ER stress–associated steatosis and steatohepatitis has been one of the most extensively studied consequences of ER stress response. The ER plays an important part in fatty acid synthesis and cholesterol metabolism. The relationship between ER stress and fatty liver is a bilateral one. Steatosis has been shown to promote ER stress; conversely, ER stress response leads to steatosis (Fig. 3). Despite many uncertainties, current evidence strongly

supports an important role for ER stress response in nonalcoholic fatty liver disease (NAFLD). Multiple mechanisms for ER stress–induced steatosis have been proposed: (1) ER stress induces TRB3 via ATF4 and CHOP. TRB3 inhibits the activity of Akt, an insulin-sensitizing kinase which mediates insulin signaling in hepatocytes.

Interestingly, TRB3 expression Alvelestat mouse is increased in the liver of diabetic mice, and knockdown of hepatic TRB3 expression leads to improved glucose tolerance.26, 27 (2) ER stress response activates JNK-mediated inhibition of insulin NVP-AUY922 chemical structure receptor substrate-1 (IRS-1), leading to insulin resistance which can promote hepatic steatosis; insulin resistance due to TRB3 and JNK leads to hyperinsulinemia and increased hepatic lipogenesis; (3) Phosphorylation of eIF2α results in induction of c/EBP proteins and increased expression of genes that regulate lipogenesis (peroxisome proliferator-activated receptor γ)28; (4) When hepatocytes are stressed, PERK-mediated shutdown of protein synthesis can lead to decreased Insig-1 protein, a negative regulator of lipid synthesis which retains sterol regulatory element binding protein (SREBP)–SREBP cleavage activating protein (SCAP) complex in the ER. Insig-1 protein has a very short half-life and falls rapidly upon ER stress response–induced translational arrest; the subsequent translocation of SREBPs to the Golgi leads to cleavage and Morin Hydrate enhanced lipogenesis29, 30; (5) PERK-mediated global protein translational arrest along with increased ERAD mediated by IRE1/JNK can result in decreased apolipoprotein B (apoB) levels promoting steatosis31; and (6) GRP78 may directly interact with

SREBP so that displacement of GRP78 may allow SREBPs to translocate to the Golgi and undergo RIP.32 Thus, a combination of enhanced lipogenesis via SREBP activation (including insulin resistance) and impaired very low density lipoprotein secretion via decreased apoB contribute to ER stress–induced fatty liver. A variety of supportive evidence suggests that prolonged UPR/ER stress response leads to steatosis: SREBPs are a family of ER resident proteins which function as transcription factors in the control of fatty acid, TG, and cholesterol synthesis.33, 34 They are synthesized as inactive precursors bound to the ER in a complex with SCAP. Once released from Insig, SREBPs are escorted to the Golgi by SCAP where they undergo RIP and promote lipogenesis.