scholarly journals Loss of Mrap2 is associated with Sim1 deficiency and increased circulating cholesterol

2016 ◽  
Vol 230 (1) ◽  
pp. 13-26 ◽  
Author(s):  
T V Novoselova ◽  
R Larder ◽  
D Rimmington ◽  
C Lelliott ◽  
E H Wynn ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Metabolic Regulation ◽  
Energy Homeostasis ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Melanocortin Receptor ◽  
Accessory Protein ◽  
Loss Of Function ◽  
Deficient Mice

Melanocortin receptor accessory protein 2 (MRAP2) is a transmembrane accessory protein predominantly expressed in the brain. Both global and brain-specific deletion of Mrap2 in mice results in severe obesity. Loss-of-function MRAP2 mutations have also been associated with obesity in humans. Although MRAP2 has been shown to interact with MC4R, a G protein-coupled receptor with an established role in energy homeostasis, appetite regulation and lipid metabolism, the mechanisms through which loss of MRAP2 causes obesity remains uncertain. In this study, we used two independently derived lines of Mrap2 deficient mice (Mrap2tm1a/tm1a) to further study the role of Mrap2 in the regulation of energy balance and peripheral lipid metabolism. Mrap2tm1a/tm1a mice have a significant increase in body weight, with increased fat and lean mass, but without detectable changes in food intake or energy expenditure. Transcriptomic analysis showed significantly decreased expression of Sim1, Trh, Oxt and Crh within the hypothalamic paraventricular nucleus of Mrap2tm1a/tm1a mice. Circulating levels of both high-density lipoprotein and low-density lipoprotein were significantly increased in Mrap2 deficient mice. Taken together, these data corroborate the role of MRAP2 in metabolic regulation and indicate that, at least in part, this may be due to defective central melanocortin signalling.

scholarly journals Loss of resistin ameliorates hyperlipidemia and hepatic steatosis in leptin-deficient mice

2008 ◽  
Vol 295 (2) ◽  
pp. E331-E338 ◽  
Author(s):  
Neel S. Singhal ◽  
Rajesh T. Patel ◽  
Yong Qi ◽  
Yun-Sik Lee ◽  
Rexford S. Ahima
Keyword(s):  
Hepatic Steatosis ◽  
High Fat Diet ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Wild Type ◽  
The Metabolic Syndrome ◽  
Expression Of Genes ◽  
Similar Body ◽  
Deficient Mice

Resistin has been linked to components of the metabolic syndrome, including obesity, insulin resistance, and hyperlipidemia. We hypothesized that resistin deficiency would reverse hyperlipidemia in genetic obesity. C57Bl/6J mice lacking resistin [resistin knockout (RKO)] had similar body weight and fat as wild-type mice when fed standard rodent chow or a high-fat diet. Nonetheless, hepatic steatosis, serum cholesterol, and very low-density lipoprotein (VLDL) secretion were decreased in diet-induced obese RKO mice. Resistin deficiency exacerbated obesity in ob/ob mice, but hepatic steatosis was drastically attenuated. Moreover, the levels of triglycerides, cholesterol, insulin, and glucose were reduced in ob/ob-RKO mice. The antisteatotic effect of resistin deficiency was related to reductions in the expression of genes involved in hepatic lipogenesis and VLDL export. Together, these results demonstrate a crucial role of resistin in promoting hepatic steatosis and hyperlipidemia in obese mice.

scholarly journals Novel strategies to target proprotein convertase subtilisin kexin 9: beyond monoclonal antibodies

2019 ◽  
Vol 115 (3) ◽  
pp. 510-518 ◽  
Author(s):  
Nabil G Seidah ◽  
Annik Prat ◽  
Angela Pirillo ◽  
Alberico Luigi Catapano ◽  
Giuseppe Danilo Norata
Keyword(s):  
Monoclonal Antibodies ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Loss Of Function ◽  
Proprotein Convertase ◽  
Innovative Strategies ◽  
Density Lipoprotein Receptor ◽  
Low Levels

