Mitochondrial respiratory chain dysfunction, a non-receptor-mediated effect of synthetic PPAR-ligands: biochemical and pharmacological implications

Scatena, Roberto; Bottoni, Patrizia; Martorana, Giuseppe; Ferrari, Franco; Sole, P. De; Rossi, Cristina; Giardina, Bruno

doi:10.1016/j.bbrc.2004.05.072

Cited by 66 publications

(61 citation statements)

References 21 publications

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“…Similar results have been found in other cellular systems (Rose et al 1999, Perez-Ortiz et al 2004. Therefore, the analysis of the redox state, DJm and ROS production indicate that WY-14 643 affects mitochondrial function, in agreement with previous studies about the effect of PPARa agonists (Rose et al 1999, Perez-Ortiz et al 2004, Scatena et al 2004). …”

Section: Wy-14 643 Impairs the Mitochondrial Function And Rapidly Actsupporting

confidence: 90%

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Rapid non-genomic regulation of Ca2+ signals and insulin secretion by PPARα ligands in mouse pancreatic islets of Langerhans

Ropero

Juan-Picó²,

Rafacho³

et al. 2008

Journal of Endocrinology

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PPARa is a ligand-activated transcription factor belonging to the nuclear receptor superfamily. PPARa is involved in the regulation of in vivo triglyceride levels, presumably through its effects on fatty acid and lipoprotein metabolism. Some nuclear receptors have been involved in rapid effects mediated by non-genomic mechanisms. In this paper, we report the rapid non-genomic effects of PPARa ligands on the intracellular calcium concentration ([Ca 2C ] i ), mitochondrial function, reactive oxygen species (ROS) generation, and secretion of insulin in freshly isolated mouse islets of Langerhans. The hypolipidemic fibrate PPARa agonist WY-14 643 decreased the glucose-induced calcium oscillations in intact islets. This effect was mimicked by the synthetic agonist GW7647 and the endogenous agonist oleylethanolamide. The WY-14 643 action was rapid in onset (5 min) and was still produced in the presence of protein and mRNA synthesis inhibitors, cycloheximide, and actinomycin-D. This suggests that it is independent of gene transcription. In addition, WY-14 623 impaired mitochondrial function, increased ROS formation and decreased insulin release. PPARa is present in b-cells, mainly in the cytosol and nucleus, with a small subpopulation localized in the plasma membrane. However, the presence of the PPARa ligand effects in mice bearing a disrupted Ppara gene raises the possibility that the rapid effects of the agonists in pancreatic b-cells are independent of the receptor. We conclude that PPARa agonists produce a decrease in glucose-induced [Ca 2C ] i signals and insulin secretion in b-cells through a rapid, non-genomic mechanism.

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Section: Wy-14 643 Impairs the Mitochondrial Function And Rapidly Actsupporting

confidence: 90%

“…7B). It has been reported that PPAR ligands can inhibit electron transport, particularly at the level of NADH oxidation (Scatena et al 2004). Our observations also point to a similar action of WY-14 643.…”

Section: Wy-14 643 Impairs the Mitochondrial Function And Rapidly Actsupporting

confidence: 85%

Rapid non-genomic regulation of Ca2+ signals and insulin secretion by PPARα ligands in mouse pancreatic islets of Langerhans

Ropero

Juan-Picó²,

Rafacho³

et al. 2008

Journal of Endocrinology

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“…38 A number of authors have reported that troglitazone produces mitochondrial changes in a hepatocyte cell line 39 and in HepG2 cells. 40 Scatena et al 41 and Brunmair et al 42 have demonstrated that PPAR-ligands decrease respiratory control, induce uncoupling of the oxidative phosphorylation, and reduce the activity of complex I in cell culture and tissue homogenates. These effects of PPAR-ligands are likely due to a direct interaction of these agents with the enzyme complex, because they inhibited complex I in sonicated tissue homogenates containing disrupted mitochondria.…”

Section: Discussionmentioning

confidence: 99%

Effects of rosiglitazone on the liver histology and mitochondrial function in ob/ob mice

