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The activation of sterol regulatory element binding proteins (SREBPs) is regulated by insulin-induced genes 1 and 2 (Insig-1 and Insig-2) and SCAP. We previously reported that feeding R-α-lipoic acid (LA) to Zucker diabetic fatty (ZDF) rats improves severe hypertriglyceridemia. In this study, we investigated the role of cyclic AMP-responsive element binding protein H (CREBH) in the lipid-lowering mechanism of LA and its involvement in the SREBP-1c and Insig pathway. Incubation of McA cells with LA (0.2 mM) or glucose (6 mM) stimulated activation of CREBH. LA treatment further induced mRNA expression of Insig-1 and Insig-2a, but not Insig-2b, in glucose-treated cells. In vivo, feeding LA to obesity-induced hyperlipidemic ZDF rats activated hepatic CREBH and stimulated transcription and translation of Insig-1 and Insig-2a. Activation of CREBH and Insigs induced by LA suppressed processing of SREBP-1c precursor into nuclear SREBP-1c, which subsequently inhibited expression of genes involved in fatty acid synthesis, including FASN, ACC and SCD-1, and reduced triglyceride (TG) contents in both glucose-treated cells and ZDF rat livers. Additionally, LA treatment also decreased abundances of very low density lipoprotein (VLDL)-associated apolipoproteins, apoB100 and apoE, in glucose-treated cells and livers of ZDF rats, leading to decreased secretion of VLDL and improvement of hypertriglyceridemia. This study unveils a novel molecular mechanism whereby LA lowers TG via activation of hepatic CREBH and increased expression of Insig-1 and Insig-2a to inhibit de novo lipogenesis and VLDL secretion. These findings provide novel insight into the therapeutic potential of LA as an anti-hypertriglyceridemia dietary molecule.

Titel:	Activation of hepatic CREBH and Insig signaling in the anti-hypertriglyceridemic mechanism of R-α-lipoic acid.
Autor/in / Beteiligte Person:	Tong, X ; Christian, P ; Zhao, M ; Wang, H ; Moreau, R ; Su, Q
Zeitschrift:	The Journal of nutritional biochemistry, Jg. 26 (2015-09-01), Heft 9, S. 921-8
Veröffentlichung:	<1996->: New York, NY : Elsevier Science ; <i>Original Publication</i>: Stoneham, MA, USA : Butterworths, c1990-, 2015
Medientyp:	academicJournal
ISSN:	1873-4847 (electronic)
DOI:	10.1016/j.jnutbio.2015.03.011
Schlagwort:	Alternative Splicing Animals Cell Line, Tumor Cyclic AMP Response Element-Binding Protein genetics Cyclic AMP Response Element-Binding Protein metabolism Hepatocytes metabolism Hypertriglyceridemia blood Hypertriglyceridemia metabolism Hypolipidemic Agents metabolism Intracellular Signaling Peptides and Proteins genetics Intracellular Signaling Peptides and Proteins metabolism Lipoproteins, VLDL blood Lipoproteins, VLDL metabolism Male Membrane Proteins genetics Membrane Proteins metabolism Protein Processing, Post-Translational Random Allocation Rats, Inbred BUF Rats, Zucker Signal Transduction Sterol Regulatory Element Binding Protein 1 antagonists & inhibitors Sterol Regulatory Element Binding Protein 1 metabolism Thioctic Acid metabolism Up-Regulation Cyclic AMP Response Element-Binding Protein agonists Dietary Supplements Hepatocytes enzymology Hypertriglyceridemia diet therapy Hypolipidemic Agents therapeutic use Intracellular Signaling Peptides and Proteins agonists Membrane Proteins agonists Thioctic Acid therapeutic use