Abstract Since the discovery of the role of proprotein convertase subtilisin kexin 9 (PCSK9) in the regulation of low-density lipoprotein cholesterol (LDL-C) in 2003, a paradigm shift in the treatment of hypercholesterolaemia has occurred. The PCSK9 secreted into the circulation is a major downregulator of the low-density lipoprotein receptor (LDLR) protein, as it chaperones it to endosomes/lysosomes for degradation. Humans with loss-of-function of PCSK9 exhibit exceedingly low levels of LDL-C and are protected from atherosclerosis. As a consequence, innovative strategies to modulate the levels of PCSK9 have been developed. Since 2015 inhibitory monoclonal antibodies (evolocumab and alirocumab) are commercially available. When subcutaneously injected every 2–4 weeks, they trigger a ∼60% LDL-C lowering and a 15% reduction in the risk of cardiovascular events. Another promising approach consists of a liver-targetable specific PCSK9 siRNA which results in ∼50–60% LDL-C lowering that lasts up to 6 months (Phases II–III clinical trials). Other strategies under consideration include: (i) antibodies targeting the C-terminal domain of PCSK9, thereby inhibiting the trafficking of PCSK9-LDLR to lysosomes; (ii) small molecules that either prevent PCSK9 binding to the LDLR, its trafficking to lysosomes or its secretion from cells; (iii) complete silencing of PCSK9 by CRISPR-Cas9 strategies; (iv) PCSK9 vaccines that inhibit the activity of circulating PCSK9. Time will tell whether other strategies can be as potent and safe as monoclonal antibodies to lower LDL-C levels.

scholarly journals SAT0521 EVALUATION OF LIPID PROFILE IN PATIENTS WITH AVASCULAR NECROSIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1216.2-1217
Author(s):  
K. Gudkevich ◽  
N. Martusevich ◽  
E. Dashkevich
Keyword(s):  
Lipid Metabolism ◽  
Avascular Necrosis ◽  
Cardiovascular Events ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Joint Involvement ◽  
Low Density ◽  
Low Density Lipoprotein Cholesterol

Background:Avascular necrosis (AN) is a disabling disease affecting predominantly young men. It steadily progresses to secondary osteoarthritis. The rate of disability is high, because hip joint is most commonly affected by AN; moreover, the rate of bilateral hip joint involvement is also high. The key event in the pathogenesis of AN is circulation disorder which results in ischemia and, furthermore, death of bone tissue.Nowadays the data about lipid metabolism in patients with AN. Besides, there is contradictory data about the role of homocysteine in the risk of cardiovascular events. Based on these, it is topical to investigate lipid metabolism and endothelial function in patients with AN.Objectives:The aim of the present study was to investigate lipid metabolism and endothelial function in patients with different stages of AN in order to find risk factors for incidence and progression of this disease.Methods:We recruited 41 patients with AN of the femoral head or femoral condyles aged 51 (35-64) years, 56,1% (n=23) were male. The inclusion criteria was diagnosis of AN confirmed by X-Ray, CT or MRI. The exclusion criteria were: traumatic AN, Legg-Calve-Pertes disease, connective tissue systemic diseases. Also we divided patients into subgroups with early (39% (n=16)) and late (61,0% (n=25)) stages of AN.Patients of the control group (n=32) were comparable by age and gender. The data was proceeded using non-parametric and descriptive statistics. We evaluated the following parameters: homocysteine, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, cholesterol ratio, apolipoprotein A1, apolipoprotein B.Results:In patients with AN we observed higher level of homocysteine (12,119 (7,771-14,38) vs. 7,911 (6,612-10,54) mcmol/l, p=0,05). The results are consistent with the data that higher homocyseine level is associated with higher risk for cardiovascular events (1). There is literature data about elevated homocysteine level in patients with AN, which was associated with lower levels of vitamin B12 and folic acid. Thus, interpretation of homocystene significance is more reliable in association with vitamin B12 and folic acid levels.Also, we observed that level of HDLP-C is higher in patients with early stages than in pate stages of AN (1,55 (1,31-1,57) vs. 1,23 (1,04-1,36) mmol/l, р=0,04). Thus, HDLP-C can be interpreted as a protective factor against contralateral joint involvement in AN patients. The data obtained is consistent with the existing data that HDLP-C lowers the risk for cardiovascular events.Conclusion:The data obtained indicate a significant role of dyslypidemia in the pathogenesis of AN in the context of vascular theory.References:[1]Steven G. Chrysant & George S. Chrysant (2018) The current status of homocysteine as a risk factor for cardiovascular disease: a mini review, Expert Review of Cardiovascular Therapy, 16:8, 559-565, DOI: 10.1080/14779072.2018.1497974.[2]Narayanan, A., Khanchandani, P., Borkar, R.M.et al.Avascular Necrosis of Femoral Head: A Metabolomic, Biophysical, Biochemical, Electron Microscopic and Histopathological Characterization.Sci Rep7, 10721 (2017).https://doi.org/10.1038/.Disclosure of Interests:Katsiarina Gudkevich: None declared, Natalia Martusevich Shareholder of: k, Elena Dashkevich: None declared

scholarly journals Understanding hyperlipidemia and atherosclerosis: lessons from genetically modified apoe and ldlr mice

