Kupffer Cells Are a Dominant Site of Uncoupling Protein 2 Expression in Rat Liver

Larrouy, Dominique; Laharrague, Patrick; Carrera, G.; Viguerie, Nathalie; Lévi-Meyrueis, Corinne; Fleury, Christophe; Pecqueur, Claire; Nibbelink, Maryse; Meynier, André; Casteilla, Louis; Ricquier, Daniel

doi:10.1006/bbrc.1997.6852

Cited by 134 publications

(114 citation statements)

References 21 publications

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“…expressed in skeletal muscle, and although the expression of UCP2 is broad, there are probably cells that do not express it, such as hepatocytes in normal rats [70]. Therefore UCP2 and UCP3 are not absolutely required for normal mitochondrial function.…”

Section: Figure 4 Proposed Links Between the Redox State Of Coenzymesmentioning

confidence: 99%

“…UCP2 was first detected immunohistochemically in rat liver by Larrouy et al [70], who used a highly sensitive antiserum against UCP1 at 1 : 2000 dilution and observed a signal in Kupffer cells, which do not express UCP1 or UCP3 but express UCP2 mRNA, suggesting that the antigen was UCP2. In the same study, Western analysis was used to show that anti-UCP1 antibodies could react with UCP2 overexpressed in yeast mitochondria.…”

Section: Immunological Detection Of Ucpsmentioning

confidence: 99%

“…The putative functions of the UCPs are related to resting or adaptive thermogenesis (including fever), metabolic adaptation to fluxes of substrates, energy partitioning and body weight regulation. In other respects, the high level of expression of the UCP2 gene in macrophages of adult mammals [30,70] and in monocytes and macrophages in foetal rodent liver [71] suggest other functions of UCP2 related to inflammation or haematopoietic system development.…”

Section: Physiology Of Ucpsmentioning

confidence: 99%

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The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP

Ricquier¹,

Bouillaud

2000

Biochemical Journal

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603

113

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Animal and plant uncoupling protein (UCP) homologues form a subfamily of mitochondrial carriers that are evolutionarily related and possibly derived from a proton\anion transporter ancestor. The brown adipose tissue (BAT) UCP1 has a marked and strongly regulated uncoupling activity, essential to the maintenance of body temperature in small mammals. UCP homologues identified in plants are induced in a cold environment and may be involved in resistance to chilling. The biochemical activities and biological functions of the recently identified mammalian UCP2 and UCP3 are not well known. However, recent data support a role for these UCPs in State 4 respiration, respiration uncoupling and proton leaks in mitochondria. Moreover, genetic studies suggest that UCP2 and UCP3 play a part in

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Section: Figure 4 Proposed Links Between the Redox State Of Coenzymesmentioning

confidence: 99%

Section: Immunological Detection Of Ucpsmentioning

confidence: 99%

Section: Physiology Of Ucpsmentioning

confidence: 99%

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The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP

Ricquier¹,

Bouillaud

2000

Biochemical Journal

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603

113

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“…[11][12][13] By tapping into the proton gradient, activated UCP2 may compete with ATP synthase for the electrochemical energy of mitochondria and result in altered cellular ATP levels. 14,15 UCP2 expression in healthy liver is primarily localized to Kupffer cells 16 ; however, UCP2 becomes strikingly abundant in hepatocytes of fatty liver. [17][18][19] Although accumulation and peroxidation of lipids in fatty hepatocytes may advance the effects of UCP2, the biological importance of these changes is not well understood.…”

mentioning

confidence: 99%

Lack of UCP2 reduces fas-mediated liver injury inob/ob mice and reveals importance of cell-specific UCP2 expression

