title: Intestinal acyl-CoA:diacylglycerol acyltransferase 2 overexpression enhances postprandial triglyceridemic response and exacerbates high fat diet-induced hepatic triacylglycerol storage.
abstract: Intestinal acyl-CoA:diacylglycerol acyltransferase 2 (DGAT2) is important in the cellular and physiological responses to dietary fat. To determine the effect of increased intestinal DGAT2 on cellular and physiological responses to acute and chronic dietary fat challenges, we generated mice with intestine-specific overexpression of DGAT2 and compared them with intestine-specific overexpression of DGAT1 and wild-type (WT) mice. We found that when intestinal DGAT2 is present in excess, triacylglycerol (TG) secretion from enterocytes is enhanced compared to WT mice; however, TG storage within enterocytes is similar compared to WT mice. We found that when intestinal DGAT2 is present in excess, mRNA levels of genes involved in fatty acid oxidation were reduced. This result suggests that reduced fatty acid oxidation may contribute to increased TG secretion by overexpression of DGAT2 in intestine. Furthermore, this enhanced supply of TG for secretion in Dgat2(Int) mice may be a significant contributing factor to the elevated fasting plasma TG and exacerbated hepatic TG storage in response to a chronic HFD. These results highlight that altering fatty acid and TG metabolism within enterocytes has the capacity to alter systemic delivery of dietary fat and may serve as an effective target for preventing and treating metabolic diseases such as hepatic steatosis.
authors: Purdue University, West Lafayette, IN, USA. kbuhman@purdue.edu
authors: Aki
authors: A
authors: Uchida
authors: Mikhail N
authors: MN
authors: Slipchenko
authors: Trisha
authors: T
authors: Eustaquio
authors: James F
authors: JF
authors: Leary
authors: Ji-Xin
authors: JX
authors: Cheng
authors: Kimberly K
authors: KK
authors: Buhman
mesh_terms: D000818:Animals; D051048:Diacylglycerol O-Acyltransferase / Q000096:biosynthesis* / Q000235:genetics; D004041:Dietary Fats / Q000009:adverse effects / Q000494:pharmacology*; D020895:Enterocytes / Q000201:enzymology; D005227:Fatty Acids / Q000235:genetics / Q000378:metabolism; D005234:Fatty Liver / Q000201:enzymology / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000235:genetics; D007422:Intestines / Q000201:enzymology*; D008099:Liver / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009928:Organ Specificity; D010084:Oxidation-Reduction / Q000187:drug effects; D019518:Postprandial Period; D014280:Triglycerides / Q000097:blood*
chemical_list: D004041:Dietary Fats; D005227:Fatty Acids; D014280:Triglycerides; C516957:DGAT2 protein, mouse; D051048:Diacylglycerol O-Acyltransferase
references: BMC Genomics. 2008 May 19;9:231
references: 18489776
references: J Biol Chem. 2002 Jul 12;277(28):25474-9
references: 11959864
references: J Clin Invest. 2012 Dec;122(12):4680-4
references: 23114594
references: J Biol Chem. 2001 Oct 19;276(42):38870-6
references: 11481335
references: Front Physiol. 2012 Feb 24;3:25
references: 22375121
references: J Biol Chem. 2002 Sep 6;277(36):33275-83
references: 12065599
references: Biochem Biophys Res Commun. 2011 Jun 24;410(1):1-6
references: 21640707
references: Biochem Biophys Res Commun. 2003 Oct 17;310(2):296-302
references: 14521909
references: J Med Chem. 2012 Feb 23;55(4):1751-7
references: 22263872
references: J Biol Chem. 2008 Oct 31;283(44):29802-11
references: 18768481
references: J Lipid Res. 2008 Nov;49(11):2283-301
references: 18757836
references: J Lipid Res. 2012 Sep;53(9):1800-10
references: 22701043
references: Am J Physiol Gastrointest Liver Physiol. 2011 May;300(5):G803-14
references: 21350192
references: J Biol Chem. 2009 Feb 20;284(8):5352-61
references: 19049983
references: Am J Physiol Gastrointest Liver Physiol. 2006 Jun;290(6):G1177-85
references: 16384875
references: Eur J Med Chem. 2012 Aug;54:324-42
references: 22683241
references: J Biol Chem. 2004 Mar 19;279(12):11767-76
references: 14668353
references: Traffic. 2008 Mar;9(3):338-52
references: 18088320
references: ACS Med Chem Lett. 2011 Mar 18;2(5):407-12
references: 24900321
references: Dev Cell. 2013 Feb 25;24(4):384-99
references: 23415954
references: Front Physiol. 2012 Feb 24;3:26
references: 22375122
references: Biochem J. 1997 Apr 1;323 ( Pt 1):17-21
references: 9173878
references: Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):13018-23
references: 9789033
references: J Biol Chem. 2011 Oct 21;286(42):36238-47
references: 21846726
references: J Biol Chem. 1978 Jan 10;253(1):69-76
references: 618869
references: J Lipid Res. 2009 Jun;50(6):1080-9
references: 19218555
references: J Nutr. 2007 Dec;137(12):2629-34
references: 18029475
references: Prog Lipid Res. 2012 Oct;51(4):350-77
references: 22705711
references: Annu Rev Physiol. 1983;45:651-77
references: 6342528
references: Ann Clin Biochem. 2010 Sep;47(Pt 5):476-81
references: 20736248
references: J Biol Chem. 2006 Dec 29;281(52):40273-82
references: 17035227
references: J Lipid Res. 2008 Aug;49(8):1762-9
references: 18421071
references: J Lipid Res. 2010 Jul;51(7):1770-80
references: 20147738
references: Biochem J. 2001 Nov 1;359(Pt 3):707-14
references: 11672446
references: Nat Med. 2009 Apr;15(4):442-6
references: 19287392
references: BMC Genomics. 2009 Mar 16;10:110
references: 19284886
references: Biochim Biophys Acta. 2011 Mar;1811(3):170-6
references: 21215818
references: Biochem Soc Trans. 1997 Feb;25(1):21S
references: 9056919
references: J Biol Chem. 1999 Dec 17;274(51):36139-45
references: 10593897
references: Gut. 2003 Jun;52(6):834-9
references: 12740339