| 释义 |
- Mechanism
- History
- Clinical relevance
- See also
- References
- Further reading
- External links
{{Infobox_gene}}Thermogenin (called uncoupling protein by its discoverers and now known as uncoupling protein 1, or UCP1)[1] is an uncoupling protein found in the mitochondria of brown adipose tissue (BAT). It is used to generate heat by non-shivering thermogenesis, and makes a quantitatively important contribution to countering heat loss in babies which would otherwise occur due to their high surface area-volume ratio. MechanismUCPs are transmembrane proteins that decrease the proton gradient generated in oxidative phosphorylation. They do this by increasing the permeability of the inner mitochondrial membrane, allowing protons that have been pumped into the intermembrane space to return to the mitochondrial matrix. UCP1-mediated heat generation in brown fat uncouples the respiratory chain, allowing for fast substrate oxidation with a low rate of ATP production. UCP1 is related to other mitochondrial metabolite transporters such as the adenine nucleotide translocator, a proton channel in the mitochondrial inner membrane that permits the translocation of protons from the mitochondrial intermembrane space to the mitochondrial matrix. UCP1 is restricted to brown adipose tissue, where it provides a mechanism for the enormous heat-generating capacity of the tissue. UCP1 is activated in the brown fat cell by fatty acids and inhibited by nucleotides. Fatty acids cause the following signaling cascade: Sympathetic nervous system terminals release Norepinephrine onto a Beta-3 adrenergic receptor on the plasma membrane. This activates adenylyl cyclase, which catalyses the conversion of ATP to cyclic AMP (cAMP). cAMP activates protein kinase A, causing its active C subunits to be freed from its regulatory R subunits. Active protein kinase A, in turn, phosphorylates triacylglycerol lipase, thereby activating it. The lipase converts triacylglycerols into free fatty acids, which activate UCP1, overriding the inhibition caused by purine nucleotides (GDP and ADP). During the termination of thermogenesis, thermogenin is inactivated and residual fatty acids are disposed of through oxidation, allowing the cell to resume its normal energy-conserving state. HistoryUncoupling protein 1 was discovered in 1978[2] and was first cloned in 1988.[3][4] Uncoupling protein two (UCP2), a homolog of UCP1, was identified in 1997. UCP2 localizes to a wide variety of tissues, and is thought to be involved in regulating reactive oxygen species (ROS). In the past decade, three additional homologs of UCP1 have been identified, including UCP3, UCP4, and BMCP1 (also known as UCP5). Clinical relevance Methods of delivering UCP1 to cells by gene transfer therapy or methods of its upregulation have been an important line of enquiry in research into the treatment of obesity, due to their ability to dissipate excess metabolic stores.[5] See also - 2,4-Dinitrophenol (A synthetic small-molecule proton shuttle with similar effects)
References 1. ^{{cite web | title = Entrez Gene: UCP1 uncoupling protein 1 (mitochondrial, proton carrier)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7350| accessdate = }}
2. ^{{cite journal | vauthors = Nicholls DG, Bernson VS, Heaton GM | title = The identification of the component in the inner membrane of brown adipose tissue mitochondria responsible for regulating energy dissipation | journal = Experientia. Supplementum | volume = 32 | issue = | pages = 89–93 | year = 1978 | pmid = 348493 | doi = 10.1007/978-3-0348-5559-4_9 }}
3. ^{{cite journal | vauthors = Kozak LP, Britton JH, Kozak UC, Wells JM | title = The mitochondrial uncoupling protein gene. Correlation of exon structure to transmembrane domains | journal = The Journal of Biological Chemistry | volume = 263 | issue = 25 | pages = 12274–7 | date = Sep 1988 | pmid = 3410843 | doi = | url = http://www.jbc.org/cgi/content/abstract/263/25/12274 }}