et al. 2006

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Fatty liver is vulnerable to conditions that challenge hepatocellular energy homeostasis. Lipidladen hepatocytes highly express uncoupling protein-2 (UCP2), a mitochondrial carrier that competes with adenosine triphosphate (ATP) synthesis by mediating proton leak. However, evidence for a link between UCP2 expression and susceptibility of liver to acute injury is lacking. We asked whether absence of UCP2 protects ob/ob mice from Fas-mediated acute liver damage. UCP2-deficient ob/ob mice (ob/ob:ucp2 ؊/؊ ) and UCP2-competent littermates (ob/ob:ucp2 ؉/؉ ) received a single dose of agonistic anti-Fas antibody (Jo2). Low-dose Jo2 (0.15 mg/kg intraperitoneally) caused less serum alanine aminotransferase (ALT) elevation and lower apoptosis rates in ob/ob:ucp2 ؊/؊ mice. High-dose Jo2 (0.40 mg/kg intraperitoneally) proved uniformly fatal; however, ob/ob:ucp2 ؊/؊ mice survived longer with less depletion of liver ATP stores, indicating that fatty hepatocytes may benefit from lack of UCP2 during Jo2 challenge. Although UCP2 reportedly controls mitochondrial oxidant production, its absence had no apparent effect on fatty liver tissue malondialdehyde levels augmented by Jo2. This finding prompted us to determine UCP2 expression in Kupffer cells, a major source of intrahepatic oxidative stress. UCP2 expression was found diminished in Kupffer cells of untreated ob/ob:ucp2 ؉/؉ mice, conceivably contributing to increased oxidative stress in fatty liver and limiting the impact of UCP2 ablation. In conclusion, whereas UCP2 abundance in fatty hepatocytes exacerbates Fas-mediated injury by compromising ATP stores, downregulation of UCP2 in Kupffer cells may account for persistent oxidative stress in fatty liver. Our data support a cell-specific approach when considering the therapeutic effects of mitochondrial uncoupling in fatty liver disease. (HEPATOLOGY 2006;44:592-601.)

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“…The liver, however, is the organ in which expression of UCPs is the lowest in basal conditions since minor expression of UCP2 can be detected in the adult liver, and it is mainly due to high expression in Kupffer cells. 41 Nevertheless, in situations of metabolic stress, UCP2 expression is induced in the liver, and enhanced expression appears mainly in hepatocytes. 42 In the present study, we found that UCP2 mRNA expression was reduced in Lou/C as compared to Wistar rats with a standard high-carbohydrate diet and increased significantly when allowed to increase their fat intake ( Figure 4).…”

Section: Discussionmentioning

confidence: 99%

Liver mitochondrial properties from the obesity-resistant Lou/C rat

et al. 2008

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Objective: The first objective was to evaluate the influence of caloric intake on liver mitochondrial properties. The second objective was aimed at determining the impact of increasing fat intake on these properties. Design: Lou/C rats, displaying an inborn low caloric intake and resistant to diet-induced obesity, were compared to Wistar rats fed either ad libitum or pair-fed. An additional group of Lou/C rats were allowed to increase their fat intake by adjusting their diet from a standard high carbohydrate low-fat diet to a high-fat carbohydrate-free diet. Measurements: Hydrogen peroxide (H 2 O 2 ) generation, oxygen consumption rate (J O2 ), membrane potential (DC), activity of respiratory chain complexes, cytochrome contents, oxidative phosphorylation efficiency (OPE) and uncoupling protein 2 (UCP2) expression were determined in liver mitochondria. Results: H 2 O 2 production was higher in Lou/C than Wistar rats with glutamate/malate and/or succinate, octanoyl-carnitine, as substrates. These mitochondrial features cannot be mimicked by pair-feeding Wistar rats and remained unaltered by increasing fat intake. Enhanced H 2 O 2 production by mitochondria from Lou/C rats is due to an increased reverse electron flow through the respiratory-chain complex I and a higher medium-chain acyl-CoA dehydrogenase activity. While J O 2 was similar over a large range of DC in both strains, Lou/C rats were able to sustain higher membrane potential and respiratory rate. In addition, mitochondria from Lou/C rats displayed a decrease in OPE that cannot be explained by increased expression of UCP2 but rather to a slip in proton pumping by cytochrome oxidase. Conclusions: Liver mitochondria from Lou/C rats display higher reactive oxygen species (ROS) generation but to deplete upstream electron-rich intermediates responsible for ROS generation, these animals increased intrinsic uncoupling of cytochrome oxidase. It is likely that liver mitochondrial properties allowed this strain of rat to display higher insulin sensitivity and resist diet-induced obesity.

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Kupffer Cells Are a Dominant Site of Uncoupling Protein 2 Expression in Rat Liver

Cited by 134 publications

References 21 publications

The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP

The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP

Lack of UCP2 reduces fas-mediated liver injury inob/ob mice and reveals importance of cell-specific UCP2 expression

Liver mitochondrial properties from the obesity-resistant Lou/C rat

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