Molecular pathways in non-alcoholic fatty liver disease

Figures & data

Figure 1 Hepatic steatosis.

Notes: The hallmark of NAFLD is triglyceride accumulation in the cytoplasm of hepatocytes as a result of an imbalance between lipid input and output: 1) an increase in FFAs uptake derived from the circulation due to increased lipolysis from adipose tissue and/or from the diet in the form of chylomicrons; 2) an increase in glucose and insulin levels in response to carbohydrate intake that promotes de novo lipogenesis; 3) a decrease in FA mitochondrial oxidation; 4) a decrease in triglyceride hepatic secretion by packaging with ApoB into VLDLs. In NAFLD patients, enhanced acquisition of FAs through uptake and de novo lipogenesis are not compensated by FA oxidation or production of VLDL particles.
Abbreviations: ApoB, apolipoprotein B; FFAs, free fatty acids; FA, fatty acid; NAFLD, non-alcoholic fatty liver disease; VLDL, very-low-density lipoprotein.

Figure 2 Transcriptional control of lipogenesis and glycolysis.

Notes: The conversion of glucose into FAs through de novo lipogenesis is nutritionally regulated by glucose and insulin signaling pathways, which induce the expression of glycolytic and lipogenic genes synergistically in response to dietary carbohydrates. Insulin activates the transcription factor SREBP1c, which induces lipogenic enzymes (ACC1, FAS, SCD1), while glucose activates the transcription factor ChREBP, which induces both lipogenic (ACCl, FAS, SCD1) and glycolytic (G6PC, GCKR) enzymes. ChREBP is also a direct target of LXRs, and modifies the ratio of MUFA/SFA in favor of MUFA by stimulating SCD1 activity. Recently, glucose was also identified as activating LXR’s genes. Hepatic FxR activation inhibits FA/TG synthesis by suppressing SREBP1c and LXRα activation, and inducing the expression of PPARα, which promotes mitochondrial oxidation of FAs.
Abbreviations: ACC, acetyl-CoA carboxylase; ChREBP, carbohydrate-responsive element-binding protein; FA, fatty acid; FAS, fatty acid synthase; FFAs, free fatty acids; FxR, farnesoid X receptor; G6PC, glucose 6-phosphatase; GCKR, glucokinase regulatory protein; LXR, liver X receptor; MUFA, monosaturated fatty acids; PPARα, peroxisomal proliferator-activated receptor alpha; SCD1, steroyl CoA desaturase 1; SFA, saturated fatty acids; SREBP1c, sterol regulatory element-binding protein 1c; TG, triglyceride.

Figure 3 Fatty acid oxidation.

Notes: In the liver, mitochondrial, peroxisomal, and microsomal FA oxidation are regulated by PPARα and metabolize energy. Increased sensing of PPARα results in energy burning and reduced fat storage. Decreased sensing of PPARα leads to a reduction in energy utilization and increased lipogenesis, resulting in steatosis and steatohepatitis.
Abbreviations: CPT1, carnitine palmitoytransferase-1; FA, fatty acid; PPARα, peroxisomal proliferator-activated receptor alpha.

Figure 4 Cytokines and NAFLD.

Notes: The balance/imbalance of pro- and anti-inflammatory cytokines secreted by adipose may profoundly affect the liver. Hepatic adiponectin mRNA expression was lower in individuals with NAFLD. However, TNFα and IL6 mRNA expression were higher in these patients. NALFD is associated with more proinflammatory cytokines and with fewer anti-inflammatory cytokines.
Abbreviations: ADIPOR2, adiponectin receptor type 2; IL6, interleukin-6; NAFLD, non-alcoholic fatty liver disease; TNFα, tumor necrosis factor alpha; TNFR, tumor necrosis factor receptor; IL6R, interleukin-6 receptor.

Figure 5 Mechanisms of CB1 involved in hepatic lipid accumulation.

Notes: The activation of CB1 receptors in adipose tissue promotes LPL activity, which results in increased FFA release into the liver. The activation of hepatic CB1 receptors contributes to liver fat accumulation by increased de novo hepatic lipogenesis, decreased FA oxidation, and decreased secretion of TG-rich VLDL.
Abbreviations: ACC1, acetyl-CoA carboxylase; CB, cannabinoid; CPT1, carnitine palmitoyltransferase-1; FA, fatty acid; FAS, fatty acid synthase; FFA, free fatty acid; LPL, lipoprotein lipase; SREBP1c, sterol regulatory element-binding protein 1c; TG, triglyceride; VLDL, very-low-density lipoprotein.