29 SREBP-1c knockout mice are protected against a high-fat diet–induced and alcohol-induced steatosis,36 favoring the view that de novo lipogenesis is a key mechanism for fat accumulation in the liver.37, 38 It appears that ER stress can override cholesterol inhibition of SREBP processing. It is thought that down-regulation of protein synthesis in response
to ER stress decreases Insig, which in turn results in the cleavage and release of SREBPs and their subsequent activation.39 SREBP activation may also be indirect; insulin resistance induced by ER stress www.selleckchem.com/products/PD-0332991.html induces SREBP expression.40, 41 A key point in this field is the significance of TG accumulation. Mounting evidence supports the view that the formation of TGs may detoxify fatty acids.42-44 In this scenario, TG accumulation is a sign of increased lipogenesis, which means that increased exposure to lipotoxic fatty acids may accompany steatosis.
Thus, the key to the pathogenetic learn more importance of ER stress in NAFLD is the bidirectional interplay of ER stress and lipogenesis that promotes insulin resistance as well as lipotoxicity. GRP78 overexpression has been shown to inhibit insulin-induced SREBP-1c activation in cultured primary hepatocytes.32 There is some evidence that the master regulator GRP78 (BIP) may play a role in retaining the SREBP-SCAP complex in the ER, but this is not fully defined. GRP78 overexpression has been shown to inhibit ER stress response and SREBP activation in ob/ob
mice.32 Induction of ER stress response by treatment with tunicamycin leads to alteration of SREBP expression and hepatic steatosis in HepG2 cells,45 with some studies reporting activation and some down-regulation of SREBP-1c depending on the severity and duration of ER stress response.45, 46 Clearly, the effects of tunicamycin are extreme and probably do not reflect the effects of UPR/ER stress response on lipid metabolism in naturally occurring liver diseases.47 IRE1α has been implicated in liver steatosis via its downstream product XBP1. Independent selleck screening library of SREBPs, XBP1 regulates genes involved in fatty acid and TG synthesis such as stearoyl-CoA desaturase 1 (Scd-1) and acetyl CoA carboxylase-2 (Acc2). Selective deletion of XBP1 in the liver resulted in marked hypocholesterolemia and hypotriglyceridemia. These mice did not demonstrate hepatic steatosis when placed on a high-carbohydrate diet.48 XBP+/− mice fed a high-fat diet for 3 weeks developed hyperinsulinemia, type 2 diabetes, and insulin resistance. An increase in PERK phosphorylation was demonstrated, as was an increase in JNK activity.49 ER stress has been shown to cause insulin resistance. ER stress promotes JNK-dependent serine phosphorylation of IRS-1, which in turn inhibits insulin receptor signaling and leads to insulin resistance.49 Inhibition of the eIF2α arm of the UPR by dephosphorylation of eIF2α via GADD34 leads to improved steatosis and glucose tolerance in mice.