucose levels are enhanced by PDK4, PEPCK and G6Pase. In addition, LPL is induced by FOXO1 and directly by PPARδ. APO B levels are decreased when PPARδ is activated. A positive impact of PPARδ is the reduction of NF-κB activity and stimulation of IκBα expression.