Acute Mitochondrial Actions of Glitazones on the Liver: a Crucial Parameter for their Antidiabetic Properties

Sanz, María-Nieves; Sánchez-Martín, Carlos; Détaille, Dominique; Vial, Guillaume; Rigoulet, Michel; El-Mir, Mohammed-Yehia; Rodríguez-Villanueva, Gloria

doi:10.1159/000335804

Cited by 26 publications

(29 citation statements)

References 47 publications

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“…Likewise, treatment of mice with PGZ for 12 weeks at a dose that has demonstrated to have pharmacologic effects (10 mg PGZ/g/day) [14] resulted in a significant decrease in complex I, but not complex III, activity. These results are consistent with those obtained by others with PGZ and other TZDs [7,8,15] and with those we have previously reported in ob/ob mice [12]. Although some authors found that this effect of PGZ on complex I activity was not dose-dependent [15], we found a clear relationship between the dose of PGZ and the decrease in complex activity (Figure 1A).…”

Section: Discussionsupporting

confidence: 93%

“…These results are consistent with those obtained by others with PGZ and other TZDs [7,8,15] and with those we have previously reported in ob/ob mice [12]. Although some authors found that this effect of PGZ on complex I activity was not dose-dependent [15], we found a clear relationship between the dose of PGZ and the decrease in complex activity (Figure 1A). In contrast, we found no effects of PGZ on complex II, IV, or V activity.…”

Section: Discussionsupporting

confidence: 93%

“…Activity of complex I can be reduced as a result of a large number of factors including mutations in complex I subunits [18], physiological molecules, such as nitric oxide [19], drugs, such as rotenone and TZD [7,15,20], or oxygen or nitrogen derived reactive substances such as peroxynitrite [21]. Moreover, defects in the assembly/stability of this complex may also result in a reduced activity of complex I.…”

Section: Discussionmentioning

confidence: 99%

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Pioglitazone leads to an inactivation and disassembly of complex I of the mitochondrial respiratory chain

et al. 2013

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BackgroundThiazolidinediones are antidiabetic agents that increase insulin sensitivity but reduce glucose oxidation, state 3 respiration, and activity of complex I of the mitochondrial respiratory chain (MRC). The mechanisms of the latter effects are unclear. The aim of this study was to determine the mechanisms by which pioglitazone (PGZ), a member of the thiazolidinedione class of antidiabetic agents, decreases the activity of the MRC. In isolated mitochondria from mouse liver, we measured the effects of PGZ treatment on MRC complex activities, fully-assembled complex I and its subunits, gene expression of complex I and III subunits, and [3H]PGZ binding to mitochondrial complexes.ResultsIn vitro, PGZ decreased activity of complexes I and III of the MRC, but in vivo only complex I activity was decreased in mice treated for 12 weeks with 10 mg/kg/day of PGZ. In vitro treatment of isolated liver mitochondria with PGZ disassembled complex I, resulting in the formation of several subcomplexes. In mice treated with PGZ, fully assembled complex I was increased and two additional subcomplexes were found. Formation of supercomplexes CI+CIII2+CIVn and CI+CIII2 decreased in mouse liver mitochondria exposed to PGZ, while formation of these supercomplexes was increased in mice treated with PGZ. Two-dimensional analysis of complex I using blue native/sodium dodecyl sulfate polyacrylamide gel electrophoresis (BN/SDS-PAGE) showed that in vitro PGZ induced the formation of four subcomplexes of 600 (B), 400 (C), 350 (D), and 250 (E) kDa, respectively. Subcomplexes B and C had NADH:dehydrogenase activity, while subcomplexes C and D contained subunits of complex I membrane arm. Autoradiography and coimmunoprecipitation assays showed [3H]PGZ binding to subunits NDUFA9, NDUFB6, and NDUFA6. Treatment with PGZ increased mitochondrial gene transcription in mice liver and HepG2 cells. In these cells, PGZ decreased intracellular ATP content and enhanced gene expression of specific protein 1 and peroxisome-proliferator activated receptor (PPAR)γ coactivator 1α (PGC-1α).ConclusionsPGZ binds complex I subunits, which induces disassembly of this complex, reduces its activity, depletes cellular ATP, and, in mice and HepG2 cells, upregulates nuclear DNA-encoded gene expression of complex I and III subunits.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

