Disturbed Cholesterol Homeostasis in a Peroxisome-Deficient <i>PEX2</i> Knockout Mouse Model

Kovacs, Werner J.; Shackelford, Janis E.; Tape, Khanichi N.; Richards, Michael J.; Faust, Phyllis L.; Fliesler, Steven J.; Krisans, Skaidrite K.

doi:10.1128/mcb.24.1.1-13.2004

Cited by 51 publications

(92 citation statements)

References 62 publications

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“…In particular, peroxisomes seem to be necessary for the maintenance of the integrity of the inner mitochondrial membrane, a finding that confirms previous observations in patients 4,[6][7][8][9] and other mouse models. 13,36,37 Some of the presently observed ultrastructural changes at the inner mitochondrial membrane were similar to the alterations in Zellweger patients. However, crystalline inclusions in mitochondria were not seen in the livers of L-Pex5 knockout mice.…”

Section: Discussionsupporting

confidence: 48%

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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Section: Discussionsupporting

confidence: 48%

Absence of peroxisomes in mouse hepatocytes causes mitochondrial and ER abnormalities

et al. 2005

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“…9). This could not be explained by biosynthesis because: (1) expression of the classic pathway CYP7A1 gene is reduced 0.5-fold in early postnatal untreated mutants 9 and remains strongly suppressed in all P36 mutants, and (2) bile acid synthesis genes are down-regulated by bile acid treatment in PEX2 Ϫ/Ϫ mice (P. Faust, manuscript in preparation). Rather, our study showed that changes in basolateral bile acid transporter expressions, including decreased Ntcp, increased Mrp3, and decreased/absent Oatps, acted to exclude bile acids and their conjugates from PEX2 Ϫ/Ϫ hepatocytes, requiring excretion from alternate renal pathways 29 that may also be limiting.…”

Section: Discussionmentioning

confidence: 99%

“…5 Control mice had either PEX2 ϩ/ϩ or ϩ/Ϫ genotypes as biochemical and morphologic measures did not differ. 8,9 All protocols for animal use and experiments were reviewed and approved by the Institutional Animal Care and Use Committee of Columbia University.…”

Section: Methodsmentioning

confidence: 99%

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Bile acid treatment alters hepatic disease and bile acid transport in peroxisome-deficientPEX2Zellweger mice

et al. 2007

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The marked deficiency of peroxisomal organelle assembly in the PEX2 ؊/؊ mouse model for Zellweger syndrome provides a unique opportunity to developmentally and biochemically characterize hepatic disease progression and bile acid products. The postnatal survival of homozygous mutants enabled us to evaluate the response to bile acid replenishment in this disease state. PEX2 mutant liver has severe but transient intrahepatic cholestasis that abates in the early postnatal period and progresses to steatohepatitis by postnatal day 36. We confirmed the expected reduction of mature C24 bile acids, accumulation of C27-bile acid intermediates, and low total bile acid level in liver and bile from these mutant mice. Treating the PEX2 ؊/؊ mice with bile acids prolonged postnatal survival, alleviated intrahepatic cholestasis and intestinal malabsorption, reduced C27-bile acid intermediate production, and prevented older mutants from developing severe steatohepatitis. However, this therapy exacerbated the degree of hepatic steatosis and worsened the already severe mitochondrial and cellular damage in peroxisome-deficient liver. Both untreated and bile acid-fed PEX2 ؊/؊ mice accumulated high levels of predominantly unconjugated bile acids in plasma because of altered expression of hepatocyte bile acid transporters. Significant amounts of unconjugated bile acids were also found in the liver and bile of PEX2 mutants, indicating a generalized defect in bile acid conjugation. Conclusion: Peroxisome deficiency widely disturbs bile acid homeostasis and hepatic functioning in mice, and the high sensitivity of the peroxisome-deficient liver to bile acid toxicity limits the effectiveness of bile acid therapy for preventing hepatic disease. (HEPATOLOGY 2007;45:982-997.)

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“…We recently examined cholesterol homeostasis in mice lacking functional peroxisomes (PEX2 Ϫ/Ϫ mice), and demonstrated that: 1) PEX2 Ϫ/Ϫ mice had significantly decreased total cholesterol and high density lipoprotein (HDL) cholesterol levels in plasma; 2) the steady-state cholesterol content in PEX2 Ϫ/Ϫ liver was decreased by 40% relative to control mouse liver; 3) PEX2 Ϫ/Ϫ mice did not lose cholesterol by catabolism to bile acids or excretion in the stool; and 4) PEX2 Ϫ/Ϫ mice failed to maintain normal cholesterol balance, despite a dramatic increase in SREBP-2, its target genes, and cholesterol biosynthesis in most tissues (12).…”

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confidence: 99%

Peroxisome Deficiency Causes a Complex Phenotype because of Hepatic SREBP/Insig Dysregulation Associated with Endoplasmic Reticulum Stress

Kovacs

Tape

Shackelford

et al. 2009

Journal of Biological Chemistry

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Regulation of hepatic cholesterol biosynthesis, lipogenesis, and insulin signaling intersect at the transcriptional level by control of SREBP and Insig genes. We previously demonstrated that peroxisome-deficient PEX2 ؊/؊ mice activate SREBP-2 pathways but are unable to maintain normal cholesterol homeostasis. In this study, we demonstrate that oral bile acid treatment normalized hepatic and plasma cholesterol levels and hepatic cholesterol synthesis in early postnatal PEX2 mutants, but SREBP-2 and its target gene expressions remained increased. SREBP-2 pathway induction was also observed in neonatal and longer surviving PEX2 mutants, where hepatic cholesterol levels were normal. Abnormal expression patterns for SREBP-1c and Insig-2a, and novel regulation of Insig-2b, further demonstrate that peroxisome deficiency widely affects the regulation of related metabolic pathways. We have provided the first demonstration that peroxisome deficiency activates hepatic endoplasmic reticulum (ER) stress pathways, especially the integrated stress response mediated by PERK and ATF4 signaling. Our studies suggest a mechanism whereby ER stress leads to dysregulation of the endogenous sterol response mechanism and concordantly activates oxidative stress pathways. Several metabolic derangements in peroxisome-deficient PEX2 ؊/؊ liver are likely to trigger ER stress, including perturbed flux of mevalonate metabolites, altered bile acid homeostasis, changes in fatty acid levels and composition, and oxidative stress.

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Disturbed Cholesterol Homeostasis in a Peroxisome-Deficient PEX2 Knockout Mouse Model

Cited by 51 publications

References 62 publications

Absence of peroxisomes in mouse hepatocytes causes mitochondrial and ER abnormalities

Absence of peroxisomes in mouse hepatocytes causes mitochondrial and ER abnormalities

Bile acid treatment alters hepatic disease and bile acid transport in peroxisome-deficientPEX2Zellweger mice

Peroxisome Deficiency Causes a Complex Phenotype because of Hepatic SREBP/Insig Dysregulation Associated with Endoplasmic Reticulum Stress

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