u-0126 and Chemical-and-Drug-Induced-Liver-Injury

Mitochondria are abundant in liver. The roles of mitochondrial protein in liver injury and related signaling pathways are still unclear. UCP1 is a novel mitochondrial transmembrane protein. Its expression pattern and function in liver still needs further investigation.. A mouse model of liver injury was established by the treatment of LPS. UCP1 expression in the liver tissue was detected by Western blot and qRT-PCR. ERK signaling activity was tested by enzymatic activity kit. ATP production was evaluated by flow cytometry. Cell apoptosis was determined by Western blot and flow cytometry. ERK signaling pathway inhibitor, U0126, was used to pre-treat mice. Liver tissue from sepsis patients was collected from the surgery.. Our data showed that the level of UCP1 was upregulated, ERK signaling was activated, ATP production was reduced, and cell apoptosis was enhanced in mice with liver injury model caused by LPS. U0126 intervention significantly suppressed UCP1 expression, inhibited ERK signaling pathway, enhanced ATP production, and restrained liver cell apoptosis in mice liver injury model. UCP1 increased, ERK signaling activated, and cell apoptosis elevated in the liver tissue of sepsis patients.. UCP1 plays a role in the liver tissue of mouse liver injury model and sepsis patients through the modulation of mitochondrial ATP production and cell apoptosis by ERK signaling pathway.

Topics: Adenosine Triphosphate; Animals; Apoptosis; Butadienes; Chemical and Drug Induced Liver Injury; Female; Humans; Lipopolysaccharides; Liver; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Nitriles; Uncoupling Protein 1

Activation of liver X receptor (LXR) inhibits atherosclerosis but induces hypertriglyceridemia. In vitro, it has been shown that mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor synergizes LXR ligand-induced macrophage ABCA1 expression and cholesterol efflux. In this study, we determined whether MEK1/2 (U0126) and LXR ligand (T0901317) can have a synergistic effect on the reduction of atherosclerosis while eliminating LXR ligand-induced fatty livers and hypertriglyceridemia. We also set out to identify the cellular mechanisms of the actions.. Wild-type mice were used to determine the effect of U0126 on a high-fat diet or high-fat diet plus T0901317-induced transient dyslipidemia and liver injury. ApoE deficient (apoE(-/-)) mice or mice with advanced lesions were used to determine the effect of the combination of T0901317 and U0126 on atherosclerosis and hypertriglyceridemia. We found that U0126 protected animals against T0901317-induced transient or long-term hepatic lipid accumulation, liver injury, and hypertriglyceridemia. Meanwhile, the combination of T0901317 and U0126 inhibited the development of atherosclerosis in a synergistic manner and reduced advanced lesions. Mechanistically, in addition to synergistic induction of macrophage ABCA1 expression, the combination of U0126 and T0901317 maintained arterial wall integrity, inhibited macrophage accumulation in aortas and formation of macrophages/foam cells, and activated reverse cholesterol transport. The inhibition of T0901317-induced lipid accumulation by the combined U0126 might be attributed to inactivation of lipogenesis and activation of lipolysis/fatty acid oxidation pathways.. Our study suggests that the combination of mitogen-activated protein kinase kinase 1/2 inhibitor and LXR ligand can function as a novel therapy to synergistically reduce atherosclerosis while eliminating LXR-induced deleterious effects.

Topics: Animals; Aorta; Aortic Diseases; Apolipoproteins E; Atherosclerosis; Butadienes; Chemical and Drug Induced Liver Injury; Cholesterol; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Fatty Liver; Female; Foam Cells; Hep G2 Cells; Humans; Hydrocarbons, Fluorinated; Hypertriglyceridemia; Liver; Liver X Receptors; Male; Mice, Inbred C57BL; Mice, Knockout; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Nitriles; Orphan Nuclear Receptors; Protein Kinase Inhibitors; Signal Transduction; Sulfonamides