Abstract 327: SR-BI Deficiency and Hypercholesterolemia Synergistically Lead to Impaired Erythropoiesis

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Zhiqing Song ◽  
Ling Guo ◽  
Xiang-An Li
Keyword(s):  
Knockout Mice ◽  
High Fat Diet ◽  
Plasma Cholesterol ◽  
Scavenger Receptor ◽  
Fold Increase ◽  
Wild Type ◽  
High Fat ◽  
Double Knockout ◽  
Scavenger Receptor Bi ◽  
Cholesterol Levels

Recent studies showed that mice deficient in scavenger receptor BI (SR-BI) exhibit impaired erythropoiesis and it has been proposed that the high cholesterol environment plays a major role in the abnormal erythropoiesis. In this study, we utilized three animal models to assess the role of SR-BI and hypercholesterolemia in erythropoiesis. First, we used a high fat diet-induced hypercholesterolemia model. High fat diet caused a 2-fold increase in plasma cholesterol levels in SR-BI +/+ (172 mg/dl to 350 mg/dl) and SR-BI -/- mice (313 mg/dl to 716 mg/dl). The high fat diet treatment markedly exacerbated the impaired erythropoiesis in SR-BI -/- mice as shown by 4-fold increase in reticulocyte percentage and 2.5-fold increase in early-to-late erythroblast ratio. Unexpectedly, high fat feeding did not induce abnormal erythropoiesis in SR-BI +/+ mice despite of hypercholesterolemia in these mice. We then used SR-BI/LDLR double knockout mice to further elucidate the contribution of hypercholesterolemia to erythropoiesis. SR-BI/LDLR double knockout mice had 2-fold increase in plasma cholesterol levels and exhibited severer impaired erythropoiesis, similar to high fat-fed SR-BI -/- mice. Interestingly, despite of hyperlipidemia, LDLR single knockout mice did not display impaired erythropoiesis. Finally, we investigated the contribution of hepatic SR-BI using ScarbI I179N mutant mice, whose hepatic SR-BI expression has been knocked down by 90% and therefore has a 1.7-fold increase in plasma cholesterol levels compared to wild type controls. ScarbI I179N mice displayed normal erythropoiesis, similar to wild type controls. These findings indicate that hypercholesterolemia does not cause abnormal erythropoiesis in the presence of SR-BI, but markedly impairs erythropoiesis in the absence of SR-BI. We conclude that SR-BI is essential for normal erythropoiesis, and that hypercholesterolemia and SR-BI deficiency synergistically exacerbated impaired erythropoiesis.

scholarly journals Tpcn2 knockout mice have improved insulin sensitivity and are protected against high-fat diet-induced weight gain

2018 ◽  
Vol 50 (8) ◽  
pp. 605-614
Author(s):  
Hong He ◽  
Katie Holl ◽  
Sarah DeBehnke ◽  
Chay Teng Yeo ◽  
Polly Hansen ◽  
...  
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Knockout Mice ◽  
High Fat Diet ◽  
Wild Type ◽  
High Fat ◽  
Male And Female ◽  
Female Mice

Type 2 diabetes is a complex disorder affected by multiple genes and the environment. Our laboratory has shown that in response to a glucose challenge, two-pore channel 2 ( Tpcn2) knockout mice exhibit a decreased insulin response but normal glucose clearance, suggesting they have improved insulin sensitivity compared with wild-type mice. We tested the hypothesis that improved insulin sensitivity in Tpcn2 knockout mice would protect against the negative effects of a high fat diet. Male and female Tpcn2 knockout (KO), heterozygous (Het), and wild-type (WT) mice were fed a low-fat (LF) or high-fat (HF) diet for 24 wk. HF diet significantly increases body weight in WT mice relative to those on the LF diet; this HF diet-induced increase in body weight is blunted in the Het and KO mice. Despite the protection against diet-induced weight gain, however, Tpcn2 KO mice are not protected against HF-diet-induced changes in glucose or insulin area under the curve during glucose tolerance tests in female mice, while HF diet has no significant effect on glucose tolerance in the male mice, regardless of genotype. Glucose disappearance during an insulin tolerance test is augmented in male KO mice, consistent with our previous findings suggesting enhanced insulin sensitivity in these mice. Male KO mice exhibit increased fasting plasma total cholesterol and triglyceride concentrations relative to WT mice on the LF diet, but this difference disappears in HF diet-fed mice where there is increased cholesterol and triglycerides across all genotypes. These data demonstrate that knockout of Tpcn2 may increase insulin action in male, but not female, mice. In addition, both male and female KO mice are protected against diet-induced weight gain, but this protection is likely independent from glucose tolerance, insulin sensitivity, and plasma lipid levels.

