Liver-Specific Loss of Lipolysis-Stimulated Lipoprotein Receptor Triggers Systemic Hyperlipidemia in Mice
| Autor: | Mauricio Berriel Diaz, Ulrike Hardeland, Prachiti Narvekar, Daniela Strzoda, Sigrid Stöhr, Marcus Frohme, Anja Krones-Herzig, Stephan Herzig |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Blood Glucose
Apolipoprotein E medicine.medical_specialty Lipolysis Endocrinology Diabetes and Metabolism Mice Obese Hyperlipidemias Ketone Bodies Fatty Acids Nonesterified Lipoproteins VLDL Biology Diabetes Mellitus Experimental Mice chemistry.chemical_compound Apolipoproteins E Internal medicine Diabetes mellitus Hyperlipidemia Internal Medicine medicine Animals Triglycerides Receptors Lipoprotein Mice Knockout Reverse Transcriptase Polymerase Chain Reaction Cholesterol Hypertriglyceridemia medicine.disease Mice Inbred C57BL Disease Models Animal Metabolism Endocrinology Diabetes Mellitus Type 2 Liver Receptors LDL chemistry lipids (amino acids peptides and proteins) Original Article RNA Interference Metabolic syndrome Dyslipidemia Lipoprotein |
| Zdroj: | Diabetes |
| ISSN: | 1939-327X 0012-1797 |
| Popis: | OBJECTIVE 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. RESEARCH DESIGN AND METHODS 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. RESULTS 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. CONCLUSIONS 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|