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Lipotoxicity, induced by saturated fatty acid (SFA)-mediated cell death, plays an important role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). The KEAP1 (kelch like ECH associated protein 1)-NFE2L2/NRF2 (nuclear factor, erythroid 2 like 2) pathway is a pivotal defense mechanism against lipotoxicity. We previously reported that SQSTM1/p62 has a cytoprotective role against lipotoxicity through activation of the noncanonical KEAP1- NFE2L2 pathway in hepatocytes. However, the unde

The pivotal functions of Srx and Prx I in protection of the liver in ethanol-fed mice was evident from the severe oxidative damage observed in mice lacking either Srx or Prx I.

The cysteine residue at the active site of peroxiredoxin (Prx) I, Prx II, or Prx III is reversibly hyperoxidized to cysteine sulfinic acid, with concomitant loss of peroxidase activity, during normal catalysis. Sulfiredoxin (Srx) is the enzyme responsible for reversing this hyperoxidation. We now show that the expression of Srx at both the mRNA and protein levels is increased markedly in the lungs of mice exposed to hyperoxia. This hyperoxia-induced expression of Srx was not evident in mice defi

The concerted action of PrxIII and Srx is important for protection against pyrazole-induced oxidative stress arising from the convergent induction of CYP2E1-derived and ER stress-derived ROS in mitochondria.

Saturated fatty acid (SFA)-induced lipotoxicity is caused by the accumulation of reactive oxygen species (ROS), which is associated with damaged mitochondria. Moreover, lipotoxicity is crucial for the progression of nonalcoholic steatohepatitis (NASH). Autophagy is required for the clearance of protein aggregates or damaged mitochondria to maintain cellular metabolic homeostasis. The NFE2L2/NRF2 (nuclear factor, erythroid 2 like 2)-KEAP1 (kelch like ECH associated protein 1) pathway is essential

Hepatic lipotoxicity is a crucial factor in nonalcoholic steatohepatitis resulting from excessive saturated fatty acid-induced reactive oxygen species (ROS)-mediated cell death, which is associated with the accumulation of endoplasmic reticulum (ER) stress in the liver. The unfolded protein response (UPR) alleviates ER stress by restoring ER protein folding homeostasis. However, whether UPR contributes ROS elimination under lipotoxicity remains unclear. The Kelch like ECH-associated protein 1 (K

Previous studies have shown that the CB1 receptor antagonist reverses steatohepatitis and its related features of metabolic syndrome, such as obesity and type 2 diabetes. However, the beneficial effects of CB1 receptor blockade on hepatic steatosis and inflammation have not been investigated independently of its effects on body weight and glycemic control. At 32 weeks of age, OLETF rats were administered with rimonabant (10 mg·kg-1·day-1) by oral gavage for 6 weeks. No significant changes in bod

Abstract Artificial liver models have been extensively developed for pathological modeling and toxicological studies. However, the prediction of existing in vitro liver models rarely corresponds to what is consequently observed in vivo owing to the structural and functional complexity of the liver. Here, a new liver model designed to enable the implantation and maintenance of liver buds in perfusable 3D hydrogels where a microvascular network develops within a 200 µm diffusion limit is developed

Nuclear factor erythroid 2-related factor 2 (Nrf2) provides a cellular defense against oxidative stress by inducing the expression of antioxidant and detoxification enzymes. The calcium antagonist, verapamil, is an FDA-approved drug prescribed for the treatment of hypertension. Here, we show that verapamil acts as a potent Nrf2 activator without causing cytotoxicity, through degradation of Kelch-like ECH-associated protein 1 (Keap1), a Nrf2 repressor. Furthermore, verapamilinduced Keap1 degradat

Endoplasmic reticulum (ER) stress is triggered by various cellular stresses that disturb protein folding or calcium homeostasis in the ER. To cope with these stresses, ER stress activates the unfolded protein response (UPR) pathway, but unresolved ER stress induces reactive oxygen species (ROS) accumulation leading to apoptotic cell death. However, the mechanisms that underlie protection from ER stress-induced cell death are not clearly defined. The nuclear factor erythroid 2-related factor 2 (N