Vasorelaxant and antiaggregatory actions of the nitroxyl donor isopropylamine NONOate are maintained in hypercholesterolemia

2011 ◽  
Vol 301 (4) ◽  
pp. H1405-H1414 ◽  
Author(s):  
Michelle L. Bullen ◽  
Alyson A. Miller ◽  
Janahan Dharmarajah ◽  
Grant R. Drummond ◽  
Christopher G. Sobey ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
High Fat Diet ◽  
Plasma Cholesterol ◽  
Soluble Guanylyl Cyclase ◽  
Vascular Diseases ◽  
Normal Diet ◽  
Wild Type ◽  
Novel Treatments ◽  
Cholesterol Levels ◽  
Deficient Mice

Nitroxyl (HNO) displays pharmacological and therapeutic actions distinct from those of its redox sibling nitric oxide (NO∙). It remains unclear, however, whether the vasoprotective actions of HNO are preserved in disease. The ability of the HNO donor isopropylamine NONOate (IPA/NO) to induce vasorelaxation, its susceptibility to tolerance development, and antiaggregatory actions were compared with those of a clinically used NO∙ donor, glyceryl trinitrate (GTN), in hypercholesterolemic mice. The vasorelaxant and antiaggregatory properties of IPA/NO and GTN were examined in isolated carotid arteries and washed platelets, respectively, from male C57BL/6J mice [wild-type (WT)] maintained on either a normal diet (WT-ND) or high fat diet (WT-HFD; 7 wk) as well as apolipoprotein E-deficient mice maintained on a HFD (ApoE−/−-HFD; 7 wk). In WT-ND mice, IPA/NO (0.1–30 μmol/l) induced concentration-dependent vasorelaxation and inhibition of collagen (30 μg/ml)-stimulated platelet aggregation, which was predominantly soluble guanylyl cyclase/cGMP dependent. Compared with WT-HFD mice, ApoE−/−-HFD mice displayed an increase in total plasma cholesterol levels ( P < 0.001), vascular ( P < 0.05) and platelet ( P < 0.05) superoxide (O2·−) production, and reduced endogenous NO∙ bioavailability ( P < 0.001). Vasorelaxant responses to both IPA/NO and GTN were preserved in hypercholesterolemia, whereas vascular tolerance developed to GTN ( P < 0.001) but not to IPA/NO. The ability of IPA/NO (3 μmol/l) to inhibit platelet aggregation was preserved in hypercholesterolemia, whereas the actions of GTN (100 μmol/l) were abolished. In conclusion, the vasoprotective effects of IPA/NO were maintained in hypercholesterolemia and, thus, HNO donors may represent future novel treatments for vascular diseases.

scholarly journals Disruption of Phospholipid Transfer Protein–Mediated High-Density Lipoprotein Maturation Reduces Scavenger Receptor BI Deficiency–Driven Atherosclerosis Susceptibility Despite Unexpected Metabolic Complications

2020 ◽  
Vol 40 (3) ◽  
pp. 611-623 ◽  
Author(s):  
Menno Hoekstra ◽  
Ronald J. van der Sluis ◽  
Reeni B. Hildebrand ◽  
Bart Lammers ◽  
Ying Zhao ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Knockout Mice ◽  
Scavenger Receptor ◽  
Density Lipoprotein ◽  
Phospholipid Transfer Protein ◽  
Double Knockout ◽  
Metabolic Complications ◽  
Scavenger Receptor Bi ◽  
Transfer Protein ◽  
Phospholipid Transfer

