Identification of hepatic molecular mechanisms of action of alpha-tocopherol using global gene expression profile analysis in rats.
The recent discovery that vitamin E (VE) regulates gene activity at the transcriptional level indicates that VE may exert part of its biological effects by mechanisms which may be independent of its well-recognised antioxidant function. The objective of this study was the identification of hepatic vitamin E-sensitive genes and examination of the effects of VE on their corresponding biological endpoints. Two groups of male rats were randomly assigned to either a VE-sufficient diet or to a control diet deficient in VE for 290 days. High-density oligonucleotide microarrays comprising over 7000 genes were used to assess the transcriptional response of the liver. Differential gene expression was monitored over a period of 9 months, at four different time-points, and rats were individually profiled. This experimental strategy identified several VE-sensitive genes, which were chronically altered by dietary VE. VE supplementation down-regulated scavenger receptor CD36, coagulation factor IX and 5-alpha-steroid reductase type 1 mRNA levels while hepatic gamma glutamyl-cysteinyl synthetase was significantly up-regulated. Measurement of the corresponding biological endpoints such as activated partial thromboplastin time, plasma dihydrotestosterone and hepatic glutathione substantiated the gene chip data which indicated that dietary VE plays an important role in a range of metabolic processes within the liver.
Barella
Luca
L
DSM Nutritional Products (registered as Roche Vitamins Ltd), Human Nutrition and Health, P O Box 3255, CH-4002 Basel, Switzerland.
Muller
Patrick Y
PY
Schlachter
Manfred
M
Hunziker
Willi
W
Stöcklin
Elisabeth
E
Spitzer
Volker
V
Meier
Nina
N
de Pascual-Teresa
Sonia
S
Minihane
Anne-Marie
AM
Rimbach
Gerald
G
D000821:Animal Feed; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D018955:CD36 Antigens; D005164:Factor IX / Q000235:genetics; D020869:Gene Expression Profiling; D005721:Glutamate-Cysteine Ligase / Q000235:genetics; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D011770:Pyruvate Kinase / Q000097:blood / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011971:Receptors, Immunologic / Q000235:genetics; D051116:Receptors, Scavenger; D013997:Time Factors; D024502:alpha-Tocopherol / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*
D018955:CD36 Antigens; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; D005164:Factor IX; D011770:Pyruvate Kinase; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D024502:alpha-Tocopherol