2005 ◽  
Vol 43 (5) ◽  
Author(s):  
Kristiaan Wouters ◽  
Ronit Shiri-Sverdlov ◽  
Patrick J. van Gorp ◽  
Marc van Bilsen ◽  
Marten H. Hofker
Keyword(s):  
Mouse Models ◽  
Molecular Mechanisms ◽  
Genetically Modified ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipid Lowering ◽  
Density Lipoprotein Receptor ◽  
Mutant Forms ◽  
Deficient Mice

AbstractHyperlipidemia is the most important risk factor for atherosclerosis, which is the major cause of cardiovascular disease. The etiology of hyperlipidemia and atherosclerosis is complex and governed by multiple interacting genes. However, mutations in two genes have been shown to be directly involved, i.e., the low-density lipoprotein receptor (LDLR) and apolipoprotein E (ApoE). Genetically modified mouse models have been instrumental in elucidating the underlying molecular mechanisms in lipid metabolism. In this review, we focus on the use of two of the most widely used mouse models, ApoE- and LDLR-deficient mice. After almost a decade of applications, it is clear that each model has unique strengths and drawbacks when carrying out studies of the role of additional genes and environmental factors such as nutrition and lipid-lowering drugs. Importantly, we elaborate on mice expressing mutant forms of APOE, including the

scholarly journals Targeting pro-protein convertase subtilisin kexin-9 as a novel therapy of hypercholesterolemia

2017 ◽  
Vol 26 (2) ◽  
pp. 152-7
Author(s):  
Bambang Dwiputra ◽  
Anwar Santoso ◽  
Kian K. Poh
Keyword(s):  
Ldl Cholesterol ◽  
Competitive Inhibition ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
High Plasma ◽  
Phase Iii ◽  
Loss Of Function ◽  
Novel Therapy ◽  
Phase Iii Clinical Trials

Reducing low density lipoprotein (LDL) cholesterol level is an established primary and secondary prevention strategy for coronary heart disease. However, not all patients are able to achieve their LDL targets as recommended by the guidelines. Over the last 10 years, high plasma LDL level is known to be associated with a higher level of pro-protein convertase subtilisin kexin-9 (PCSK-9). Loss-of-function mutations in the PCSK-9 gene is associated with lower plasma LDL level and cardiovascular risk. Since its discovery in 2003, PCSK-9 has triggered many researchers to design a PCSK-9 inhibitor to reduce LDL cholesterol through competitive inhibition of this molecule. Some phase III clinical trials have showed promising results of PCSK-9 inhibitor efficacy in lowering LDL level and improving clinical outcome. This article aims to discuss the role of PCSK-9 in LDL metabolism and the efficacy of PCSK-9 inhibitor in reducing plasma LDL level.

scholarly journals Dj1 deficiency protects against atherosclerosis with anti-inflammatory response in macrophages

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tharini Sivasubramaniyam ◽  
Jiaqi Yang ◽  
Henry S. Cheng ◽  
Alexandra Zyla ◽  
Angela Li ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Atherogenic Diet ◽  
Whole Body ◽  
Anti Oxidant ◽  
Anti Inflammatory ◽  
Atherosclerosis Treatment ◽  
Deficient Mice

AbstractInflammation is a key contributor to atherosclerosis with macrophages playing a pivotal role through the induction of oxidative stress and cytokine/chemokine secretion. DJ1, an anti-oxidant protein, has shown to paradoxically protect against chronic and acute inflammation. However, the role of DJ1 in atherosclerosis remains elusive. To assess the role of Dj1 in atherogenesis, we generated whole-body Dj1-deficient atherosclerosis-prone Apoe null mice (Dj1−/−Apoe−/−). After 21 weeks of atherogenic diet, Dj1−/− Apoe−/−mice were protected against atherosclerosis with significantly reduced plaque macrophage content. To assess whether haematopoietic or parenchymal Dj1 contributed to atheroprotection in Dj1-deficient mice, we performed bone-marrow (BM) transplantation and show that Dj1-deficient BM contributed to their attenuation in atherosclerosis. To assess cell-autonomous role of macrophage Dj1 in atheroprotection, BM-derived macrophages from Dj1-deficient mice and Dj1-silenced macrophages were assessed in response to oxidized low-density lipoprotein (oxLDL). In both cases, there was an enhanced anti-inflammatory response which may have contributed to atheroprotection in Dj1-deficient mice. There was also an increased trend of plasma DJ-1 levels from individuals with ischemic heart disease compared to those without. Our findings indicate an atheropromoting role of Dj1 and suggests that targeting Dj1 may provide a novel therapeutic avenue for atherosclerosis treatment or prevention.

