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Absence of peroxisomes in mouse hepatocytes causes mitochondrial and ER abnormalities
Author(s) -
Dirkx Ruud,
Vanhorebeek Ilse,
Martens Katrin,
Schad Arno,
Grabenbauer Markus,
Fahimi Dariush,
Declercq Peter,
Van Veldhoven Paul P.,
Baes Myriam
Publication year - 2005
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.20628
Subject(s) - peroxisome , biology , hepatocyte , endoplasmic reticulum , mitochondrion , medicine , endocrinology , microbiology and biotechnology , lipid droplet , peroxisome proliferator activated receptor , lipid metabolism , peroxisome proliferator activated receptor alpha , mitochondrial biogenesis , biochemistry , receptor , nuclear receptor , transcription factor , gene , in vitro
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-alpha) regulated genes indicated that PPAR-alpha is activated in the peroxisome-deficient 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).