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Pioglitazone leads to an inactivation and disassembly of complex I of the mitochondrial respiratory chain

et al. 2013

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“…Several recent studies have proposed that PPAR γ could not be completely responsible for the insulin-sensitizing efficacy of the classical TZDs [7, 34, 35]. The identification of a novel binding site for TZDs in the mitochondrial membrane has instead suggested the presence of an alternative, PPAR γ -independent mode of action for this class of TZD drugs, which in turn signals the possibility of rationally designing insulin sensitizers that are distinct from PPAR-activating compounds.…”

Section: Pparγ-sparing Compoundsmentioning

confidence: 99%

Discovery of Novel Insulin Sensitizers: Promising Approaches and Targets

Chen

Zhu

et al. 2017

PPAR Research

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Insulin resistance is the undisputed root cause of type 2 diabetes mellitus (T2DM). There is currently an unmet demand for safe and effective insulin sensitizers, owing to the restricted prescription or removal from market of certain approved insulin sensitizers, such as thiazolidinediones (TZDs), because of safety concerns. Effective insulin sensitizers without TZD-like side effects will therefore be invaluable to diabetic patients. The specific focus on peroxisome proliferator-activated receptor γ- (PPARγ-) based agents in the past decades may have impeded the search for novel and safer insulin sensitizers. This review discusses possible directions and promising strategies for future research and development of novel insulin sensitizers and describes the potential targets of these agents. Direct PPARγ agonists, selective PPARγ modulators (sPPARγMs), PPARγ-sparing compounds (including ligands of the mitochondrial target of TZDs), agents that target the downstream effectors of PPARγ, along with agents, such as heat shock protein (HSP) inducers, 5′-adenosine monophosphate-activated protein kinase (AMPK) activators, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) selective inhibitors, biguanides, and chloroquines, which may be safer than traditional TZDs, have been described. This minireview thus aims to provide fresh perspectives for the development of a new generation of safe insulin sensitizers.

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“…More specifically, hepatic steatosis and inflammation markedly impair the ability of insulin to inhibit liver glucose production, leading to hyperglycemia and hyperinsulinemia [9, 10]. Therefore, strategies to counteract hepatic steatosis, inflammation, and increased hepatic glucose production are crucial to the prevention and treatment of chronic metabolic diseases.…”

Section: Introductionmentioning

confidence: 99%

Palmitoleic Acid (N-7) Attenuates the Immunometabolic Disturbances Caused by a High-Fat Diet Independently of PPARα

Souza

Teixeira

Lima

et al. 2014

Mediators of Inflammation

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Palmitoleic acid (PMA) has anti-inflammatory and antidiabetic activities. Here we tested whether these effects of PMA on glucose homeostasis and liver inflammation, in mice fed with high-fat diet (HFD), are PPAR-α dependent. C57BL6 wild-type (WT) and PPAR-α-knockout (KO) mice fed with a standard diet (SD) or HFD for 12 weeks were treated after the 10th week with oleic acid (OLA, 300 mg/kg of b.w.) or PMA 300 mg/kg of b.w. Steatosis induced by HFD was associated with liver inflammation only in the KO mice, as shown by the increased hepatic levels of IL1-beta, IL-12, and TNF-α; however, the HFD increased the expression of TLR4 and decreased the expression of IL1-Ra in both genotypes. Treatment with palmitoleate markedly attenuated the insulin resistance induced by the HFD, increased glucose uptake and incorporation into muscle in vitro, reduced the serum levels of AST in WT mice, decreased the hepatic levels of IL1-beta and IL-12 in KO mice, reduced the expression of TLR-4 and increased the expression of IL-1Ra in WT mice, and reduced the phosphorylation of NF 𝜅B (p65) in the livers of KO mice. We conclude that palmitoleate attenuates diet-induced insulin resistance, liver inflammation, and damage through mechanisms that do not depend on PPAR-α.

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Acute Mitochondrial Actions of Glitazones on the Liver: a Crucial Parameter for their Antidiabetic Properties

Cited by 26 publications

References 47 publications

Pioglitazone leads to an inactivation and disassembly of complex I of the mitochondrial respiratory chain

Pioglitazone leads to an inactivation and disassembly of complex I of the mitochondrial respiratory chain

Discovery of Novel Insulin Sensitizers: Promising Approaches and Targets

Palmitoleic Acid (N-7) Attenuates the Immunometabolic Disturbances Caused by a High-Fat Diet Independently of PPARα

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