Objective: We tested the hypothesis that enlarged, dysfunctional HDL (high-density lipoprotein) particles contribute to the augmented atherosclerosis susceptibility associated with SR-BI (scavenger receptor BI) deficiency in mice. Approach and Results: We eliminated the ability of HDL particles to fully mature by targeting PLTP (phospholipid transfer protein) functionality. Particle size of the HDL population was almost fully normalized in male and female SR-BI×PLTP double knockout mice. In contrast, the plasma unesterified cholesterol to cholesteryl ester ratio remained elevated. The PLTP deficiency-induced reduction in HDL size in SR-BI knockout mice resulted in a normalized aortic tissue oxidative stress status on Western-type diet. Atherosclerosis susceptibility was—however—only partially reversed in double knockout mice, which can likely be attributed to the fact that they developed a metabolic syndrome-like phenotype characterized by obesity, hypertriglyceridemia, and a reduced glucose tolerance. Mechanistic studies in chow diet–fed mice revealed that the diminished glucose tolerance was probably secondary to the exaggerated postprandial triglyceride response. The absence of PLTP did not affect LPL (lipoprotein lipase)-mediated triglyceride lipolysis but rather modified the ability of VLDL (very low-density lipoprotein)/chylomicron remnants to be cleared from the circulation by the liver through receptors other than SR-BI. As a result, livers of double knockout mice only cleared 26% of the fractional dose of [ 14 C]cholesteryl oleate after intravenous VLDL-like particle injection. Conclusions: We have shown that disruption of PLTP-mediated HDL maturation reduces SR-BI deficiency-driven atherosclerosis susceptibility in mice despite the induction of proatherogenic metabolic complications in the double knockout mice.

Abstract P312: The Essential Role Of Prak In Preserving Cardiac Function And Insulin Resistance In High Fat Diet-induced Diabetes

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Yu T Zhao ◽  
Jianfeng Du ◽  
Thomas J Zhao ◽  
Hao Wang ◽  
Marshall Kadin ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Cardiac Function ◽  
Western Blot ◽  
Knockout Mice ◽  
High Fat Diet ◽  
Metabolic Disorders ◽  
Tolerance Test ◽  
Wild Type ◽  
High Fat

Background: p38 regulated/activated protein kinase (PRAK) plays a crucial role in modulating cell death and survival. However, the role of PRAK in mediating cardiac dysfunction and metabolic disorders remains unclear. We examined the effects of deletion of PRAK on modulating cardiac function and insulin resistance in mice exposed to a high fat diet (HFD). Methods: Wild type and PRAK -/- mice at 8 weeks old were exposed to either chow food or HFD for a consecutive 16 weeks. Glucose tolerance test and insulin tolerance test were employed to assess insulin resistance. Echocardiography was employed to assess myocardial function. Western blot was used to determine the molecular signaling involved in phosphorylation of IRS-1, AMPKα, ERK-44/42, and irisin. Real time-PCR was used to assess the hypertrophic genes of the myocardium. Histological analysis was employed to assess the hypertrophic response, interstitial myocardial fibrosis, and apoptosis in the heart. Results: HFD induced metabolic stress is indicated by glucose intolerance and insulin intolerance. PRAK knockout aggravated insulin resistance, as indicated by glucose intolerance and insulin intolerance testing as compared to wild type littermates. As compared to wild type, hyperglycemia and hypercholesterolemia were manifested in PRAK-knockout mice following high fat diet intervention. High fat diet intervention displayed a decline in fractional shortening (FS) and ejection fraction (EF). However, deletion of PRAK exacerbated the decline in EF and FS as compared to wild type mice following HFD treatment. In addition, PRAK knockout mice enhanced the expression of myocardial hypertrophic genes including ANP, BNP, and βMHC in HFD treatment, which was also associated with an increase in cardiomyocyte size and interstitial fibrosis. Western blot indicated that deletion of PRAK induces decreases in phosphorylation of IRS-1, AMPKα, and ERK44/42 as compared to wild type controls. Conclusion: Our finding indicates that deletion of PRAK promoted myocardial dysfunction, cardiac remodeling, and metabolic disorders in response to HFD.

Studies of UCP2 transgenic and knockout mice reveal that liver UCP2 is not essential for the antiobesity effects of fish oil

2008 ◽  
Vol 294 (3) ◽  
pp. E600-E606 ◽  
Author(s):  
Nobuyo Tsuboyama-Kasaoka ◽  
Kayo Sano ◽  
Chikako Shozawa ◽  
Toshimasa Osaka ◽  
Osamu Ezaki
Keyword(s):  
Transgenic Mice ◽  
Fish Oil ◽  
Knockout Mice ◽  
High Fat Diet ◽  
Uncoupling Protein ◽  
Dietary Fats ◽  
Similar Degree ◽  
Safflower Oil ◽  
Wild Type ◽  
High Fat

