New Protein Could Prove Powerful Target for Cholesterol Lowering Drugs
A protein has been discovered that may have a profound effect on cholesterol metabolism. That discovery raises the possibility that the protein, dubbed IDOL, could be a powerful target for cholesterol-lowering drugs, says corresponding author Peter Tontonoz of the Howard Hughes Medical Institute and the University of California, Los Angeles. The research is published in the May 2011 edition of the journal Molecular and Cellular Biology.
The mechanism is simple. The major regulator of cholesterol levels in the blood is the low density lipoprotein receptor. It controls blood cholesterol levels by transporting cholesterol from the blood into the cells. Tontonoz and his collaborators recently discovered that IDOL can break down low density lipoprotein receptors, thus preventing them from removing cholesterol from the blood. (IDOL stands for Inducible Degrader Of the Low-density lipoprotein receptor.)
In the study, in order to test their hypothesis that interfering with IDOL could boost cholesterol transport out of the blood, the researchers developed and characterized embryonic stem cells that lack the IDOL gene. "We showed that cells lacking IDOL exhibit markedly elevated levels of the low density lipoprotein receptor protein, and increased rates of low density lipoprotein uptake by the cells," says Tontonoz. They also found that absent IDOL, the lifetimes of low density lipoprotein receptors are prolonged. They demonstrated further that the increases in low density lipoprotein receptor caused by the absence of IDOL, and by statin drugs are additive, suggesting that inactivating IDOL might ultimately enhance statins' cholesterol lowering effects in humans.
A further finding is that IDOL functions independently of another protein previously known to regulate low density lipoproteins, called PCSK9.
"Our study raises the possibility that IDOL could be a target for drugs to lower human cholesterol levels; however, future work is needed to test this idea," says Tontonoz. "Our current study analyzed only cells that lack IDOL. An important next step is to analyze whole mice that lack IDOL in order to determine the importance of IDOL in vivo."
Despite the negative effects too much blood cholesterol has to cardiovascular health, this compound plays critical roles in living systems, including as a precursor to steroid hormones, and in developmental signaling, and control of membrane fluidity.
(E. Scotti, C. Hong, Y. Yoshinaga, Y. Tu, Y. Hu, N. Zelccer, R. Boyadjian, P.J. de Jong, S.G. Young, L.G. Fong, and P. Tontonoz, 2011. Targeted disruption of the idol gene alters cellular regulation of the low-density lipoprotein receptor by sterols and liver X receptor agonists. Mol. Cell. Biol. 31:1885-1893.)
Boston Researchers Identify New Dental Cavity-Causing Species
A team of scientists from Boston has confirmed that the bacterium Streptococcus mutans is a primary culprit in early childhood caries (EEC) cavities on the first set of teeth, and has identified a new species of bacterium, Scardovia wiggsiae, which they suspect is also a major contributor. They report their findings in the Journal of Clinical Microbiology.
The study's ultimate goal was to determine which bacterial species should be suppressed "to prevent cavity formation," says Anne Tanner, of the Forsyth Institute, Cambridge, MA. EEC is the most common chronic infectious disease of childhood in the US. It afflicts one quarter of the relevant population, and more than one half among certain disadvantaged socioeconomic groups.
In this study, the researchers compared the bacterial populations in samples of dental plaque taken from deep cavities in afflicted children, with plaque from matched sites in cavity-free children. They identified species using 16S ribosomal RNA (16S rRNA). Ribosomes are the machinery that translate the genetic code into protein, and 16S rRNA differs among species. Since high acidity causes caries, and since only acid tolerant bacteria can survive in levels of acidity associated with active caries, they cultured bacteria under acidic conditions to select for species likely to play important roles in cariogenesis.
"We detected the major caries pathogen of childhood caries, S. mutans, in many of the children with advanced caries," says Tanner. In addition, they the found the new species, S. wiggsiae, in a high proportion of plaque samples from cavities, including in several such samples from which S. mutans was absent. S. wiggsiae can tolerate the level of acidity in active caries, leading the team to speculate that it causes cavities.
Over and above normal dental care, measures to suppress cariogenic bacteria include mouth rinses such as chlorhexidine, Povodine iodine, fluoride, and the use of sugar substitutes, says Tanner. "By removing a primary sugar carbohydrate from the diet, the more cariogenic bacteria would make less acid, and might no longer be able to outcompete non-cariogenic plaque bacteria." Managing very young children for severe caries is difficult, and they are often treated under general anaesthesia.
A.C.R. Tanner, J.M.J. Mathney, R.L. Kent, Jr., N.I. Chalmers, C.V. Hughes, C.Y. Loo, N. Pradhan, E. Kanasi, J. Hwang, M.A. Dahlan, E. Papadopolou, and F.E. Dewhirst, 2011. Cultivable anaerobic microbiota of severe early childhood caries. J. Clin. Microbiol. 49:1464-1474.
Genomic Archeology Reveals Early Evolution of Sex Chromosomes
A team from Uppsala University, Uppsala, Sweden, is using genomics to shed light on the early evolutionary history of sex chromosomes. The research is published in the April 2011 Eukaryotic Cell.