scholarly journals Coreopsis Tinctoria Modulates Lipid Metabolism by Decreasing Low-Density Lipoprotein and Improving Gut Microbiota

2018 ◽  
Vol 48 (3) ◽  
pp. 1060-1074 ◽  
Author(s):  
Zhigang Ren ◽  
Yali Li ◽  
Jiangyun Liu ◽  
Haitao Li ◽  
Ang Li ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Gut Microbiota ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Blood Lipid ◽  
Low Density ◽  
Biochemical Tests ◽  
Coreopsis Tinctoria ◽  
Normal Controls

Background/Aims: The prevalence of hyperlipidemia is increasing rapidly. The role of Coreopsis tinctoria (CT) in amending lipid metabolism in hyperlipidemia patients has not been reported. This study aims to evaluate the role of CT in altering lipid metabolism in hyperlipidemia patients and to explore the possible mechanisms mediated by gut microbiota in hyperlipidemia mice models. Methods: A retrospective analysis in 40 hyperlipidemia patients was conducted, in which 20 patients took fenofibrate and another 20 patients normatively drank water with CT. Hyperlipidemia mice models were also established. Blood biochemical tests were performed using an automatic biochemical analyzer. Liver histopathology was observed by hematoxylin and eosin staining. Ileocecal samples were collected from mice, and bacterial DNA was extracted and sequenced by MiSeq sequencing. Bacterial composition and differences were analyzed. Results: In hyperlipidemia patients, CT was associated with decreased triglyceride and low-density lipoprotein (LDL) levels without liver injury. The experimental hyperlipidemia model also verified a similar result. Gut microbial richness and diversity were significantly decreased in hyperlipidemic mice, but increased after CT treatment. Bacterial communities were significantly differentiated between normal controls and hyperlipidemic mice. CT administration improved gut microbiota composition to an approximately normal status. Meanwhile, CT administration attenuated bacterial alterations at the class, order, family, and genus levels in hyperlipidemic mice. Importantly, the genera Barnesiella, Lactobacillus, and Helicobacter achieved high discriminatory power in hyperlipidemic mice relative to normal controls. Conclusions: CT can modulate blood lipid metabolism with improvement of liver function by decreasing LDL and improving gut microbiota compositions. These findings may provide novel therapeutic strategies for patients with hyperlipidemia.

scholarly journals Lipid Metabolism and Microbial Profiles Between Shaziling and Yorkshire Pigs

2021 ◽  
Author(s):  
Jie Ma ◽  
Yehui Duan ◽  
Xiaoxiao Liang ◽  
Tiejun Li ◽  
Xingguo Huang ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Acid Biosynthesis ◽  
Indigenous Breed ◽  
Α Diversity ◽  
Microbial Development ◽  
Yorkshire Pigs ◽  
Host Metabolism

Abstract Background: Shaziling pig, a Chinese indigenous breed, has been classified as a fatty pig model, while the lipid metabolism and gut microbial development in Shaziling pigs were rarely reported. Methods: Here, we compared the metabolic and microbial profiles at 30, 60, 90, 120, 150, 210, and 300 days of age between Shaziling and Yorkshire pigs. Results: Predictably, there were marked difference in the liver lipids (i.e., cholesterol, glucose, and low density lipoprotein) and the expressions (i.e., SREBP1/2, LXRα/β, DGAT1/2, and FABP1-3) between Shaziling and Yorkshire pigs. Bacteria in the ileal digesta and mucosa were further analyzed, and the results showed that Shaziling pigs had a higher α-diversity and the abundances of probiotics, such as Lactobacillus_johnosonii, Lactobacillus_amylovorus, and Clostridium_butyricum. 35 differentiated metabolites were identified in the mucosa between Shaziling and Yorkshire pigs, which were enriched in the carbohydrate, protein, glucose and amino acid metabolism and bile acid biosynthesis. Furthermore, 7 differentiated microbial species were markedly correlated with 35 metabolites, indicating the role of gut microbiota in host metabolism. Conclusions: In conclusion, Shaziling pigs exhibited different metabolic and microbial profiles compared with the Yorkshire pigs, which might contribute to the diverse metabolic phenotypes.

