دورية أكاديمية
أعرض في EDS

Hepatic glucokinase regulatory protein and carbohydrate response element binding protein attenuation reduce de novo lipogenesis but do not mitigate intrahepatic triglyceride accumulation in Aldob deficiency.

التفاصيل البيبلوغرافية
العنوان: Hepatic glucokinase regulatory protein and carbohydrate response element binding protein attenuation reduce de novo lipogenesis but do not mitigate intrahepatic triglyceride accumulation in Aldob deficiency.
المؤلفون: Buziau AM; Department of Internal Medicine, Division of Endocrinology and Metabolic Disease, Maastricht University Medical Center+, Maastricht, the Netherlands; Department of Internal Medicine, CARIM, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands., Oosterveer MH; Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands., Wouters K; Department of Internal Medicine, Division of Endocrinology and Metabolic Disease, Maastricht University Medical Center+, Maastricht, the Netherlands; Department of Internal Medicine, CARIM, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands., Bos T; Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands., Tolan DR; Department of Biology, Boston University, Boston, MA, USA., Agius L; Biosciences Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK., Ford BE; Biosciences Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK., Cassiman D; Department of Gastroenterology-Hepatology and Metabolic Center, University Hospital Leuven, Leuven, Belgium., Stehouwer CDA; Department of Internal Medicine, CARIM, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht University Medical Center+, Maastricht, the Netherlands., Schalkwijk CG; Department of Internal Medicine, Division of Endocrinology and Metabolic Disease, Maastricht University Medical Center+, Maastricht, the Netherlands; Department of Internal Medicine, CARIM, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands., Brouwers MCGJ; Department of Internal Medicine, Division of Endocrinology and Metabolic Disease, Maastricht University Medical Center+, Maastricht, the Netherlands; Department of Internal Medicine, CARIM, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands; Department of Internal Medicine, CARIM, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht University Medical Center+, Maastricht, the Netherlands. Electronic address: mcgj.brouwers@mumc.nl.
المصدر: Molecular metabolism [Mol Metab] 2024 Sep; Vol. 87, pp. 101984. Date of Electronic Publication: 2024 Jul 06.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Elsevier GmbH Country of Publication: Germany NLM ID: 101605730 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2212-8778 (Electronic) Linking ISSN: 22128778 NLM ISO Abbreviation: Mol Metab Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [München] : Elsevier GmbH, 2012-
مواضيع طبية MeSH: Lipogenesis* , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors*/metabolism , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors*/genetics , Liver*/metabolism , Triglycerides*/metabolism , Fructose-Bisphosphate Aldolase*/metabolism , Fructose-Bisphosphate Aldolase*/genetics , Mice, Knockout*, Animals ; Mice ; Male ; Mice, Inbred C57BL ; Adaptor Proteins, Signal Transducing/metabolism ; Adaptor Proteins, Signal Transducing/genetics ; Glucose/metabolism ; Transcription Factors/metabolism ; Transcription Factors/genetics ; Carrier Proteins
مستخلص: Objective: Stable isotope studies have shown that hepatic de novo lipogenesis (DNL) plays an important role in the pathogenesis of intrahepatic lipid (IHL) deposition. Furthermore, previous research has demonstrated that fructose 1-phosphate (F1P) not only serves as a substrate for DNL, but also acts as a signalling metabolite that stimulates DNL from glucose. The aim of this study was to elucidate the mediators of F1P-stimulated DNL, with special focus on two key regulators of intrahepatic glucose metabolism, i.e., glucokinase regulatory protein (GKRP) and carbohydrate response element binding protein (ChREBP).
Methods: Aldolase B deficient mice (Aldob -/- ), characterized by hepatocellular F1P accumulation, enhanced DNL, and hepatic steatosis, were either crossed with GKRP deficient mice (Gckr -/- ) or treated with short hairpin RNAs directed against hepatic ChREBP.
Results: Aldob -/- mice showed higher rates of de novo palmitate synthesis from glucose when compared to wildtype mice (p < 0.001). Gckr knockout reduced de novo palmitate synthesis in Aldob -/- mice (p = 0.017), without affecting the hepatic mRNA expression of enzymes involved in DNL. In contrast, hepatic ChREBP knockdown normalized the hepatic mRNA expression levels of enzymes involved in DNL and reduced fractional DNL in Aldob -/- mice (p < 0.05). Of interest, despite downregulation of DNL in response to Gckr and ChREBP attenuation, no reduction in intrahepatic triglyceride levels was observed.
Conclusions: Both GKRP and ChREBP mediate F1P-stimulated DNL in aldolase B deficient mice. Further studies are needed to unravel the role of GKRP and hepatic ChREBP in regulating IHL accumulation in aldolase B deficiency.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)
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فهرسة مساهمة: Keywords: Aldolase B; ChREBP; Fructose; GKRP; Glucose signalling; de novo lipogenesis
المشرفين على المادة: 0 (Basic Helix-Loop-Helix Leucine Zipper Transcription Factors)
0 (Mlxipl protein, mouse)
0 (Triglycerides)
EC 4.1.2.13 (Fructose-Bisphosphate Aldolase)
0 (glucokinase regulatory protein)
0 (Adaptor Proteins, Signal Transducing)
0 (Gckr protein, mouse)
IY9XDZ35W2 (Glucose)
0 (Transcription Factors)
0 (Carrier Proteins)
تواريخ الأحداث: Date Created: 20240707 Date Completed: 20240805 Latest Revision: 20240808
رمز التحديث: 20240808
مُعرف محوري في PubMed: PMC11300931
DOI: 10.1016/j.molmet.2024.101984
PMID: 38972375
قاعدة البيانات: MEDLINE
الوصف
تدمد:2212-8778
DOI:10.1016/j.molmet.2024.101984