Metabolic aspects of peroxisomal β-oxidation

Osmundsen, Harald; Bremer, Jon; Pedersen, Jan I.

doi:10.1016/0005-2760(91)90089-z

Cited by 270 publications

(152 citation statements)

References 202 publications

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“…This could be due to elevated concentrations of intracellular fatty acids within the liver parenchyma that have already been shown to be directly toxic to hepatocytes, leading to oxidative stress, inflammation and fibrogenesis, but not to mitochondrial toxicity. 33,34 This could also be due to the overexpression of genes such as IGF2, IGFB4 and IGFBP acid labile unit or Claudin3 or hepsin acting through TGFB1 activation of Kupffer cells/macrophages or stellate cells leading to remodelling of extracellular matrix or activating cells to growth as in liver regeneration or activating apoptosis in hepatic cells to control the hepatocyte mass. [35][36][37][38] TGFB1 and IGF2 protein expression was increased in most of the samples exhibiting either steatosis or steatohepatitis and corroborate our results of gene expression profiling.…”

Section: Discussionmentioning

confidence: 99%

Exploration of global gene expression in human liver steatosis by high-density oligonucleotide microarray

Chiappini

Barrier

Saffroy

et al. 2006

Laboratory Investigation

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Understanding the molecular mechanisms underlying fatty liver disease (FLD) in humans is of major importance. We used high-density oligonucleotide microarrays (22.3 K) to assess the mechanisms responsible for the development of human liver steatosis. We compared global gene expression in normal (n ¼ 9) and steatotic (n ¼ 9) livers without histological signs of inflammation or fibrosis. A total of 34 additional human samples including normal (n ¼ 11), steatosis (n ¼ 11), HCV-related steatosis (n ¼ 4) or steatohepatitis associated with alcohol consumption (n ¼ 4) or obesity (n ¼ 4) were used for immunohistochemistry or quantitative realtime PCR studies. With unsupervised classification (no gene selection), all steatotic liver samples clustered together. Using step-down maxT multiple testing procedure for controlling the Family-Wise Error-Rate at level 5%, 110 cDNAs (100 over-and 10 underexpressed) were found to be differentially expressed in steatotic and normal livers. Of them were genes involved in mitochondrial phosphorylative and oxidative metabolism. The mean ratio of mitochondrial DNA to nuclear DNA content was higher in liver steatosis compared to normal liver biopsies (1.1270.14 vs 0.6770.10; P ¼ 0.01). An increased expression of genes involved in inflammation (IL-1R family, TGFB) was also observed and confirmed by quantitative RT-PCR or immunochemistry. In steatohepatitis, an increase of the protein expression of mitochondrial antigens, IL-1R1, IGF2 and TGFB1 was also observed, interleukin 1 receptor being always strongly expressed in steatohepatitis linked to alcohol or obesity. In conclusion, mitochondrial alterations play a major role in the development of steatosis per se. Activation of inflammatory pathways is present at a very early stage of steatosis, even if no morphological sign of inflammation is observed. Laboratory Investigation (2006) 86, 154-165.

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Section: Discussionmentioning

confidence: 99%

Exploration of global gene expression in human liver steatosis by high-density oligonucleotide microarray

Chiappini

Barrier

Saffroy

et al. 2006

Laboratory Investigation

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“…The contribution of mitochondria and peroxisomes to fatty-acid oxidation highly depends on the fatty acid (Osmundsen et al, 1991). In their study on tissue homogenates, Reubsaet etal (1989) (1986) observed that 22:4n-6 and 20:5n-3 were oxidized to a greater extent in peroxisomes than 18:1 n-9, 18:2n-6, 20:4n-6 and 22:6n-3.…”

Section: Dietary Sources Of Essential Fatty Acidsmentioning

confidence: 99%

“…In livers of rats fed high-fat diets, peroxisomal (3-oxidation is stimulated, in particular when the diet contains a high proportion of very long-chain fatty acids, as in hydrogenated fish oils, known to be poorly P-oxidized in mitochondria (Osmundsen et al, 1991). Polyunsaturated n-3 fatty acids are particularly potent stimulators of oxidation.…”

Section: Dietary Sources Of Essential Fatty Acidsmentioning

confidence: 99%

The metabolism and availability of essential fatty acids in animal and human tissues

Bézard

Blond²,

Bernard³

et al. 1994

Reprod. Nutr. Dev.

