39 research outputs found

    Coordinate Regulation of Lipid Metabolism by Novel Nuclear Receptor Partnerships

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    Mammalian nuclear receptors broadly influence metabolic fitness and serve as popular targets for developing drugs to treat cardiovascular disease, obesity, and diabetes. However, the molecular mechanisms and regulatory pathways that govern lipid metabolism remain poorly understood. We previously found that the Caenorhabditis elegans nuclear hormone receptor NHR-49 regulates multiple genes in the fatty acid beta-oxidation and desaturation pathways. Here, we identify additional NHR-49 targets that include sphingolipid processing and lipid remodeling genes. We show that NHR-49 regulates distinct subsets of its target genes by partnering with at least two other distinct nuclear receptors. Gene expression profiles suggest that NHR-49 partners with NHR-66 to regulate sphingolipid and lipid remodeling genes and with NHR-80 to regulate genes involved in fatty acid desaturation. In addition, although we did not detect a direct physical interaction between NHR-49 and NHR-13, we demonstrate that NHR-13 also regulates genes involved in the desaturase pathway. Consistent with this, gene knockouts of these receptors display a host of phenotypes that reflect their gene expression profile. Our data suggest that NHR-80 and NHR-13's modulation of NHR-49 regulated fatty acid desaturase genes contribute to the shortened lifespan phenotype of nhr-49 deletion mutant animals. In addition, we observed that nhr-49 animals had significantly altered mitochondrial morphology and function, and that distinct aspects of this phenotype can be ascribed to defects in NHR-66– and NHR-80–mediated activities. Identification of NHR-49's binding partners facilitates a fine-scale dissection of its myriad regulatory roles in C. elegans. Our findings also provide further insights into the functions of the mammalian lipid-sensing nuclear receptors HNF4α and PPARα

    Partner in fat metabolism: role of KLFs in fat burning and reproductive behavior

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    The abnormalities caused by excess fat accumulation can result in pathological conditions which are linked to several interrelated diseases, such as cardiovascular disease and obesity. This set of conditions, known as metabolic syndrome, is a global pandemic of enormous medical, economic, and social concern affecting a significant portion of the world’s population. Although genetics, physiology and environmental components play a major role in the onset of disease caused by excessive fat accumulation, little is known about how or to what extent each of these factors contributes to it. The worm, Caenorhabditis elegans offers an opportunity to study disease related to metabolic disorder in a developmental system that provides anatomical and genomic simplicity relative to the vertebrate animals and is an excellent eukaryotic genetic model which enable us to answer the questions concerning fat accumulation which remain unresolved. The stored triglycerides (TG) provide the primary source of energy during periods of food deficiency. In nature, lipid stored as TGs are hydrolyzed into fatty acids which are broken down through β-oxidation to yield acetyl-CoA. Our recent study suggests that a member of C. elegans Krüppel-like factor, klf-3 regulates lipid metabolism by promoting FA β-oxidation and in parallel may contribute in normal reproduction and fecundity. Genetic and epigenetic factors that influence this pathway may have considerable impact on fat related diseases in human. Increasing number of studies suggest the role of mammalian KLFs in adipogenesis. This functional conservation should guide our further effort to explore C. elegans as a legitimate model system for studying the role of KLFs in many pathway components of lipid metabolism

    Environmental and Demographic Determinants of Avian Influenza Viruses in Waterfowl across the Contiguous United States

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    Outbreaks of avian influenza in North American poultry have been linked to wild waterfowl. A first step towards understanding where and when avian influenza viruses might emerge from North American waterfowl is to identify environmental and demographic determinants of infection in their populations. Laboratory studies indicate water temperature as one determinant of environmental viral persistence and we explored this hypothesis at the landscape scale. We also hypothesized that the interval apparent prevalence in ducks within a local watershed during the overwintering season would influence infection probabilities during the following breeding season within the same local watershed. Using avian influenza virus surveillance data collected from 19,965 wild waterfowl across the contiguous United States between October 2006 and September 2009 We fit Logistic regression models relating the infection status of individual birds sampled on their breeding grounds to demographic characteristics, temperature, and interval apparent prevalence during the preceding overwintering season at the local watershed scale. We found strong support for sex, age, and species differences in the probability an individual duck tested positive for avian influenza virus. In addition, we found that for every seven days the local minimum temperature fell below zero, the chance an individual would test positive for avian influenza virus increased by 5.9 percent. We also found a twelve percent increase in the chance an individual would test positive during the breeding season for every ten percent increase in the interval apparent prevalence during the prior overwintering season. These results suggest that viral deposition in water and sub-freezing temperatures during the overwintering season may act as determinants of individual level infection risk during the subsequent breeding season. Our findings have implications for future surveillance activities in waterfowl and domestic poultry populations. Further study is needed to identify how these drivers might interact with other host-specific infection determinants, such as species phylogeny, immunological status, and behavioral characteristics

    Entrainment of larval fish assemblages from the inner shelf into the East Australian Current and into the western Tasman Front

