The incidence and prevalence of non-alcoholic fatty liver disease(NAFLD)is constantly increasing.Despite this is apparently associated with the growing increase in obesity,insulin resistance and obesity-related metabo...The incidence and prevalence of non-alcoholic fatty liver disease(NAFLD)is constantly increasing.Despite this is apparently associated with the growing increase in obesity,insulin resistance and obesity-related metabolic disturbances their presence is not a necessary or sufficient condition to explain the accumulation of fatin the liver.Conversely,NAFLD is a predictor of other metabolic risks.NAFLD is currently the most frequent chronic liver disease but should not be considered benign or anecdotic because a considerable proportion of patients with NAFLD progress to cirrhosis and endstage liver disease.Consequently,the search for alternative molecular mechanisms with therapeutic implications in NAFLD and associated disorders deserves a careful consideration.Mitochondria are possible targets as these organelles generate energy from nutrient oxidation.Some findings,generated in patients with extreme obesity and in murine models,support the notion that NAFLD could be a mitochondrial disease.This is plausible because mitochondrial dysfunction affects the accumulation of lipids in hepatocytes and promotes lipid peroxidation,the production of reactive oxygen species,the release of cytokines causing inflammation and cell death.Here we discuss basic research and mechanistic studies targeting the role of chemokine ligand 2 in liver inflammation and that of the paraoxonases in the oxidative stress.Their combination and association with mitochondrial dysfunction may uncover mechanisms underlying the progression of NAFLD and may help to identify novel therapeutic targets.展开更多
Background The activation of extracellular signal-re gulated kinase1/2 (ERK 1/2 ) has been shown to be important signaling pathway in the ischemic preconditioning (IPC) response. Recently, some studies suggest a k...Background The activation of extracellular signal-re gulated kinase1/2 (ERK 1/2 ) has been shown to be important signaling pathway in the ischemic preconditioning (IPC) response. Recently, some studies suggest a key role for the mitochondrial ATP-sensitive potassium channel (mK ATP ) as both a trigger and an end effector of acute and delayed protection of IPC. Hence, this study was undertaken to elucidate the relationship between mK ATP and ERK 1/2 in the delayed p rotection mechanism of anoxic preconditioning (APC). Methods An APC model was established using cultured neonatal rat cardiomyocytes. Pharmacological agents [diazoxide, 5-hydroxydecanoate (5-HD), 2-mercaptopro pionylglycine (MPG), and PD98059] were used to modulate mK ATP and ERK 1/2 activation. Cellular injury was evaluated by mea suring cellular superoxide dismutase (SOD) activity, cell viability, and lactate dehydrogenase (LDH) release. The generation of cellular reactive oxygen species (ROS) and the activation of ERK 1/2 were determined at different time points starting from the beginning of preconditioning with anoxia or diazoxide (an mK ATP open er). Results Cell viability and SOD activity in the APC [(81.9±11.4)%, (13.6 ± 3.7) U/L] and diazoxide [(79.2±12.4)%, (16.5±4.6) U/L] groups were significantly higher than in the anoxia/reoxygenation (A/R) [(42.2±7.3)%, (8.8±2. 8) U/L] group (all P<0.01). LDH activity in the APC group [(101.9±18.9) U/L] and diazoxide group [(97.5±17.7) U/L] was significantly lower than in the A/R group [(250.5±43.6) U/L] (all P<0.01). Both APC and diazoxide simultaneously facilitated intracellular ROS generation and rapid ERK 1/2 activation. But the effects of APC and diazoxide were remarkedly attenuated by 5-HP (an mK ATP blocker) and by MPG (a free radical scavenger). In addition, the ERK 1/2 inhibitor PD98059 also abolished the cellular protective effects induced by diazoxide. Conclusion mK ATP may mediate ERK 1/2 activation during anoxia preconditioning by generating ROS, which then triggers the delayed protection of APC in rat cardiomyocytes.展开更多
基金Supported by Instituto de Salud CarlosⅢ,No.PI08/1381,and No.PI11/00130Carlos Ⅲ Health Institute,Madrid,Spainthe Fondo Europeo de Desarrollo Regional
文摘The incidence and prevalence of non-alcoholic fatty liver disease(NAFLD)is constantly increasing.Despite this is apparently associated with the growing increase in obesity,insulin resistance and obesity-related metabolic disturbances their presence is not a necessary or sufficient condition to explain the accumulation of fatin the liver.Conversely,NAFLD is a predictor of other metabolic risks.NAFLD is currently the most frequent chronic liver disease but should not be considered benign or anecdotic because a considerable proportion of patients with NAFLD progress to cirrhosis and endstage liver disease.Consequently,the search for alternative molecular mechanisms with therapeutic implications in NAFLD and associated disorders deserves a careful consideration.Mitochondria are possible targets as these organelles generate energy from nutrient oxidation.Some findings,generated in patients with extreme obesity and in murine models,support the notion that NAFLD could be a mitochondrial disease.This is plausible because mitochondrial dysfunction affects the accumulation of lipids in hepatocytes and promotes lipid peroxidation,the production of reactive oxygen species,the release of cytokines causing inflammation and cell death.Here we discuss basic research and mechanistic studies targeting the role of chemokine ligand 2 in liver inflammation and that of the paraoxonases in the oxidative stress.Their combination and association with mitochondrial dysfunction may uncover mechanisms underlying the progression of NAFLD and may help to identify novel therapeutic targets.
文摘Background The activation of extracellular signal-re gulated kinase1/2 (ERK 1/2 ) has been shown to be important signaling pathway in the ischemic preconditioning (IPC) response. Recently, some studies suggest a key role for the mitochondrial ATP-sensitive potassium channel (mK ATP ) as both a trigger and an end effector of acute and delayed protection of IPC. Hence, this study was undertaken to elucidate the relationship between mK ATP and ERK 1/2 in the delayed p rotection mechanism of anoxic preconditioning (APC). Methods An APC model was established using cultured neonatal rat cardiomyocytes. Pharmacological agents [diazoxide, 5-hydroxydecanoate (5-HD), 2-mercaptopro pionylglycine (MPG), and PD98059] were used to modulate mK ATP and ERK 1/2 activation. Cellular injury was evaluated by mea suring cellular superoxide dismutase (SOD) activity, cell viability, and lactate dehydrogenase (LDH) release. The generation of cellular reactive oxygen species (ROS) and the activation of ERK 1/2 were determined at different time points starting from the beginning of preconditioning with anoxia or diazoxide (an mK ATP open er). Results Cell viability and SOD activity in the APC [(81.9±11.4)%, (13.6 ± 3.7) U/L] and diazoxide [(79.2±12.4)%, (16.5±4.6) U/L] groups were significantly higher than in the anoxia/reoxygenation (A/R) [(42.2±7.3)%, (8.8±2. 8) U/L] group (all P<0.01). LDH activity in the APC group [(101.9±18.9) U/L] and diazoxide group [(97.5±17.7) U/L] was significantly lower than in the A/R group [(250.5±43.6) U/L] (all P<0.01). Both APC and diazoxide simultaneously facilitated intracellular ROS generation and rapid ERK 1/2 activation. But the effects of APC and diazoxide were remarkedly attenuated by 5-HP (an mK ATP blocker) and by MPG (a free radical scavenger). In addition, the ERK 1/2 inhibitor PD98059 also abolished the cellular protective effects induced by diazoxide. Conclusion mK ATP may mediate ERK 1/2 activation during anoxia preconditioning by generating ROS, which then triggers the delayed protection of APC in rat cardiomyocytes.
