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词条 Diglyceride acyltransferase
释义

  1. Isoforms

  2. Mutations

  3. Knockout studies

  4. Therapeutic application

  5. References

{{enzyme
| Name = diacylglycerol O-acyltransferase
| EC_number = 2.3.1.20
| CAS_number = 9029-98-5
| IUBMB_EC_number = 2/3/1/20
| GO_code = 0004144
| image =
| width =
| caption =
}}{{infobox protein |Name=diacylglycerol O-acyltransferase 1 |caption= |image= |width= |HGNCid=2843 |Symbol=DGAT1 |AltSymbols= |EntrezGene=8694 |OMIM=604900 |RefSeq=NM_012079 |UniProt=O75907 |PDB= |ECnumber= |Chromosome=8 |Arm=q |Band=24.3 |LocusSupplementaryData=}}{{infobox protein |Name=diacylglycerol O-acyltransferase 2 |caption= |image= |width= |HGNCid=16940 |Symbol=DGAT2 |AltSymbols= |EntrezGene=84649 |OMIM=606983 |RefSeq=NM_032564 |UniProt=Q96PD7 |PDB= |ECnumber= |Chromosome=11 |Arm=q |Band=13.3 |LocusSupplementaryData=}}

Diglyceride acyltransferase (or O-acyltransferase), DGAT, catalyzes the formation of triglycerides from diacylglycerol and Acyl-CoA. The reaction catalyzed by DGAT is considered the terminal and only committed step in triglyceride synthesis and to be essential for intestinal absorption (i.e. DGAT1) [1] and adipose tissue formation (i.e. DGAT2).[2]

The protein is homologous to other membrane-bound O-acyltransferases.

Isoforms

There are two isozymes of DGAT encoded by the genes DGAT1[3] and DGAT2.[4] Although both isozymes catalyze similar reactions, they have no sequence homology to each other.

[https://www.ncbi.nlm.nih.gov/gene/8694 DGAT1] is mainly located in absorptive enterocyte cells that line the intestine and duodenum where it reassembles triglycerides that were decomposed through lipolysis in the process of intestinal absorption. DGAT1 reconstitutes triglycerides in a committed step after which they are packaged together with cholesterol and proteins to form chylomicrons.

[https://www.ncbi.nlm.nih.gov/gene/84649 DGAT2] is mainly located in fat, liver and skin cells.

Mutations

In humans, DGAT1 mutations have been linked to congenital diarrheal disorders [5][6][7]. The [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3344208/ congenital diarrheal disorder] presents 2-3 days after birth with projectile vomiting and failure to thrive. The congenital diarrheal disorder may be treated with total parenteral nutrition avoiding sepsis with most symptoms resolving at 10 to 12 months of age. The congenital diarrheal disorder requires a strict diet with little or no fat (i.e fatty acids, monoglycerides, diglycerides, and triglycerides which break down and combine to form DGAT1 substrates that build up and irritate the intestinal mucosa). The precise cause of diarrhea is unknown, and is speculated to relate to abnormal fat absorption and buildup of DGAT1 substrates in the intestinal mucosa.

Knockout studies

Mice with genetic disruption of the DGAT1 or DGAT2 genes have been made by the Farese laboratory at UCSF. Surprisingly, DGAT1−/− mice[8] are healthy and fertile and have no changes in triglyceride levels. These mice are also lean and resistant to diet-induced obesity, consequently generating interest in DGAT1 inhibitors for the treatment of obesity. However, these mice also fail to lactate, showing a complete lack of milk production due to their inability to produce milk lipid droplets.[8] In contrast, DGAT2−/− mice[9] have reduced triglyceride levels but are lipopenic, suffer from skin barrier abnormalities (including the inability to retain moisture), and die shortly after birth.