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    Entrainment and transport of larval fish assemblages by the East Australian Current (EAC) were examined from the coastal waters of northern New South Wales (NSW) to the western Tasman Front, via the separation of the EAC from the coast, during the austral spring of 2004. Shore-normal transects from the coast to the EAC off northern NSW revealed an inner shelf assemblage of near-shore families (Clupeidae, Engraulidae, Platycephalidae and Triglidae), an EAC assemblage dominated by Myctophidae and Gonostomatidae, and a broadly distributed assemblage over the continental shelf dominated by Scombridae and Carangidae. Further south and after the EAC had separated from the coast, we observed a western Tasman Front assemblage of inner shelf and shelf families (Clupeidae, Engraulidae, Serranidae, Scombridae, Carangidae, Bothidae and Macroramphosidae). The abundance of these families declined with distance from the coast. Surprisingly, there was no distinctive or abundant larval fish assemblage in the chlorophyll- and zooplankton-enriched waters of the Tasman Sea. Water type properties (temperature-salinity, T-S), the larval fish assemblages and family-specific T-S signatures revealed the western Tasman Front to be an entrained mix of EAC and coastal water types. We found an abundance of commercially important species including larval sardine (Sardinops sagax, Clupeidae), blue mackerel (Scomber australasicus, Scombridae) and anchovy (Engraulis australis, Engraulidae). The entrainment and transport of larval fish from the northern inner shelf to the western Tasman Front by the EAC reflects similar processes with the Gulf Stream Front and the Kuroshio Extension. © 2011 Blackwell Publishing Ltd

    Biological properties across the Tasman Front off southeast Australia

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    Physical, geochemical and biological observations across the Tasman Front off southeast Australia provide the first detailed view of the relationship between physical forcing and biological properties within the frontal system. At the beginning of the austral spring of 2004, high resolution measurements were taken using a CTD and a towed undulating vehicle along transects perpendicular to the Tasman Front at 152{ring operator} 00′ E, 153{ring operator} 00′ E and 153{ring operator} 30′ E. The front was characterised by a sharp surface gradient in physical and biological properties and a sub-surface intrusion of low-salinity water. In general the surface temperature changes across the front from 19 {ring operator} C in the Coral Sea waters to the north to 17 {ring operator} C in the Tasman Sea waters over ∼ 10 km. Over the same distance we observed (1) an increase of the mixed layer depth from ∼ 40 to ∼ 100 m; (2) a 3-8-fold increase in the depth-integrated chlorophyll; (3) an order of magnitude increase in biovolume of particulate matter in the size range of 357-2223 μ m; (4) a 2-fold increase in filtered particulate organic matter; (5) a 3 ‰ increase in δ13 CPOM; and (6) a 4 ‰ increase in δ15 NPOM. The particulate matter in the warmer Coral Sea waters is well approximated by a linear fit of the normalised biomass size spectrum (NBSS) with a slope of between - 0.95 and - 0.99, while the Tasman Sea waters have a more non-linear and less negative (- 0.59 to - 0.8) spectrum. The low-salinity intrusion that penetrates to within 40 m of the surface between the Coral Sea and Tasman Sea waters is biologically unproductive, with low oxygen, fluorescence and particulate matter counts. The unproductive low salinity intrusion of the Tasman Front contrasts with the highly productive intrusion observed at the Gulf Stream Front off Cape Hatteras, USA. Observations are consistent with Coral Sea and Tasman Sea waters being found in close proximity with steep gradients in biological properties across the front suggesting minimal cross-front mixing. North of the front, the stratified, oligotrophic Coral Sea waters are relatively unproductive, while the vertically well-mixed waters south of the front exhibit strong biological activity. © 2008 Elsevier Ltd. All rights reserved

    Identification Of Kif21A Mutations As A Rare Cause Of Congenital Fibrosis Of The Extraocular Muscles Type 3 (Cfeom3)

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    PURPOSE. Three congenital fibrosis of the extraocular muscles phenotypes (CFEOM1-3) have been identified. Each represents a specific form of paralytic strabismus characterized by congenital restrictive ophthalmoplegia, often with accompanying ptosis. It has been demonstrated that CFEOM1 results from mutations in KIF21A and CFEOM2 from mutations in PHOX2A. This study was conducted to determine the incidence of KIF21A and PHOX2A mutations among individuals with the third CFEOM phenotype, CFEOM3. METHODS. All pedigrees and sporadic individuals with CFEOM3 in the authors' database were identified, whether the pedigrees were linked or consistent with linkage to the FEOM1, FEOM2, and/or FEOM3 loci was determined, and the appropriate pedigrees and the sporadic individuals were screened for mutations in KIF21A and PHOX2A. RESULTS. Twelve CFEOM3 pedigrees and 10 CFEOM3 sporadic individuals were identified in the database. The structures of eight of the pedigrees permitted the generation of meaningful linkage data. KIF21A was screened in 17 probands, and mutations were identified in two CFEOM3 pedigrees. One pedigree harbored a novel mutation (2841G-->A, M947I) and one harbored the most common and recurrent of the CFEOM1 mutations identified previously (2860C-->T, R954W). None of CFEOM3 pedigrees or sporadic individuals harbored mutations in PHOX2A. CONCLUSIONS. The results demonstrate that KIF21A mutations are a rare cause of CFEOM3 and that KIF21A mutations can be nonpenetrant. Although KIF21A is the first gene to be associated with CFEOM3, the results imply that mutations in the unidentified FEOM3 gene are the more common cause of this phenotype.WoSScopu
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