title: Lactase gene transcription is activated in response to hypoxia in intestinal epithelial cells.
abstract: Lactase-phlorizin hydrolase, a brush-border membrane disaccharidase, is a marker of intestinal epithelial cell differentiation and digestive function. The intestine is susceptible to conditions of hypoxia resulting from vascular perfusion deficits. We hypothesized that lactase gene induction may provide a mechanism to efficiently increase nutrient energy substrates during gut hypoxia. These studies sought to characterize expression of the lactase gene in response to hypoxia and to characterize a role for hypoxia-inducible factor (HIF-1) in mediating the hypoxic response. Microarray analysis and confirmatory RT-PCR identified a 4-fold induction of lactase mRNA abundance in intestinal epithelial Caco-2 cells exposed to hypoxia. Lactase promoter activity was similarly induced by hypoxia in cells stably transfected with a 2.0-kb 5' flanking region of the rat lactase gene linked to a reporter gene. Transient cotransfection with HIF-1alpha and beta stimulated lactase promoter activity 2.4- and 3.5-fold under conditions of normoxia and hypoxia, respectively. We conclude that HIF-1 can activate the lactase promoter in intestinal epithelial cells exposed to hypoxia. Induction of lactase transcription may represent an adaptive response to gut hypoxia.
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: So Young
authors.initials: SY
authors.lastname: Lee
authors.forename: Ashima
authors.initials: A
authors.lastname: Madan
authors.forename: Glenn T
authors.initials: GT
authors.lastname: Furuta
authors.forename: Sean P
authors.initials: SP
authors.lastname: Colgan
authors.forename: Eric
authors.initials: E
authors.lastname: Sibley
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D000860:Hypoxia / Q000201:enzymology* / Q000235:genetics; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007413:Intestinal Mucosa / Q000201:enzymology* / Q000502:physiology; D043322:Lactase; D010694:Lactase-Phlorizin Hydrolase / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D014157:Transcription Factors; D015533:Transcriptional Activation; D001616:beta-Galactosidase / Q000235:genetics* / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; C497444:Hif1a protein, rat; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D043322:Lactase; D001616:beta-Galactosidase; D010694:Lactase-Phlorizin Hydrolase