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Atherogenesis and metabolic dysregulation in LDL receptor-knockout rats.

ABSTRACT: Mechanisms of atherogenesis have been studied extensively in genetically engineered mice with disturbed cholesterol metabolism such as those lacking either the LDL receptor (Ldlr) or apolipoprotein E (apoe). Few other animal models of atherosclerosis are available. WT rabbits or rats, even on high-fat or high-cholesterol diets, develop sparse atherosclerotic lesions. We examined the effects of Ldlr deletion on lipoprotein metabolism and atherosclerotic lesion formation in Sprague-Dawley rats. Deletion of Ldlr resulted in the loss of the LDLR protein and caused a significant increase in plasma total cholesterol and triglycerides. On normal chow, Ldlr-KO rats gained more weight and were more glucose intolerant than WT rats. Plasma proprotein convertase subtilisin kexin 9 (PCSK9) and leptin levels were higher and adiponectin levels were lower in KO than WT rats. On the Western diet, the KO rats displayed exaggerated obesity and age-dependent increases in glucose intolerance. No appreciable aortic lesions were observed in KO rats fed normal chow for 64 weeks or Western diet for 16 weeks; however, after 34-52 weeks of Western diet, the KO rats developed exuberant atherosclerotic lesions in the aortic arch and throughout the abdominal aorta. The Ldlr-KO rat may be a useful model for studying obesity, insulin resistance, and early-stage atherosclerosis.

SUBMITTER: Sithu SD

PROVIDER: S-EPMC5414561 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Atherogenesis and metabolic dysregulation in LDL receptor-knockout rats.

Sithu Srinivas D SD Malovichko Marina V MV Riggs Krista A KA Wickramasinghe Nalinie S NS Winner Millicent G MG Agarwal Abhinav A Hamed-Berair Rihab E RE Kalani Anuradha A Riggs Daniel W DW Bhatnagar Aruni A Srivastava Sanjay S

JCI insight 20170504 9

Mechanisms of atherogenesis have been studied extensively in genetically engineered mice with disturbed cholesterol metabolism such as those lacking either the LDL receptor (Ldlr) or apolipoprotein E (apoe). Few other animal models of atherosclerosis are available. WT rabbits or rats, even on high-fat or high-cholesterol diets, develop sparse atherosclerotic lesions. We examined the effects of Ldlr deletion on lipoprotein metabolism and atherosclerotic lesion formation in Sprague-Dawley rats. De ...[more]

PMID: 28469073

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Project description:Angiotensin-converting enzyme 2 (ACE2) polymorphisms are associated with increased risk of type 2 diabetes mellitus (T2DM), obesity and dyslipidemia, which have been determined in various populations. Consistently, ACE2 knockout (ACE2 KO) mice display damaged energy metabolism in multiple tissues, especially the key metabolic tissues such as liver, skeletal muscle and epididymal white adipose tissue (eWAT) and show even more severe phenotype under high-fat diet (HFD) induced metabolic stress. However, the effects of ACE2 on global metabolomics profiling and the tissue sensitivity remain unclear. To understand how tissues independently and collectively respond to ACE2, we performed untargeted metabolomics in serum in ACE2 KO and control wild type (WT) mice both on normal diet (ND) and HFD, and in three key metabolic tissues (liver, skeletal muscle and eWAT) after HFD treatment. The results showed significant alterations in metabolic profiling in ACE2 KO mice. We identified 275 and 168 serum metabolites differing significantly between WT and ACE2 KO mice fed on ND and HFD, respectively. And the altered metabolites in the ACE2 KO group varied from 90 to 196 in liver, muscle and eWAT. The alterations in ND and HFD serum were most similar. Compared with WT mice, ACE2 KO mice showed an increase in N-phenylacetylglutamine (PAGln), methyl indole-3-acetate, 5-hydroxytryptophol, cholic acid, deoxycholic acid and 12(S)-HETE, while LPC (19:0) and LPE (16:1) decreased. Moreover, LPC (20:0), LPC (20:1) and PC (14:0e/6:0) were reduced in both ND and HFD serum, paralleling the decreases identified in HFD skeletal muscle. Interestingly, DL-tryptophan, indole and Gly-Phe decreased in both ND and HFD serum but were elevated in HFD liver of ACE2 KO mice. A low level of l-ergothioneine was observed among liver, muscle, and epididymal fat tissue of ACE2 KO mice. Pathway analysis demonstrated that different tissues exhibited different dysregulated metabolic pathways. In conclusion, these results revealed that ACE2 deficiency leads to an overall state of metabolic distress, which may provide a new insight into the underlying pathogenesis in metabolic disorders in both ACE2 KO mice and in patients with certain genetic variant of ACE2 gene.

Project description:ObjectiveMelanocortin-4 receptors (MC4Rs) are highly expressed by dopamine-secreting neurons of the mesolimbic tract, but their functional role has not been fully resolved. Voluntary wheel running (VWR) induces adaptations in the mesolimbic dopamine system and has a myriad of long-term beneficial effects on health. In the present experiments we asked whether MC4R function regulates the effects of VWR, and whether VWR ameliorates MC4R-associated symptoms of the metabolic syndrome.MethodsElectrically evoked dopamine release was measured in slice preparations from sedentary wild-type and MC4R-deficient Mc4r (K314X) (HOM) rats. VWR was assessed in wild-type and HOM rats, and in MC4R-deficient loxTB (Mc4r) mice, wild-type mice body weight-matched to loxTB (Mc4r) mice, and wild-type mice with intracerebroventricular administration of the MC4R antagonist SHU9119. Mesolimbic dopamine system function (gene/protein expression) and metabolic parameters were examined in wheel-running and sedentary wild-type and HOM rats.ResultsSedentary obese HOM rats had increased electrically evoked dopamine release in several ventral tegmental area (VTA) projection sites compared to wild-type controls. MC4R loss-of-function decreased VWR, and this was partially independent of body weight. HOM wheel-runners had attenuated markers of intracellular D1-type dopamine receptor signaling despite increased dopamine flux in the VTA. VWR increased and decreased ΔFosB levels in the nucleus accumbens (NAc) of wild-type and HOM runners, respectively. VWR improved metabolic parameters in wild-type wheel-runners. Finally, moderate voluntary exercise corrected many aspects of the metabolic syndrome in HOM runners.ConclusionsCentral dopamine dysregulation during VWR reinforces the link between MC4R function and molecular and behavioral responding to rewards. The data also suggest that exercise can be a successful lifestyle intervention in MC4R-haploinsufficient individuals despite reduced positive reinforcement during exercise training.

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Atherogenesis and metabolic dysregulation in LDL receptor-knockout rats.

Publications

Atherogenesis and metabolic dysregulation in LDL receptor-knockout rats.

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