et al. 2007

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Insulin resistance is present in almost all patients with nonalcoholic steatohepatitis (NAFLD), and mitochondrial dysfunction likely plays a critical role in the progression of fatty liver into nonalcoholic steatohepatitis. Rosiglitazone, a selective ligand of peroxisome proliferator-activated receptor gamma (PPAR␥), is an insulin sensitizer drug that has been used in a number of insulin-resistant conditions, including NAFLD. The aim of this study was to analyze the effects of rosiglitazone on the liver histology and mitochondrial function in a model of NAFLD. All studies were carried out in wild-type and leptin-deficient (ob/ob) C57BL/6J mice. Ob/ob mice were treated with 1 mg/kg/day, and activity of mitochondrial respiratory chain (MRC), beta-oxidation, lipid peroxidation, glutathione content in mitochondria, and 3-tyrosine-nitrated proteins in mitochondria were measured. In addition, histological and ultrastructural changes induced by rosiglitazone were also noted. Rosiglitazone treatment increased liver steatosis, particularly microvesicular steatosis. In these animals, mitochondria were markedly swollen with cristae peripherally placed. In ob/ob mice, this drug increased PPAR␥ protein expression and lipid peroxide content in liver tissue and decreased glutathione concentration in mitochondria. Rosiglitazone suppressed the activity of complex I of the MRC in ob/ob mice, but did not affect beta-oxidation. 3-Tyrosine nitrated mitochondrial proteins, significantly increased in ob/ob mice, were not modified by rosiglitazone treatment. Conclusion: Treatment of ob/ob mice with rosiglitazone did not reverse histological lesions of NAFLD or improve MRC activity. On the contrary, rosiglitazone reduced activity of complex I and increased oxidative stress and liver steatosis.

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“…Lastly, exogenously added peroxisome proliferators have been shown to induce a depolarization of the mitochondrial membrane and derangement of the mitochondrial respiratory chain. 48,49 In peroxisome-deficient hepatocytes, PPAR-␣ is activated, probably as a result of increased concentrations of endogenous PPAR-␣ ligands. In fact, phytanic acid, which strongly accumulates in L-Pex5 knockout livers, was previously shown to be a PPAR-␣ activator.…”

Section: Discussionmentioning

confidence: 99%

Absence of peroxisomes in mouse hepatocytes causes mitochondrial and ER abnormalities

et al. 2005

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Peroxisome deficiency in men causes severe pathology in several organs, particularly in the brain and liver, but it is still unknown how metabolic abnormalities trigger these defects. In the present study, a mouse model with hepatocyte-selective elimination of peroxisomes was generated by inbreeding Pex5-loxP and albumin-Cre mice to investigate the consequences of peroxisome deletion on the functioning of hepatocytes. Besides the absence of catalase-positive peroxisomes, multiple ultrastructural alterations were noticed, including hepatocyte hypertrophy and hyperplasia, smooth endoplasmic reticulum proliferation, and accumulation of lipid droplets and lysosomes. Most prominent was the abnormal structure of the inner mitochondrial membrane, which bore some similarities with changes observed in Zellweger patients. This was accompanied by severely reduced activities of complex I, III, and V and a collapse of the mitochondrial inner membrane potential. Surprisingly, these abnormalities provoked no significant disturbances of adenosine triphosphate (ATP) levels and redox state of the liver. However, a compensatory increase of glycolysis as an alternative source of ATP and mitochondrial proliferation were observed. No evidence of oxidative damage to proteins or lipids nor elevation of oxidative stress defence mechanisms were found. Altered expression of peroxisome proliferator-activated receptor alpha (PPAR-␣) regulated genes indicated that PPAR-␣ is activated in the peroxisomedeficient cells. In conclusion, the absence of peroxisomes from mouse hepatocytes has an impact on several other subcellular compartments and metabolic pathways but is not detrimental to the function of the liver parenchyma. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html). P eroxisomes are indispensable in cellular metabolism, because they harbor enzymes essential for the degradation of very long chain and branched chain fatty acids, for the conversion of cholesterol in bile acids and for the synthesis of ether phospholipids and polyunsaturated fatty acids. They also participate in the catabolism of purines, polyamines, and pipecolic acid. 1 The importance of peroxisomes is stressed by the existence of a group of genetic disorders in which one or more peroxisomal functions are impaired. The most severe is the cerebrohepatorenal syndrome of Zellweger, a peroxisome assembly disorder characterized by the absence of functional peroxisomes due to a disturbance in the peroxisomal protein import machinery. 2 At birth, Zellweger syndrome patients suffer from neurological and eye abnormalities, hypotonia, characteristic craniofacial dysmorphism, and renal cysts. 2 Hepatic pathology develops in the postnatal period, including hepatomegaly, fibrosis, micronodular cirrhosis, cholestasis, hyperbilirubinemia, and elevation of aminotransferases. 2,3 The biochemical hallmarks of this syndrome include the accumulation of very long chain and branched chain fatty aci...

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Mitochondrial respiratory chain dysfunction, a non-receptor-mediated effect of synthetic PPAR-ligands: biochemical and pharmacological implications

Cited by 66 publications

References 21 publications

Rapid non-genomic regulation of Ca2+ signals and insulin secretion by PPARα ligands in mouse pancreatic islets of Langerhans

Rapid non-genomic regulation of Ca2+ signals and insulin secretion by PPARα ligands in mouse pancreatic islets of Langerhans

Effects of rosiglitazone on the liver histology and mitochondrial function in ob/ob mice

Absence of peroxisomes in mouse hepatocytes causes mitochondrial and ER abnormalities

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