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

Péter Fülöp, Zoltán Derdák, Anthony Sheets, Edmond Sabo, Eric P. Berthiaume, Murray B. Resnick, Jack R. Wands, G. Paragh, György Baffy

Research output: Contribution to journalArticle

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Abstract

Fatty liver is vulnerable to conditions that challenge hepatocellular energy homeostasis. Lipid-laden 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 oblob:ucp2-/- mice. High-dose Jo2 (0.40 mg/kg intraperitoneally) proved uniformly fetal; 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 Ui fatty liver. Our data support a cell-specific approach when considering the therapeutic effects of mitochondrial uncoupling in fatty liver disease.

Original languageEnglish
Pages (from-to)592-601
Number of pages10
JournalHepatology
Volume44
Issue number3
DOIs
Publication statusPublished - Sep 2006

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Liver
Wounds and Injuries
Fatty Liver
Kupffer Cells
Hepatocytes
Oxidative Stress
Adenosine Triphosphate
Uncoupling Protein 2
Therapeutic Uses
Leptin
Malondialdehyde
Alanine Transaminase
Oxidants
Protons
Adipose Tissue
Liver Diseases
Anti-Idiotypic Antibodies
Homeostasis
Down-Regulation
Apoptosis

ASJC Scopus subject areas

  • Hepatology

Cite this

Fülöp, P., Derdák, Z., Sheets, A., Sabo, E., Berthiaume, E. P., Resnick, M. B., ... Baffy, G. (2006). Lack of UCP2 reduces Fas-mediated liver injury in ob/ob mice and reveals importance of cell-specific UCP2 expression. Hepatology, 44(3), 592-601. https://doi.org/10.1002/hep.21310

Lack of UCP2 reduces Fas-mediated liver injury in ob/ob mice and reveals importance of cell-specific UCP2 expression. / Fülöp, Péter; Derdák, Zoltán; Sheets, Anthony; Sabo, Edmond; Berthiaume, Eric P.; Resnick, Murray B.; Wands, Jack R.; Paragh, G.; Baffy, György.

In: Hepatology, Vol. 44, No. 3, 09.2006, p. 592-601.

Research output: Contribution to journalArticle

Fülöp, P, Derdák, Z, Sheets, A, Sabo, E, Berthiaume, EP, Resnick, MB, Wands, JR, Paragh, G & Baffy, G 2006, 'Lack of UCP2 reduces Fas-mediated liver injury in ob/ob mice and reveals importance of cell-specific UCP2 expression', Hepatology, vol. 44, no. 3, pp. 592-601. https://doi.org/10.1002/hep.21310
Fülöp, Péter ; Derdák, Zoltán ; Sheets, Anthony ; Sabo, Edmond ; Berthiaume, Eric P. ; Resnick, Murray B. ; Wands, Jack R. ; Paragh, G. ; Baffy, György. / Lack of UCP2 reduces Fas-mediated liver injury in ob/ob mice and reveals importance of cell-specific UCP2 expression. In: Hepatology. 2006 ; Vol. 44, No. 3. pp. 592-601.
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