Among other things, the genome is a place where the distant past can be investigated. Researchers have used it most notably to trace the relationships among species far more accurately than can be done with conventional methods.
Sex chromosomes in animals are so ancientin the hundreds of millions of years old--that they retain few traces of the historical events that drove their evolution. But the researchers had found in earlier studies that the mating type chromosomes in the self-fertilizing fungus, Neurospora tetrasperma, which are analogous to X and Y in sexually reproducing organisms, have a region of suppressed recombination that is roughly as recent as the split between chimpanzees and homininsless than six million years old.
Suppressed recombination preserves the genomic landscape, because normally, chromosomes recombine during mating, which shuffles the genes like a deck of cards. But suppressed recombination also interferes with natural selection, by forcing genes to be selected or deselected in packages, like the packages of options on new cars that force you to buy the navigation system, the satellite radio, and the MP3 system if you want the side curtain airbags.
The Uppsala researchers' major discovery is that many preferred codons disappeared from regions of the mating type chromosomes where recombination was suppressed. Codons are the "words" of the genetic code. Different codons code for each of the 20 amino acids used in living systems. They code for amino acids, which are the building blocks of proteins, the molecules that form both most of the structure, and most of the machinery cells. Like words in human language, codons often have synonyms. But "Many organisms studied to date preferentially use a specific set of preferred codons which are believed to promote efficient and accurate protein synthesis," says corresponding author Hanna Johannesson. Thus, they are known as "preferred codons."
The suppressed recombination the researchers had found earlier in N. tetrasperma is accompanied by the loss of these preferred codons.
Beyond this, "Our study furthers the understanding of factors driving mutational changes in genomes, which is a key issue in medical and natural science," says Johannesson. "For example, the onset of mutations, and the ability, or inability of organisms to eliminate them from their genome underlie key processes such as the onset of diseases in animals, and the rate of species extinctions. Our study advances the understanding of when and how young regions of suppressed recombination in sex regulating chromosomes accumulate mutations, and why evolution may fail to remove these harmful changes in an efficient manner."
(C. A. Whittle, Y. Sun, and H. Johannesson , 2011. Degeneration in Codon Usage within the Region of Suppressed Recombination in the Mating-Type Chromosomes of Neurospora tetrasperma.
Eukaryotic Cell. 10: 594-603.)
New Understanding of Chronic Otitis Media May Inform Future Treatment
In most children with chronic otitis media, biofilms laden with Haemophilus influenzae cling to the adenoids, while among a similar population suffering from obstructive sleep apnea, that pathogen is usually absent, according to a paper in the April 2011 Journal of Clinical Microbiology. This has major implications for treatment of chronic otitis media.
For one thing, biofilms are notoriously resistant to antibiotics. Earlier clinical studies had suggested that adenoids might be reservoirs for middle ear pathogens, and a 1987 study had suggested that adenoidectomy was effective in treating children prone to middle ear infections. Then, in 2006, Luanne Hall-Stoodley of the Wellcome Trust Clinical Research Facility, Southhampton, UK, et al. showed in children undergoing installation of tympanostomy tubes for treatment of chronic otitis media that the culprit bacteria inhabited biofilms attached to the middle ear mucosa, along with other bacteria that cause ear infections. "We therefore wondered if these pathogens might also form biofilms on the adenoid surface," says Hall-Stoodley.
To that end, this team of academic and clinical investigators used a device called the PlexID that can detect a broad range of bacteria in a clinical sample, and then used PCR and fluorescence in situ hybridization (FISH) probes to corroborate the presence of middle ear pathogens in the biofilms. That work fingered H. influenzae as the major culprit. "Clinically, our data explain why adenoidectomy helps with otitis media effusion since it removes a reservoir of pathogenic bacteria in the upper respiratory tract that can lead to otitis media," says Hall-Stoodley. That doesn't necessarily mean that clinicians will automatically recommend adenoidectomy as the primary surgical treatment, she adds. Nonetheless, "We are convinced that H. influenzae is a uniquely important pathogen in chronic otitis media," she says.
"I think that scientists have begun to think about chronic otitis media in a new way, and investigation of the pathogenesis of this complex disease will help in the design of novel therapies that do not depend on antibiotic treatment alone," says Hall-Stoodley. "Chronic middle ear infection can cause hearing impairment, which can affect verbal ability and education in children."
Hall-Stoodley notes that the use of bacterial culture to try to understand complex diseases such as otitis media has failed to provide a "complete understanding of the microbial complexitythe microbiomethat may be present in the nasopharynx," and that culture alone can no longer be the gold standard for identification of pathogens.
(L. Nistico, R. Kreft, A. Gieseke, J.M. Coticchia, A. Borrows, P. Khampang, Y. Liu, J.E. Kerschner, J.C. Post, S. Lonergan, R. Sampath, F.Z. Hu, G.D. Ehrlich, P. Stoodley, and L. Hall-Stoodley, 2011. Adenoid reservoir for pathogenic biofilm bacteria. J. Clin. Microbiol. 49:1411-1420.)
|Contact: Jim Sliwa|
American Society for Microbiology