Uncoupling protein 2 (UCP2) is a possible target molecule for energy dissipation. Many dietary fats, including safflower oil and lard, induce obesity in C57BL/6 mice, whereas fish oil does not. Fish oil increases UCP2 expression in hepatocytes and may enhance UCP2 activity by activating the UCP2 molecule or altering the lipid bilayer environment. To examine the role of liver UCP2 in obesity, we created transgenic mice that overexpressed human UCP2 in hepatocytes and examined whether UCP2 transgenic mice showed less obesity when fed a high-fat diet (safflower oil or lard). In addition, we examined whether fish oil had antiobesity effects in UCP2 knockout mice. UCP2 transgenic and wild-type mice fed a high-fat diet (safflower oil or lard) developed obesity to a similar degree. UCP2 knockout and wild-type mice fed fish oil had lower rates of obesity than mice fed safflower oil. Remarkably, safflower oil did not induce obesity in female UCP2 knockout mice, an unexpected phenotype for which we presently have no explanation. However, this unexpected effect was not observed in male UCP2 knockout mice or in UCP2 knockout mice fed a high-lard diet. These data indicate that liver UCP2 is not essential for fish oil-induced decreases in body fat.

scholarly journals The Essential Role of PRAK in Preserving Cardiac Function and Insulin Resistance in High-Fat Diet-Induced Diabetes

2021 ◽  
Vol 22 (15) ◽  
pp. 7995
Author(s):  
Jianfeng Du ◽  
Yu Tina Zhao ◽  
Hao Wang ◽  
Ling X. Zhang ◽  
Gangjian Qin ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Cardiac Function ◽  
Western Blot ◽  
Glucose Intolerance ◽  
Knockout Mice ◽  
High Fat Diet ◽  
Metabolic Disorders ◽  
Wild Type ◽  
High Fat

Regulated/activated protein kinase (PRAK) plays a crucial role in modulating biological function. However, the role of PRAK in mediating cardiac dysfunction and metabolic disorders remains unclear. We examined the effects of deletion of PRAK on modulating cardiac function and insulin resistance in mice exposed to a high-fat diet (HFD). Wild-type and PRAK−/− mice at 8 weeks old were exposed to either chow food or HFD for a consecutive 16 weeks. Glucose tolerance tests and insulin tolerance tests were employed to assess insulin resistance. Echocardiography was employed to assess myocardial function. Western blot was used to determine the molecular signaling involved in phosphorylation of IRS-1, AMPKα, ERK-44/42, and irisin. Real time-PCR was used to assess the hypertrophic genes of the myocardium. Histological analysis was employed to assess the hypertrophic response, interstitial myocardial fibrosis, and apoptosis in the heart. Western blot was employed to determine cellular signaling pathway. HFD-induced metabolic stress is indicated by glucose intolerance and insulin intolerance. PRAK knockout aggravated insulin resistance, as indicated by glucose intolerance and insulin intolerance testing as compared with wild-type littermates. As compared with wild-type mice, hyperglycemia and hypercholesterolemia were manifested in PRAK-knockout mice following high-fat diet intervention. High-fat diet intervention displayed a decline in fractional shortening and ejection fraction. However, deletion of PRAK exacerbated the decline in cardiac function as compared with wild-type mice following HFD treatment. In addition, PRAK knockout mice enhanced the expression of myocardial hypertrophic genes including ANP, BNP, and βMHC in HFD treatment, which was also associated with an increase in cardiomyocyte size and interstitial fibrosis. Western blot indicated that deletion of PRAK induces decreases in phosphorylation of IRS-1, AMPKα, and ERK44/42 as compared with wild-type controls. Our finding indicates that deletion of PRAK promoted myocardial dysfunction, cardiac remodeling, and metabolic disorders in response to HFD.