Role of Low Density Lipoprotein Receptor in the Clearance of Coagulation Factor VIII In Vivo.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1925-1925
Author(s):  
Koen Mertens ◽  
Niels Bovenschen ◽  
Louis M. Havekes ◽  
Bart J.M. van Vlijmen
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Factor Ix ◽  
Low Density ◽  
Lipoprotein Receptor ◽  
Low Density Lipoprotein Receptor ◽  
Density Lipoprotein Receptor ◽  
Deficient Mice

Abstract Low Density Lipoprotein Receptor (LDLR) is the archetype of the family of endocytic receptors that also includes Low-density lipoprotein Receptor-related Protein (LRP), Megalin, and Very Low Density Lipoprotein Receptor (VLDLR). While most of these receptors bind a variety of ligands, LDLR has restricted specifity. Its known ligands are apolipoprotein E (apoE) and apolipoprotein B100 (apoB100). Ligand binding to the LDL-receptor family is inhibited by the Receptor-Associated Protein (RAP). We have previously reported that RAP overexpression elevates plasma levels of factor VIII (FVIII) in both normal mice and mice with hepatic LRP deficiency [Bovenschen et al. (2003) Blood 101, 3933–3939]. This implies that LRP, but also another RAP-sensitive mechanism contributes to the regulation of FVIII in vivo. This study addresses the question whether LDLR, despite its restricted ligand specificity, binds FVIII and contributes to its clearance. In vitro binding was studied using a recombinant LDLR fragment spanning the extracellular domain of complement-type repeats 1–7. The purified fragment efficiently bound to immobilized ApoE and apoB-100 containing LDL. The immobilized LDLR fragment also bound human FVIII, with half-maximal binding at 156 nM FVIII, and binding was inhibited by RAP. Human von Willebrand Factor (VWF) or non-activated factor IX did not bind to the LDLR fragment. The relevance of the FVIII-LDLR interaction was assessed in vivo employing LDLR−/− mice, cre/loxP-mediated conditional LRP-deficient mice (LRP−), and mice with the combined deficiency. Plasma FVIII levels of controls, LDLR−/− and LRP− mice were 1.1, 0.9 and 1.8 U/ml, respectively. This suggests that LRP, but not LDLR regulates FVIII in plasma. Surprisingly, however, mice that combined LDLR deficiency with hepatic LRP deficiency displayed much higher FVIII levels (median value 4.6 U/ml) than mice lacking LRP alone. This suggests that LDLR does have the potential of regulating FVIII levels. LDLR−/− LRP− mice further displayed elevated levels of VWF (median value 3.3 U/ml), but not of factor V or factor IX. The possibility was considered that FVIII levels were elevated secondary to the profound changes in lipoprotein profiles. To this end, we also examined ApoE deficient mice, which have reduced LDL, and mice that overexpress ApoC1, which is associated with elevated levels of cholesterol- and triglyceride VLDL. ApoE−/− LDLR−/−LRP− mice had a median FVIII level of 4.2 U/ml, which is close to that of LDLR−/−LRP− mice. Mice that overexpressed human ApoC1 had elevated levels of cholesterol and triglycerides, but 0.5 U/ml FVIII. This demonstrates that elevated FVIII levels were independent of lipoprotein levels. The role of LDLR and LRP in FVIII clearance were further studied by analyzing the pharmacokinetics of human FVIII. In normal mice the Mean Residence Time (MRT) was 160 min [68% confidence intervals (CI) 117–218 min]. MRT was 200 [CI 154–259] min in LDLR−/− mice, and 263 [CI 206–336] min in LRP− mice. This confirms the previously described role of LRP in FVIII clearance. Strikingly, in LDLR−/−LRP− mice the MRT of FVIII was 760 [691–826] min, which is approximately 5-fold longer than in control mice. These data demonstrate that LRP and LDLR act in concert in regulating FVIII levels in plasma. In the absence of LDLR, LRP maintains normal FVIII levels, while hepatic LRP deficiency is largely compensated by LDLR. This regulatory role of LDLR represents a novel link between LDLR and the hemostatic system.

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