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Liver-specific loss of lipolysis-stimulated lipoprotein receptor triggers systemic hyperlipidemia in mice

  • In mammals, proper storage and distribution of lipids in and between tissues is essential for the maintenance of energy homeostasis. In contrast, aberrantly high levels of triglycerides in the blood ("hypertriglyceridemia") represent a hallmark of the metabolic syndrome and type 2 diabetes. As hypertriglyceridemia has been identified as an important risk factor for cardiovascular complications, in this study we aimed to identify molecular mechanisms in aberrant triglyceride elevation under these conditions. To determine the importance of hepatic lipid handling for systemic dyslipidemia, we profiled the expression patterns of various hepatic lipid transporters and receptors under healthy and type 2 diabetic conditions. A differentially expressed lipoprotein receptor was functionally characterized by generating acute, liver-specific loss- and gain-of-function animal models. We show that the hepatic expression of lipid transporter lipolysis-stimulated lipoprotein receptor (LSR) is specifically impaired in mouse models of obesity and type 2 diabetes and can be restored by leptin replacement. Experimental imitation of this pathophysiological situation by liver-specific knockdown of LSR promotes hypertriglyceridemia and elevated apolipoprotein (Apo)B and E serum levels in lean wild-type and ApoE knockout mice. In contrast, genetic restoration of LSR expression in obese animals to wild-type levels improves serum triglyceride levels and serum profiles in these mice. The dysregulation of hepatic LSR under obese and diabetic conditions may provide a molecular rationale for systemic dyslipidemia in type 2 diabetes and the metabolic syndrome and represent a novel target for alternative treatment strategies in these patients.

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URN:urn:nbn:de:kobv:526-opus4-19954
Publisher DOI:https://doi.org/10.2337/db08-1184
Author:Prachiti Narvekar, Mauricio Berriel DiazORCiD, Anja Krones-Herzig, Ulrike Hardeland, Daniela Strzoda, Sigrid Stöhr, Marcus FrohmeORCiDGND, Stephan HerzigORCiD
Parent Title (English):Diabetes
Document Type:Article
Language:English
Year of Publication:2009
Volume:58
Issue:5
First Page:1040
Last Page:1049
Publisher:American Diabetes Association
Faculties an central facilities:Fachbereich Ingenieurwesen / Wirtschaftsingenieurwesen (bis 8/2014)
Publishing Institution:Technische Hochschule Wildau
Source:Prachiti Narvekar, Mauricio Berriel Diaz, Anja Krones-Herzig, Ulrike Hardeland, Daniela Strzoda, Sigrid Stöhr, Marcus Frohme, Stephan Herzig; Liver-Specific Loss of Lipolysis-Stimulated Lipoprotein Receptor Triggers Systemic Hyperlipidemia in Mice. Diabetes 1 May 2009; 58 (5): 1040–1049. https://doi.org/10.2337/db08-1184
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 612 Humanphysiologie
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 616 Krankheiten
Licence (German):Creative Commons - CC BY-NC-ND 3.0 - Namensnennung - Nicht-kommerziell - Keine Bearbeitung 3.0 Unported
Release Date:2025/02/14
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