PL-006 Expression of molecular markers of hepatic cholesterol metabolism are altered by a short-term high-fat diet

2018 ◽  
Vol 1 (1) ◽  
Author(s):  
Jean-Marc Lavoie
Keyword(s):  
Lipid Accumulation ◽  
High Fat Diet ◽  
Metabolic Disorders ◽  
Cholesterol Metabolism ◽  
Plasma Cholesterol ◽  
Hepatic Cholesterol ◽  
High Fat ◽  
Short Term ◽  
Cholesterol Levels ◽  
Ldl Particles

Objective Metabolic disorders are often associated with liver steatosis and increased plasma cholesterol levels. However, the link between excessive lipid accumulation and impairments in cholesterol metabolism remains uninvestigated in the liver. Hence, a short treatment with a high-fat diet (HFD) was previously shown to promote excessive lipid accumulation in liver prior to the development of metabolic disorders. The present study intended to characterize how increases in liver fat alter the expression of several key regulators of hepatic cholesterol metabolism in response to a short-term HFD. Methods Young Wistar rats were randomly submitted either to HFD (n = 8) or a regular chow diet (RCD; n = 8) for 14 days.Liver tissue and blood were sampled . Results Increases in triglycerides were highly significant (P< 0.01) in liver but marginal in plasma of HFD rats. In contrast, the HFD resulted in higher (P< 0.01) cholesterol levels in plasma but not in liver samples. Gene expression of key markers involved in cholesterol uptake (LDL particles) including low density lipoprotein receptor-related protein-1 (LRP-1) and protein convertase subtilisin/kexin type 9 (PCSK9) along with ATP-binding cassette, superfamily G, member 5 (ABCG5) involved in cholesterol exportation viabile ducts were found to be higher (P< 0.05) in response to the HFD. In contrast, expression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), involved in cholesterol synthesis was down-regulated in liver Conclusions The data support the concept that excessive accumulation of lipids promptly alters the expression of key genes regulating cholesterol metabolism in liver. On a clinical point of view, this indicates that increases in plasma cholesterol occur after a short-term high fat diet.

scholarly journals Short-Chain Inulin Modulates the Cecal Microbiota Structure of Leptin Knockout Mice in High-Fat Diet

2021 ◽  
Vol 12 ◽  
Author(s):  
Yan Feng ◽  
Jianghao Feng ◽  
Lei Wang ◽  
Ai Meng ◽  
Siang Wei ◽  
...  
Keyword(s):  
Knockout Mice ◽  
High Fat Diet ◽  
Pathogenic Bacteria ◽  
Sugar Metabolism ◽  
Diet Group ◽  
Normal Diet ◽  
Short Chain ◽  
Wild Type ◽  
High Fat ◽  
Cecal Microbiota

The aim of this study was to explore the effect of short-chain inulin on cecal microbiota of high-fat diet-fed leptin knockout mice and the different influences of cecal microbiota on wild-type and leptin knockout mice. A total of 18 specific pathogen-free male C57BL/6J wild-type mice and 18 C57BL/6J leptin knockout mice (OB/OB mice) were selected. Mice were divided into six groups according to their genotype: wild-type mice have three groups, including the normal diet group (CT), 60% high-fat diet group (CH), and 60% high fat with 10% short-chain inulin group (CHI); OB/OB mice were also divided into three groups, including the normal diet group (OT), 60% high-fat diet group (OH), and 60% high fat with 10% short-inulin group (OHI). The mice were fed for 8 weeks to analyze the diversity of cecal microbiota. The results show that compared with CH and OH, the variety of cecal microbiota was significantly reduced in CH and OH and further reduced in CHI and OHI. Bifidobacterium and Lactobacillus are the biomarkers in genus level. Dietary short-chain inulin significantly enhanced Bifidobacterium in OHI compared with OH (p &lt; 0.01) and significantly reduced in CHI and compared with CH (p &lt; 0.01). Lactobacillus was significantly enhanced in CHI and OHI compared with CH and OH, respectively (p &lt; 0.01). Blautia was significantly enhanced in CH and OH compared with other groups (p &lt; 0.01). Both Escherichia-Shigella and Enterococcus were significantly reduced in CHI and OHI, compared with CH and OH, respectively (p &lt; 0.05). Escherichia-Shigella was even lower than CT and OT in CHI and OHI. Functional prediction of microbial communities showed that the abundance of amino acid sugar and nucleotide sugar metabolism pathways were significantly enhanced (p &lt; 0.05) in CH and OH, and OH was significantly higher than CH (p &lt; 0.05). Among the leptin knockout groups, PICRUSt2 function prediction showed that the fatty acid metabolism pathway significantly reduced (p &lt; 0.05) in OHI and OT compared with OH. In conclusion, short-chain inulin modulated the dysbiosis induced by high-fat diet, improved probiotics growth and inhibited conditioned pathogenic bacteria, and the influences were significantly different in wild-type and leptin knockout mice.

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