Table 1.
Death receptor activation by FFAs in cultured hepatocytes, mouse NAFLD models and humans.
| TRAIL/TRAILR | Ref. | |
| Human | TNFRSF10B mRNA elevated in livers from patients with NASH. | 144 |
| Human hepatocytes | TRAILR2 (D5), but not TRAILR1 (D4) is activated after PA exposure promoting apoptosis via caspase 8. | 145 |
| Exacerbated ER stress increases protein levels and activation of TRAILR2. | 146 | |
| TNFRSF10B (TRAILR2) knockdown attenuates FFAs-induced apoptosis. | 147 | |
| Mouse | Increased Tnfrsf10b (encoding TRAILR), the mouse single ortholog for both human TNFRSF10A and TNFRSF10B (encoding TRAILR1 and TRAILR2, respectively) in mice fed a MCD diet. | 148 |
| Tnfrsf10b null mice displays reduced steatosis, hepatocyte apoptosis, macrophage-associated inflammation and fibrosis after a high-fructose, high-fat, high-cholesterol diet (HFHFHCD). | 149 | |
| TNFα/TNFR1 | ||
| Human | TNFα and its receptor 1 (TNFR1), are both upregulated in NASH patients. | 150,151 |
| Human hepatocytes | Treatment of HepG2 cells with a mixture of OA and PA (2:1) resulted in lysosomal permeabilization associated with Bax translocation and release of cathepsin B which, in turn, evoked the induction of Tnfa mRNA and promoted a modest rate of apoptosis. However, it is not clear whether both cathepsin B-dependent effects are related to each other. | 152 |
| Mouse | Tnfrsf1a (encoding TNFR1)-deficient mice fed a HS diet did not exhibit hepatic steatosis despite the fact that they became obese. | 152 |
| Tnfrsf1a gain of function mutation aggravates NAFLD features. | 153 | |
| HFD-fed Tnfrsf1a knockout mice displayed an exacerbated inflammatory response, insulin resistance and liver steatosis, suggesting a cross-talk between the TNFR1 and lipid accumulation in the liver that promotes an accelerated progression from NAFL towards a more severe phenotypes of NAFLD. | 154 | |
| Fas ligand/Fas (CD95, APO-1) | ||
| Human | Fas expression is enhanced in NASH patients. | 8,155 |
| Human hepatocytes | HepG2 hepatocytes treated with a mixture of OA/PA showed upregulated Fas expression and increased sensitivity to Fas-mediated apoptosis. | 156 |
| Mouse | Liver-specific Fas overexpression compromises FAO and mitochondrial respiration, promoting lipid accumulation and insulin resistance. | 157 |
| Pharmacological or genetic Fas depletion in the liver protects mice from hepatic steatosis and insulin resistance in NASH mice models. | 155,157 | |
| Mouse and Human | In normal liver, the hepatocyte growth factor receptor Met binds to Fas, preventing its activation, whereas in both human and experimental NAFLD Fas sequestration by Met is abrogated, favouring the formation of Fas-Fas ligand complexes, and eventually inducing apoptosis. | 158 |