Therapeutic application

DGAT1 inhibitors have potential for the treatment of obesity[10][11] and a number of DGAT-1 inhibitors are in clinical trials for this indication.[12]

However, recent findings prompt concern for DGAT1 inhibition in humans because of the severe side effects which include nausea, diarrhea, and vomiting following meals containing fat [13]. However it is important to note that these symptoms were observed in case of total loss of function in DGAT due to knockout mutation. Such symptoms are not observed in case of partial inhibition of DGAT activity such as those induced via medication.

References

1. ^{{cite journal|last1=Haas|first1=JT|last2=Winter|first2=HS|last3=Lim|first3=E|last4=Kirby|first4=A|last5=Blumenstiel|first5=B|last6=DeFelice|first6=M|last7=Gabriel|first7=S|last8=Jalas|first8=C|last9=Branski|first9=D|last10=Grueter|first10=CA|last11=Toporovski|first11=MS|last12=Walther|first12=TC|last13=Daly|first13=MJ|last14=Farese RV|first14=Jr|title=DGAT1 mutation is linked to a congenital diarrheal disorder.|journal=The Journal of Clinical Investigation|date=December 2012|volume=122|issue=12|pages=4680-4|doi=10.1172/JCI64873|pmid=23114594|pmc=3533555}}
2. ^{{cite journal | vauthors = Cases S, Smith SJ, Zheng YW, Myers HM, Lear SR, Sande E, Novak S, Collins C, Welch CB, Lusis AJ, Erickson SK, Farese RV | title = Identification of a gene encoding an acyl CoA:diacylglycerol acyltransferase, a key enzyme in triacylglycerol synthesis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 22 | pages = 13018–23 | date = October 1998 | pmid = 9789033 | pmc = 23692 | doi = 10.1073/pnas.95.22.13018 }}
3. ^{{cite journal | vauthors = Oelkers P, Behari A, Cromley D, Billheimer JT, Sturley SL | title = Characterization of two human genes encoding acyl coenzyme A:cholesterol acyltransferase-related enzymes | journal = The Journal of Biological Chemistry | volume = 273 | issue = 41 | pages = 26765–71 | date = October 1998 | pmid = 9756920 | doi = 10.1074/jbc.273.41.26765 }}
4. ^{{cite journal | vauthors = Cases S, Stone SJ, Zhou P, Yen E, Tow B, Lardizabal KD, Voelker T, Farese RV | title = Cloning of DGAT2, a second mammalian diacylglycerol acyltransferase, and related family members | journal = The Journal of Biological Chemistry | volume = 276 | issue = 42 | pages = 38870–6 | date = October 2001 | pmid = 11481335 | doi = 10.1074/jbc.M106219200 }}
5. ^{{cite journal|last1=Haas|first1=JT|last2=Winter|first2=HS|last3=Lim|first3=E|last4=Kirby|first4=A|last5=Blumenstiel|first5=B|last6=DeFelice|first6=M|last7=Gabriel|first7=S|last8=Jalas|first8=C|last9=Branski|first9=D|last10=Grueter|first10=CA|last11=Toporovski|first11=MS|last12=Walther|first12=TC|last13=Daly|first13=MJ|last14=Farese RV|first14=Jr|title=DGAT1 mutation is linked to a congenital diarrheal disorder.|journal=The Journal of Clinical Investigation|date=December 2012|volume=122|issue=12|pages=4680-4|doi=10.1172/JCI64873|pmid=23114594|pmc=3533555}}
6. ^{{cite journal|last1=Gluchowski|first1=NL|last2=Chitraju|first2=C|last3=Picoraro|first3=JA|last4=Mejhert|first4=N|last5=Pinto|first5=S|last6=Xin|first6=W|last7=Kamin|first7=DS|last8=Winter|first8=HS|last9=Chung|first9=WK|last10=Walther|first10=TC|last11=Farese RV|first11=Jr|title=Identification and characterization of a novel DGAT1 missense mutation associated with congenital diarrhea.|journal=Journal of Lipid Research|date=June 2017|volume=58|issue=6|pages=1230-1237|doi=10.1194/jlr.P075119|pmid=28373485|pmc=5454518}}