4. ^{{cite journal | vauthors = Bouillaud F, Raimbault S, Ricquier D | title = The gene for rat uncoupling protein: complete sequence, structure of primary transcript and evolutionary relationship between exons | journal = Biochemical and Biophysical Research Communications | volume = 157 | issue = 2 | pages = 783–92 | date = Dec 1988 | pmid = 3202878 | doi = 10.1016/S0006-291X(88)80318-8 }}
5. ^{{cite journal | vauthors = Kozak LP, Anunciado-Koza R | title = UCP1: its involvement and utility in obesity | journal = International Journal of Obesity | volume = 32 Suppl 7 | issue = Suppl 7 | pages = S32-8 | date = Dec 2008 | pmid = 19136989 | pmc = 2746324 | doi = 10.1038/ijo.2008.236 }}
Further reading {{refbegin | 2}}- {{cite journal |last1=Macher |first1=Gabriel |last2=Koehler |first2=Melanie |last3=Rupprecht |first3=Anne |last4=Kreiter |first4=Jürgen |last5=Hinterdorfer |first5=Peter |last6=Pohl |first6=Elena E. |title=Inhibition of mitochondrial UCP1 and UCP3 by purine nucleotides and phosphate |journal=Biochimica et Biophysica Acta (BBA) - Biomembranes |date=March 2018 |volume=1860 |issue=3 |pages=664–672 |doi=10.1016/j.bbamem.2017.12.001}}
- {{cite journal |last1=Urbánková |first1=Eva |last2=Voltchenko |first2=Anna |last3=Pohl |first3=Peter |last4=Ježek |first4=Petr |last5=Pohl |first5=Elena E. |title=Transport Kinetics of Uncoupling Proteins |journal=Journal of Biological Chemistry |date=29 August 2003 |volume=278 |issue=35 |pages=32497–32500 |doi=10.1074/jbc.M303721200}}
- {{cite journal | vauthors = Ricquier D, Bouillaud F | title = The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP | journal = The Biochemical Journal | volume = 345 Pt 2 | issue = 2 | pages = 161–79 | date = Jan 2000 | pmid = 10620491 | pmc = 1220743 | doi = 10.1042/0264-6021:3450161 }}
- {{cite journal | vauthors = Muzzin P | title = The uncoupling proteins | journal = Annales d'Endocrinologie | volume = 63 | issue = 2 Pt 1 | pages = 106–10 | date = Apr 2002 | pmid = 11994670 | doi = }}
- {{cite journal | vauthors = Del Mar Gonzalez-Barroso M, Ricquier D, Cassard-Doulcier AM | title = The human uncoupling protein-1 gene (UCP1): present status and perspectives in obesity research | journal = Obesity Reviews | volume = 1 | issue = 2 | pages = 61–72 | date = Oct 2000 | pmid = 12119988 | doi = 10.1046/j.1467-789x.2000.00009.x}}
- {{cite journal | vauthors = Cassard AM, Bouillaud F, Mattei MG, Hentz E, Raimbault S, Thomas M, Ricquier D | title = Human uncoupling protein gene: structure, comparison with rat gene, and assignment to the long arm of chromosome 4 | journal = Journal of Cellular Biochemistry | volume = 43 | issue = 3 | pages = 255–64 | date = Jul 1990 | pmid = 2380264 | doi = 10.1002/jcb.240430306 }}
- {{cite journal | vauthors = Bouillaud F, Villarroya F, Hentz E, Raimbault S, Cassard AM, Ricquier D | title = Detection of brown adipose tissue uncoupling protein mRNA in adult patients by a human genomic probe | journal = Clinical Science | volume = 75 | issue = 1 | pages = 21–7 | date = Jul 1988 | pmid = 3165741 | doi = 10.1042/cs0750021}}
- {{cite journal | vauthors = Oppert JM, Vohl MC, Chagnon M, Dionne FT, Cassard-Doulcier AM, Ricquier D, Pérusse L, Bouchard C | title = DNA polymorphism in the uncoupling protein (UCP) gene and human body fat | journal = International Journal of Obesity and Related Metabolic Disorders | volume = 18 | issue = 8 | pages = 526–31 | date = Aug 1994 | pmid = 7951471 | doi = }}
- {{cite journal | vauthors = Clément K, Ruiz J, Cassard-Doulcier AM, Bouillaud F, Ricquier D, Basdevant A, Guy-Grand B, Froguel P | title = Additive effect of A-->G (-3826) variant of the uncoupling protein gene and the Trp64Arg mutation of the beta 3-adrenergic receptor gene on weight gain in morbid obesity | journal = International Journal of Obesity and Related Metabolic Disorders | volume = 20 | issue = 12 | pages = 1062–6 | date = Dec 1996 | pmid = 8968850 | doi = }}
