Enhanced inflammatory responses in α-tocopherol transfer protein null mice

Schock, Bettina; Vliet, Albert van der; Corbacho, Ana; Leonard, Scott W.; Finkelstein, Erik I.; Valacchi, Giuseppe; Obermueller-Jevic, Ute; Cross, Carroll E.; Traber, Maret G.

doi:10.1016/j.abb.2003.12.009

Cited by 41 publications

(42 citation statements)

References 50 publications

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“…The results are presented in Table 1 and are similar to those reported earlier by our laboratory [23,24] and indicate that the plasma levels of aT decline by 10X when TTP is completely removed and gT declined as well going below the detection limit of the HPLC based assay in the case of the TTP -/-TRAMP+ animals. …”

Section: Plasma Tocopherol Levelssupporting

confidence: 87%

Producing a Mouse Model to Explore the Linkages Between Tocopherol Biology and Prostate Cancer

Davis¹

2005

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Section: Plasma Tocopherol Levelssupporting

confidence: 87%

Producing a Mouse Model to Explore the Linkages Between Tocopherol Biology and Prostate Cancer

Davis¹

2005

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“…Taken together, the available evidence indicates that serum ␣-tocopherol concentration is correlated with serum lipid concentration but is not affected by hepatic ␣-TTP level in animals with acute liver injury. Since ␣-TTP knockout mice have very low ␣-tocopherol concentrations in the serum and peripheral tissues, it has been suggested that extremely low levels of hepatic ␣-TTP could reduce ␣-tocopherol transfer activity from the liver to the serum (3)(4)(5). In the case of ␣-TTP hetero-knockout mice, in which hepatic ␣-TTP content is about 50% of that in normal animals, serum and peripheral ␣-tocopherol concentrations at 3 mo of age are 30% lower than normal (4).…”

Section: Resultsmentioning

confidence: 99%

“…It has now been established that ␣ -TTP, through this mechanism, is a major determinant of plasma ␣ -tocopherol level. In fact, humans with a defective ␣ -TTP gene have severe vitamin E deficiency ( 2 ), and depletion of the ␣ -TTP gene in mice results in severely reduced plasma and tissue ␣ -tocopherol concentrations (3)(4)(5). Although genetic ␣ -TTP deficiency severely affects serum and peripheral tissue ␣ -tocopherol concentrations, effects of the reduction of hepatic ␣ -TTP level on serum or liver ␣ -tocopherol under physiological conditions have been reported in only a very few cases ( 6 , 7 ).…”

mentioning

confidence: 99%

Galactosamine-Induced Acute Liver Injury in Rats Reduces Hepatic .ALPHA.-Tocopherol Transfer Protein Production

Takenaka

Kita

Ikeya

et al. 2007

J Nutr Sci Vitaminol

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SummaryThe liver plays the main role in the secretion of food-derived ␣ -tocopherol into the circulation through the functioning of ␣ -tocopherol transfer protein ( ␣ -TTP). However, the effect of liver disease on ␣ -TTP level and ␣ -tocopherol metabolism has not been clarified. We examined the amount of liver ␣ -TTP and its effect on serum ␣ -tocopherol concentration in liver injury. Male Wistar rats were injected intraperitoneally with D -galactosamine at 800 mg/kg body weight, and liver and serum lipid concentrations, ␣ -tocopherol concentrations, and hepatic ␣ -TTP mRNA and protein levels were measured at 24, 48, and 72 h after injection. On the basis of body weight changes and serum transaminase activities, the livers were found to be in an injured state 24 and 48 h after galactosamine injection but had recovered by 72 h. The hepatic ␣ -TTP mRNA level was reduced throughout the experimental period, and at 48 h after injection the ␣ -TTP protein level had begun to decrease. Lipid and ␣ -tocopherol concentrations in the serum were decreased at 24 and 48 h after injection and increased at 72 h. Liver lipid concentrations were increased at 24 and 48 h after injection, but the liver ␣ -tocopherol concentration was unchanged. These results show that galactosamine-induced liver injury decreases hepatic ␣ -TTP synthesis in rats. Serum ␣ -tocopherol concentration was not directly affected by the acute change in hepatic ␣ -TTP level, suggesting that the chronic changes in ␣ -TTP activity would be necessary to regulate serum ␣ -tocopherol concentration.