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. Language: English [J Nutr Biochem] 2015 Sep; Vol. 26 (9), pp. 921-8. <i>Date of Electronic Publication: </i>2015 May 07. MeSH Terms: Dietary Supplements* ; Cyclic AMP Response Element-Binding Protein / agonists ; Hepatocytes / enzymology ; Hypertriglyceridemia / diet therapy ; Hypolipidemic Agents / therapeutic use ; Intracellular Signaling Peptides and Proteins / agonists ; Membrane Proteins / agonists ; Thioctic Acid / *therapeutic use ; Alternative Splicing ; Animals ; Cell Line, Tumor ; Cyclic AMP Response Element-Binding Protein / genetics ; Cyclic AMP Response Element-Binding Protein / metabolism ; Hepatocytes / metabolism ; Hypertriglyceridemia / blood ; Hypertriglyceridemia / metabolism ; Hypolipidemic Agents / metabolism ; Intracellular Signaling Peptides and Proteins / genetics ; Intracellular Signaling Peptides and Proteins / metabolism ; Lipoproteins, VLDL / blood ; Lipoproteins, VLDL / metabolism ; Male ; Membrane Proteins / genetics ; Membrane Proteins / metabolism ; Protein Processing, Post-Translational ; Random Allocation ; Rats, Inbred BUF ; Rats, Zucker ; Signal Transduction ; Sterol Regulatory Element Binding Protein 1 / antagonists & inhibitors ; Sterol Regulatory Element Binding Protein 1 / metabolism ; Thioctic Acid / metabolism ; Up-Regulation References: Cell Metab. 2006 Jan;3(1):15-24. (PMID: 16399501) ; Biochim Biophys Acta. 2009 Oct;1790(10):1149-60. (PMID: 19664690) ; Biochem Biophys Res Commun. 2010 Jan 8;391(2):1222-7. (PMID: 20006574) ; Nutr Metab (Lond). 2012 Feb 21;9:14. (PMID: 22353470) ; J Lipid Res. 2010 Feb;51(2):352-9. (PMID: 19690335) ; J Biol Chem. 1999 Dec 10;274(50):35711-8. (PMID: 10585451) ; Cell. 2010 Feb 5;140(3):338-48. (PMID: 20144759) ; Dev Cell. 2007 Sep;13(3):365-76. (PMID: 17765680) ; Nat Cell Biol. 2005 Feb;7(2):186-94. (PMID: 15665855) ; Biochem Cell Biol. 2010 Apr;88(2):251-67. (PMID: 20453928) ; Hepatology. 2009 Jul;50(1):77-84. (PMID: 19434737) ; Proc Natl Acad Sci U S A. 2004 May 4;101(18):7106-11. (PMID: 15096598) ; J Biochem. 2011 May;149(5):507-18. (PMID: 21454302) ; Am J Physiol Regul Integr Comp Physiol. 2012 Mar 1;302(5):R587-97. (PMID: 22049228) ; Nat Rev Mol Cell Biol. 2007 Jul;8(7):519-29. (PMID: 17565364) ; Antioxid Redox Signal. 2007 Dec;9(12):2305-21. (PMID: 17887918) ; Mol Cell Biol. 2006 Nov;26(21):7999-8010. (PMID: 16940180) ; J Biol Chem. 2002 Aug 30;277(35):31516-25. (PMID: 12072432) ; Hepatology. 2012 Apr;55(4):1070-82. (PMID: 22095841) ; Nat Med. 2011 Jul;17(7):812-5. (PMID: 21666694) ; Br J Nutr. 2008 Jul;100(1):79-87. (PMID: 18062843) ; Mol Cell Biochem. 2010 Nov;344(1-2):99-107. (PMID: 20607591) ; Traffic. 2010 Jan;11(1):48-69. (PMID: 19883396) ; Diabetologia. 2004 Aug;47(8):1452-61. (PMID: 15309295) ; Physiol Genomics. 2013 Dec 1;45(23):1136-43. (PMID: 24104204) ; Hepatology. 2008 Nov;48(5):1477-86. (PMID: 18972440) ; Cell. 2002 Aug 23;110(4):489-500. (PMID: 12202038) ; Obesity (Silver Spring). 2006 Feb;14 Suppl 1:41S-49S. (PMID: 16642962) ; Nutrition. 2001 Oct;17(10):888-95. (PMID: 11684397) ; Proc Natl Acad Sci U S A. 2003 Mar 18;100(6):3155-60. (PMID: 12624180) ; Arch Biochem Biophys. 2009 May 1;485(1):63-71. (PMID: 19232511) ; Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):12753-8. (PMID: 12242332) ; Biochem Biophys Res Commun. 2013 Sep 27;439(3):390-5. (PMID: 23994635) ; Biochemistry. 2002 Jun 4;41(22):6978-87. (PMID: 12033930) ; Altern Med Rev. 2007 Dec;12(4):343-51. (PMID: 18069903) Grant Information: P20 GM104320 United States GM NIGMS NIH HHS; P20 GM104320-01A1 United States GM NIGMS NIH HHS Contributed Indexing: Keywords: Apolipoproteins; Cell signaling; Dyslipidemias; Sterol regulatory element binding proteins; Triglyceride metabolism; Very low density lipoprotein Substance Nomenclature: 0 (Creb3l3 protein, rat) ; 0 (Cyclic AMP Response Element-Binding Protein) ; 0 (Hypolipidemic Agents) ; 0 (Insig1 protein, rat) ; 0 (Insig2 protein, rat) ; 0 (Intracellular Signaling Peptides and Proteins) ; 0 (Lipoproteins, VLDL) ; 0 (Membrane Proteins) ; 0 (Srebf1 protein, rat) ; 0 (Sterol Regulatory Element Binding Protein 1) ; 73Y7P0K73Y (Thioctic Acid) Entry Date(s): Date Created: 20150527 Date Completed: 20160531 Latest Revision: 20210316 Update Code: 20231215 PubMed Central ID: PMC4547883

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Activation of hepatic CREBH and Insig signaling in the anti-hypertriglyceridemic mechanism of R-α-lipoic acid.