- {{cite journal | vauthors = Schleiff E, Shore GC, Goping IS | title = Human mitochondrial import receptor, Tom20p. Use of glutathione to reveal specific interactions between Tom20-glutathione S-transferase and mitochondrial precursor proteins | journal = FEBS Letters | volume = 404 | issue = 2-3 | pages = 314–8 | date = Mar 1997 | pmid = 9119086 | doi = 10.1016/S0014-5793(97)00145-2 }}
- {{cite journal | vauthors = Urhammer SA, Fridberg M, Sørensen TI, Echwald SM, Andersen T, Tybjaerg-Hansen A, Clausen JO, Pedersen O | title = Studies of genetic variability of the uncoupling protein 1 gene in Caucasian subjects with juvenile-onset obesity | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 82 | issue = 12 | pages = 4069–74 | date = Dec 1997 | pmid = 9398715 | doi = 10.1210/jc.82.12.4069 }}
- {{cite journal | vauthors = Jezek P, Urbánková E | title = Specific sequence of motifs of mitochondrial uncoupling proteins | journal = IUBMB Life | volume = 49 | issue = 1 | pages = 63–70 | date = Jan 2000 | pmid = 10772343 | doi = 10.1080/713803586 }}
- {{cite journal | vauthors = Mori H, Okazawa H, Iwamoto K, Maeda E, Hashiramoto M, Kasuga M | title = A polymorphism in the 5' untranslated region and a Met229-->Leu variant in exon 5 of the human UCP1 gene are associated with susceptibility to type II diabetes mellitus | journal = Diabetologia | volume = 44 | issue = 3 | pages = 373–6 | date = Mar 2001 | pmid = 11317671 | doi = 10.1007/s001250051629 }}
- {{cite journal | vauthors = Nibbelink M, Moulin K, Arnaud E, Duval C, Pénicaud L, Casteilla L | title = Brown fat UCP1 is specifically expressed in uterine longitudinal smooth muscle cells | journal = The Journal of Biological Chemistry | volume = 276 | issue = 50 | pages = 47291–5 | date = Dec 2001 | pmid = 11572862 | doi = 10.1074/jbc.M105658200 }}
- {{cite journal | vauthors = Echtay KS, Roussel D, St-Pierre J, Jekabsons MB, Cadenas S, Stuart JA, Harper JA, Roebuck SJ, Morrison A, Pickering S, Clapham JC, Brand MD | title = Superoxide activates mitochondrial uncoupling proteins | journal = Nature | volume = 415 | issue = 6867 | pages = 96–9 | date = Jan 2002 | pmid = 11780125 | doi = 10.1038/415096a }}
- {{cite journal | vauthors = Rousset S, del Mar Gonzalez-Barroso M, Gelly C, Pecqueur C, Bouillaud F, Ricquier D, Cassard-Doulcier AM | title = A new polymorphic site located in the human UCP1 gene controls the in vitro binding of CREB-like factor | journal = International Journal of Obesity and Related Metabolic Disorders | volume = 26 | issue = 5 | pages = 735–8 | date = May 2002 | pmid = 12032762 | doi = 10.1038/sj.ijo.0801973 }}
- {{cite journal | vauthors = Rim JS, Kozak LP | title = Regulatory motifs for CREB-binding protein and Nfe2l2 transcription factors in the upstream enhancer of the mitochondrial uncoupling protein 1 gene | journal = The Journal of Biological Chemistry | volume = 277 | issue = 37 | pages = 34589–600 | date = Sep 2002 | pmid = 12084707 | doi = 10.1074/jbc.M108866200 }}
- {{cite journal | vauthors = Kieć-Wilk B, Wybrańska I, Malczewska-Malec M, Leszczyńska-Gołabek L, Partyka L, Niedbał S, Jabrocka A, Dembińska-Kieć A | title = Correlation of the -3826A >G polymorphism in the promoter of the uncoupling protein 1 gene with obesity and metabolic disorders in obese families from southern Poland | journal = Journal of Physiology and Pharmacology | volume = 53 | issue = 3 | pages = 477–90 | date = Sep 2002 | pmid = 12375583 | doi = }}
{{refend}} External links - Seaweed anti-obesity tablet hope (BBC - Thermogenin mentioned as part of process)
- {{MeshName|thermogenin}}
2 : Cellular respiration|Mitochondria |