title: Activation of hepatic CREBH and Insig signaling in the anti-hypertriglyceridemic mechanism of R-α-lipoic acid.
abstract: 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.
authors.affiliation: Key Laboratory of Laboratory Medicine, Zhejiang Provincial Key Laboratory of Medical Genetics, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Department of Nutrition and Health Sciences, University of Nebraska Lincoln, Lincoln, NE 68583-0806, USA.
authors.forename: Xuedong
authors.initials: X
authors.lastname: Tong
authors.affiliation: Department of Nutrition and Health Sciences, University of Nebraska Lincoln, Lincoln, NE 68583-0806, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Christian
authors.affiliation: Department of Nutrition and Health Sciences, University of Nebraska Lincoln, Lincoln, NE 68583-0806, USA.
authors.forename: Miaoyun
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Nutrition and Health Sciences, University of Nebraska Lincoln, Lincoln, NE 68583-0806, USA.
authors.forename: Hai
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Nutrition and Health Sciences, University of Nebraska Lincoln, Lincoln, NE 68583-0806, USA.
authors.forename: Regis
authors.initials: R
authors.lastname: Moreau
authors.affiliation: Department of Nutrition and Health Sciences, University of Nebraska Lincoln, Lincoln, NE 68583-0806, USA. Electronic address: qsu2@unl.edu.
authors.forename: Qiaozhu
authors.initials: Q
authors.lastname: Su
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D019587:Dietary Supplements; D022781:Hepatocytes / Q000201:enzymology* / Q000378:metabolism; D015228:Hypertriglyceridemia / Q000097:blood / Q000178:diet therapy* / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000378:metabolism / Q000627:therapeutic use*; D047908:Intracellular Signaling Peptides and Proteins / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000097:blood / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011897:Random Allocation; D011915:Rats, Inbred BUF; D011924:Rats, Zucker; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008063:Thioctic Acid / Q000378:metabolism / Q000627:therapeutic use*; D015854:Up-Regulation
chemical_list: C000607973:Creb3l3 protein, rat; D017362:Cyclic AMP Response Element-Binding Protein; D000960:Hypolipidemic Agents; C491574:Insig1 protein, rat; C000607974:Insig2 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008079:Lipoproteins, VLDL; D008565:Membrane Proteins; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D008063:Thioctic Acid
keywords: Apolipoproteins; Cell signaling; Dyslipidemias; Sterol regulatory element binding proteins; Triglyceride metabolism; Very low density lipoprotein