title: Liver-specific loss of lipolysis-stimulated lipoprotein receptor triggers systemic hyperlipidemia in mice.
abstract: 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.
  
  
  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.
authors.affiliation: Emmy Noether and Marie Curie Research Group Molecular Metabolic Control, DKFZ-ZMBH Alliance, German Cancer Research Center Heidelberg, Heidelberg, Germany.
authors.forename: Prachiti
authors.initials: P
authors.lastname: Narvekar
authors.forename: Mauricio
authors.initials: M
authors.lastname: Berriel Diaz
authors.forename: Anja
authors.initials: A
authors.lastname: Krones-Herzig
authors.forename: Ulrike
authors.initials: U
authors.lastname: Hardeland
authors.forename: Daniela
authors.initials: D
authors.lastname: Strzoda
authors.forename: Sigrid
authors.initials: S
authors.lastname: Stöhr
authors.forename: Marcus
authors.initials: M
authors.lastname: Frohme
authors.forename: Stephan
authors.initials: S
authors.lastname: Herzig
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D001786:Blood Glucose / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D004195:Disease Models, Animal; D005230:Fatty Acids, Nonesterified / Q000097:blood; D006949:Hyperlipidemias / Q000503:physiopathology*; D007657:Ketone Bodies / Q000097:blood; D008066:Lipolysis; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008099:Liver / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D034622:RNA Interference; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D018110:Receptors, Lipoprotein / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014280:Triglycerides / Q000097:blood
chemical_list: D001057:Apolipoproteins E; D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007657:Ketone Bodies; D008079:Lipoproteins, VLDL; D011973:Receptors, LDL; D018110:Receptors, Lipoprotein; D014280:Triglycerides; C085992:lipolysis-stimulated receptor; D002784:Cholesterol