7. ^{{cite journal|last1=Stephen|first1=J|last2=Vilboux|first2=T|last3=Haberman|first3=Y|last4=Pri-Chen|first4=H|last5=Pode-Shakked|first5=B|last6=Mazaheri|first6=S|last7=Marek-Yagel|first7=D|last8=Barel|first8=O|last9=Di Segni|first9=A|last10=Eyal|first10=E|last11=Hout-Siloni|first11=G|last12=Lahad|first12=A|last13=Shalem|first13=T|last14=Rechavi|first14=G|last15=Malicdan|first15=MC|last16=Weiss|first16=B|last17=Gahl|first17=WA|last18=Anikster|first18=Y|title=Congenital protein losing enteropathy: an inborn error of lipid metabolism due to DGAT1 mutations.|journal=European Journal of Human Genetics |date=August 2016|volume=24|issue=9|pages=1268-73|doi=10.1038/ejhg.2016.5|pmid=26883093|pmc=4989215}}
8. ^1 {{cite journal | vauthors = Smith SJ, Cases S, Jensen DR, Chen HC, Sande E, Tow B, Sanan DA, Raber J, Eckel RH, Farese RV | title = Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking Dgat | journal = Nature Genetics | volume = 25 | issue = 1 | pages = 87–90 | date = May 2000 | pmid = 10802663 | doi = 10.1038/75651 }}
9. ^{{cite journal | vauthors = Stone SJ, Myers HM, Watkins SM, Brown BE, Feingold KR, Elias PM, Farese RV | title = Lipopenia and skin barrier abnormalities in DGAT2-deficient mice | journal = The Journal of Biological Chemistry | volume = 279 | issue = 12 | pages = 11767–76 | date = March 2004 | pmid = 14668353 | doi = 10.1074/jbc.M311000200 }}
10. ^{{cite journal | vauthors = Chen HC, Farese RV | title = Inhibition of triglyceride synthesis as a treatment strategy for obesity: lessons from DGAT1-deficient mice | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 25 | issue = 3 | pages = 482–6 | date = March 2005 | pmid = 15569818 | doi = 10.1161/01.ATV.0000151874.81059.ad }}
11. ^{{cite journal | vauthors = Cheng D, Iqbal J, Devenny J, Chu CH, Chen L, Dong J, Seethala R, Keim WJ, Azzara AV, Lawrence RM, Pelleymounter MA, Hussain MM | title = Acylation of acylglycerols by acyl coenzyme A:diacylglycerol acyltransferase 1 (DGAT1). Functional importance of DGAT1 in the intestinal fat absorption | journal = The Journal of Biological Chemistry | volume = 283 | issue = 44 | pages = 29802–11 | date = October 2008 | pmid = 18768481 | pmc = 2662058 | doi = 10.1074/jbc.M800494200 }}
12. ^{{cite news |url=https://www.reuters.com/article/health-SP/idUSN2743563720070827 |title=Pfizer, Bristol finalize deal on metabolic drugs | work=Reuters |accessdate=2007-08-27 |format= | date=2007-08-27}}
13. ^{{cite journal|last1=Haas|first1=JT|last2=Winter|first2=HS|last3=Lim|first3=E|last4=Kirby|first4=A|last5=Blumenstiel|first5=B|last6=DeFelice|first6=M|last7=Gabriel|first7=S|last8=Jalas|first8=C|last9=Branski|first9=D|last10=Grueter|first10=CA|last11=Toporovski|first11=MS|last12=Walther|first12=TC|last13=Daly|first13=MJ|last14=Farese RV|first14=Jr|title=DGAT1 mutation is linked to a congenital diarrheal disorder.|journal=The Journal of Clinical Investigation|date=December 2012|volume=122|issue=12|pages=4680-4|doi=10.1172/JCI64873|pmid=23114594|pmc=3533555}}
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1 : EC 2.3.1
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