191

109

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Summary ― Essential fatty acids (EFA), which are not synthesized in animal and human tissues, belong to the n-6 and n-3 families of polyunsaturated fatty acids (PUFA), derived from linoleic acid (LA,) and a-linolenic acid (LNA,. Optimal requirements are 3-6% of ingested energy for LA and 0.5-1% for LNA in adults. Requirements in LNA are higher in development. Dietary sources of LA and LNA are principally plants, while arachidonic acid (AA,) is found in products from terrestrian animals, and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)

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“…The etiology of NASH remains elusive, but most investigators agree that a baseline of steatosis requires a second "hit" capable of inducing inflammation, fibrosis, or necrosis in order to develop NASH. Oxidative stress, with the accumulation of lipid peroxidation products, mitochondrial dysfunction [3][4][5], endotoxins derived from the gut, and inflammatory cytokines in the liver have been implicated in the initiation of liver injury in NASH [5][6][7][8]. Glutathione (GSH) is a major endogenous antioxidant, and GSH prodrugs are attractive therapy for many forms of liver injury.…”

Section: Introductionmentioning

confidence: 99%

Glutathione‐enhancing agents protect against steatohepatitis in a dietary model

Chen

et al. 2006

J Biochem & Molecular Tox

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Nonalcoholic fatty liver (NAFL) and steatohepatitis (NASH) may accompany obesity, diabetes, parenteral nutrition, jejeuno-ileal bypass, and chronic inflammatory bowel disease. Currently there is no FDA approved and effective therapy available. We investigated the potential efficacy of those agents that stimulate glutathione (GSH) biosynthesis on the development of experimental steatohepatitis. Rats fed (ad libitum) amino acid based methionine-choline deficient (MCD) diet were further gavaged with (1) vehicle (MCD), (2) S-adenosylmethionine (SAMe), or (3) 2(RS)-n-propylthiazolidine-4(R)-carboxylic acid (PTCA). Results: MCD diet significantly reduced hematocrit, and this abnormality improved in the treated groups ( p < 0.01). Serum transaminases were considerably elevated (AST: 5.8-fold; ALT: 3.22-fold) in MCD rats. However, administration of GSH-enhancing agents significantly suppressed these abnormal enzyme activities. MCD rats developed severe liver pathology manifested by fatty degeneration, inflammation, and necrosis, which significantly improved with therapy. Blood levels of GSH were significantly depleted in MCD rats but normalized in the treated groups. Finally, RT-PCR measurements showed a significant upregulation of genes involved in tissue remodeling and fibrosis (matrix metalloproteinases, collagen-␣1), suppressor of cytokines signaling1, and the inflammatory cytokines (IL-1␤, IL-6, TNF-␣, and TGF-␤) in the livers of rats fed MCD. GSH-enhancing therapies significantly attenuated the expression of deleterious proinflammatory and fibrogenic genes in this dietary model. This is the first report that oral administration of SAMe and PTCA provide protection against liver injury in this model and suggests therapeutic applications of these compounds in NASH patients. C

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Metabolic aspects of peroxisomal β-oxidation

Cited by 270 publications

References 202 publications

Exploration of global gene expression in human liver steatosis by high-density oligonucleotide microarray

Exploration of global gene expression in human liver steatosis by high-density oligonucleotide microarray

The metabolism and availability of essential fatty acids in animal and human tissues

Glutathione‐enhancing agents protect against steatohepatitis in a dietary model

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