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“…Vitamin C treatment was shown to increase eNOS activity in ECs specifically via chemical stabilization of BH 4 (9,21). Augmentation of endothelial BH 4 levels by adenovirus-mediated overexpression of the ratelimiting enzyme for BH 4 synthesis, GTP cyclohydrolase 1 (GTPCH), was similarly found to restore eNOS activity in high-glucose-treated human ECs in culture (7) in rodent blood vessels of ApoE-null (42) and streptozotocin models (36) of atherosclerosis and diabetes, respectively. BH 4 supplementation was also shown to acutely improve endothelial dysfunction in chronic smokers (20) and patients with hypercholesterolemia (46), diabetes (37,44), or ischemia-reperfusion injury (48).…”

mentioning

confidence: 99%

Ratio of 5,6,7,8-tetrahydrobiopterin to 7,8-dihydrobiopterin in endothelial cells determines glucose-elicited changes in NO vs. superoxide production by eNOS

Crabtree¹,

Smith²,

Lam³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

178

191

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Crabtree MJ, Smith CL, Lam G, Goligorsky MS, Gross SS. Ratio of 5,6,7,8-tetrahydrobiopterin to 7,8-dihydrobiopterin in endothelial cells determines glucose-elicited changes in NO vs. superoxide production by eNOS. Am J Physiol Heart Circ Physiol 294: H1530-H1540, 2008. First published January 11, 2008 doi:10.1152/ajpheart.00823.2007 is an essential cofactor of nitric oxide synthases (NOSs). Oxidation of BH4, in the setting of diabetes and other chronic vasoinflammatory conditions, can cause cofactor insufficiency and uncoupling of endothelial NOS (eNOS), manifest by a switch from nitric oxide (NO) to superoxide production. Here we tested the hypothesis that eNOS uncoupling is not simply a consequence of BH4 insufficiency, but rather results from a diminished ratio of BH4 vs. its catalytically incompetent oxidation product, 7,8-dihydrobiopterin (BH2). In support of this hypothesis, [ 3 H]BH4 binding studies revealed that BH4 and BH2 bind eNOS with equal affinity (Kd Ϸ 80 nM) and BH2 can rapidly and efficiently replace BH4 in preformed eNOS-BH4 complexes. Whereas the total biopterin pool of murine endothelial cells (ECs) was unaffected by 48-h exposure to diabetic glucose levels (30 mM), BH2 levels increased from undetectable to 40% of total biopterin. This BH2 accumulation was associated with diminished calcium ionophore-evoked NO activity and accelerated superoxide production. Since superoxide production was suppressed by NOS inhibitor treatment, eNOS was implicated as a principal superoxide source. Importantly, BH4 supplementation of ECs (in low and high glucose-containing media) revealed that calcium ionophore-evoked NO bioactivity correlates with intracellular BH4: BH2 and not absolute intracellular levels of BH4. Reciprocally, superoxide production was found to negatively correlate with intracellular BH4:BH2. Hyperglycemia-associated BH4 oxidation and NO insufficiency was recapitulated in vivo, in the Zucker diabetic fatty rat model of type 2 diabetes. Together, these findings implicate diminished intracellular BH4:BH2, rather than BH4 depletion per se, as the molecular trigger for NO insufficiency in diabetes. nitric oxide; diabetes; endothelial dysfunction NITRIC OXIDE (NO) is a biological messenger that is produced by enzymes of the nitric oxide synthase (NOS) gene family, comprising endothelial (eNOS), inducible (iNOS), and neuronal (nNOS) isoforms. In the vasculature, eNOS-derived NO plays a pivotal role in physiological regulation of vessel tone and inflammatory status (58). Diminished availability of eNOS-derived NO is common to chronic vascular disorders that share endothelial dysfunction as a hallmark, e.g., diabetes (11,37,60), hypertension (28), and atherosclerosis (28,46). While the mechanistic basis for this attenuated NO bioavailability is uncertain, both slowed NO synthesis and accelerated NO scavenging by reactive oxygen species (ROS) have been implicated as causes (16). In contrast, levels of eNOS protein are typically unchanged or paradoxically increased. Oxidative stress, imposed by exce...

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Enhanced inflammatory responses in α-tocopherol transfer protein null mice

Cited by 41 publications

References 50 publications

Producing a Mouse Model to Explore the Linkages Between Tocopherol Biology and Prostate Cancer

Producing a Mouse Model to Explore the Linkages Between Tocopherol Biology and Prostate Cancer

Galactosamine-Induced Acute Liver Injury in Rats Reduces Hepatic .ALPHA.-Tocopherol Transfer Protein Production

Ratio of 5,6,7,8-tetrahydrobiopterin to 7,8-dihydrobiopterin in endothelial cells determines glucose-elicited changes in NO vs. superoxide production by eNOS

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