Dexamethasone decreases cholestatic liver injury via inhibition of intrinsic pathway with simultaneous enhancement of mitochondrial biogenesis.

BACKGROUND: Mitochondria are known to be involved in cholestatic liver injury. We tested the hypothesis that glucocorticoids can modulate mitochondrial function to alleviate cholestatic liver injury. METHODS: A rat model of cholestasis was established by bile duct ligation (BDL), with a sham group receiving laparotomy without BDL, and a group receiving dexamethasone (DEX) treatment after BDL. RESULTS: The liver function including total bilirubin levels, alanine transaminase and aspartate transaminase activities was significantly improved in the DEX treatment group in comparison to the BDL group. There was a significant upregulation of liver peroxisome proliferator-activated receptor γ coactivator-1α and mitochondrial transcriptional factor A protein between 6 and 72 h was found in the DEX group. DEX treatment significantly down-regulated Bax, caspase 9 and caspase 3 expression induced by BDL at 24-72 h, but had little effect on the expression of caspase 8, Bcl(2,) Fas and Fas-FasL complex. Consequently, the number of apoptotic liver cells in the DEX group was significantly less than in the BDL group at 72 h. CONCLUSION: Our results indicate that glucocorticoids decreases cholestatic liver injury within hours after BDL. Early glucocorticoids treatment can enhance the mitochondrial biogenesis and modulate the intrinsic but not extrinsic pathway of apoptosis following BDL.

Mitochondrial dysfunction and biogenesis in the pathogenesis of Parkinson's disease.

Parkinson's disease (PD) is a progressive neurological disorder marked by nigrostriatal dopaminergic degeneration and development of cytoplasmic aggregates known as Lewy bodies. The impact of this disease is indicated by the fact that mortality is two to five times as high among affected persons as among age-matched controls. However, the cause of PD is still unknown and no cure is available at present. Several biochemical abnormalities have been described in the brains of patients with PD, including oxidative stress and mitochondrial dysfunction. Recent identification of specific gene mutations that cause PD has further reinforced the relevance of oxidative stress and mitochondrial dysfunction in the familial and sporadic forms of the disease. The proteins that are reported to be related to familial PD-PTEN-induced putative kinase 1 (PINK1), DJ-1, alpha- synuclein, leucine-rich repeat kinase 2 (LRRK2), and, possibly, parkin-are either mitochondrial proteins or are associated with mitochondria, and all are involved in pathways that elicit oxidative stress or free radical damage. Mitochondria are continually exposed to reactive oxygen species and accumulate oxidative damage more rapidly than the rest of the cell. Therefore, Parkinson's disease has been suggested to be associated with mitochondrial dysfunction. Since mitochondria are the major intracellular organelles that regulate both cell survival and death, clarifying the involvement of mitochondrial dysfunction and biogenesis during the process of PD could provide treatment strategies that might successfully intervene in the pathogenesis and slow the progression of the disease.

The role of mitochondria in cholestatic liver injury.

There is increasing evidence that the integrity of antioxidant defenses is of vital importance in extrahepatic cholestasis, particularly with regard to the functioning of the liver's mitochondria. Although the mechanisms by which cholestasis causes oxidant/antioxidant imbalance in mitochondria are poorly understood, hepatic injury caused by cholestasis may be due to oxidative stress from the mitochondria. The injury has been observed in experimental models of cholestasis, especial in a model of biliary cholestasis established in rats with bile duct ligation (BDL). In the BDL rat model, the mitochondrial DNA copy number is changed and apoptosis is activated in the liver. In addition, Peroxisome Proliferator-activated Receptor-Coactivator-1alpha and transcriptional factor A are impaired. Compared to sham-operated rats, glutathione activity is decreased after BDL. Peroxidation of the mitochondrial phospholipids may cause cell necrosis and the level of a by-product of this peroxidation, malondialdehyde, may contribute to cell death after BDL. The disturbance of the oxidant-antioxidant balance, especially in mitochondria, may be responsible for cholestatic liver injury in cholestasis rats. This review describes recent development in the pathogenesis of cholestasis from the viewpoint of mitochondrial biogenesis and suggests possible directions for future study.

Early transcriptional deregulation of hepatic mitochondrial biogenesis and its consequent effects on murine cholestatic liver injury.

Mitochondria are known to be involved in cholestatic liver injury, but the damage and biogenesis of mitochondria in response to the early stage of cholestasis is unknown. A rat model of cholestasis was established by bile duct ligation (BDL), with simultaneous creation of the sham group receiving laparotomy without BDL. A significant decrease of liver peroxisome proliferators-activated receptor gamma coactivator-1alpha, mitochondrial transcriptional factor A (Tfam) and glutathione peroxidase (GPx) mRNA and Tfam protein from 6 to 72 h after BDL was found, which was associated with significant decrease of the glutathione, GPx and catalase activity at 72 h. At 72 h after BDL, mitochondrial DNA copy number reached the lowest level, while caspase 9 and 3 activity, but not caspase 8, Bax, Bcl(2), Fas L and Fas-Fas L complex, were upregulated significantly in the liver homogenates of BDL rats. The apoptotic liver cells appeared in large amounts in the rat liver by 72 h after BDL. Our results indicate that transcriptional regulation of the mitochondrial biogenesis is impaired within a few hours after complete bile duct obstruction, resulting in later mitochondrial dysfunction and consequent cholestatic liver injury via the intrinsic apoptosis pathway.