Abstract | OBJECTIVE: 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.
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Authors | Prachiti Narvekar, Mauricio Berriel Diaz, Anja Krones-Herzig, Ulrike Hardeland, Daniela Strzoda, Sigrid Stöhr, Marcus Frohme, Stephan Herzig |
Journal | Diabetes
(Diabetes)
Vol. 58
Issue 5
Pg. 1040-9
(May 2009)
ISSN: 1939-327X [Electronic] United States |
PMID | 19188430
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Apolipoproteins E
- Blood Glucose
- Fatty Acids, Nonesterified
- Ketone Bodies
- Lipoproteins, VLDL
- Receptors, LDL
- Receptors, Lipoprotein
- Triglycerides
- lipolysis-stimulated receptor
- Cholesterol
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Topics |
- Animals
- Apolipoproteins E
(deficiency)
- Blood Glucose
(metabolism)
- Cholesterol
(blood)
- Diabetes Mellitus, Experimental
(physiopathology)
- Diabetes Mellitus, Type 2
(physiopathology)
- Disease Models, Animal
- Fatty Acids, Nonesterified
(blood)
- Hyperlipidemias
(physiopathology)
- Ketone Bodies
(blood)
- Lipolysis
- Lipoproteins, VLDL
(metabolism)
- Liver
(physiology)
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Mice, Obese
- RNA Interference
- Receptors, LDL
(deficiency, genetics, physiology)
- Receptors, Lipoprotein
(physiology)
- Reverse Transcriptase Polymerase Chain Reaction
- Triglycerides
(blood)
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