Abstract 234: Reduction of LpX and Improvement in Kidney Function in LCAT-KO Mice by Enzyme Replacement Therapy

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Boris L Vaisman ◽  
Edward B Neufeld ◽  
Lita A Freeman ◽  
Maureen L Sampson ◽  
Milton Pryor ◽  
...  
Keyword(s):  
Mouse Model ◽  
Renal Disease ◽  
Kidney Function ◽  
Chow Diet ◽  
Creatinine Ratio ◽  
Kidney Dysfunction ◽  
Albumin Creatinine Ratio ◽  
Normal Chow ◽  
Lcat Deficiency ◽  
Normal Chow Diet

Familial LCAT Deficiency (FLD) is associated with the gradual development of severe kidney dysfunction from the renal deposition of LpX, an abnormal lipoprotein that accumulates in this disorder. The aim of our study was to develop an efficient mouse model of FLD in which elevated plasma LpX and kidney dysfunction can be rapidly induced in order to test whether recombinant human LCAT (rhLCAT) injections can prevent renal disease. We used the previously described LCAT-Ko x SREBP1a transgenic mouse model (Zhu et al., 2004) with the transgene placed under control of PEPCK promoter, which can be induced by high protein diets. We demonstrate that high levels of LpX plasma particles appeared within 5-7 days after 2-3 month old mice were switched to a protein rich carbohydrate low diet (PRCL). Kidney dysfunction measured by albumin/creatinine ratio after 9 days on PRCL diet increased by 32±12 fold. On the PRCL diet, plasma VLDL-C and LDL-C fractions of LCAT-Ko x SREBP1a mice increased 2-4 fold compared to mice on a normal chow diet. Transmission electron microscopy clearly demonstrated the presence of multilamellar LpX particles in plasma and renal glomeruli, as well as robust accumulation lipid droplets in hepatocytes of mice kept on the PRCL diet for 7 days. All these changes were reversible; when mice were returned to the normal chow diet their plasma lipid characteristics and kidney function quickly returned within days to the level observed before the diet was initiated. When LCAT-Ko x SREBP1a mice were placed on PRCL diet and simultaneously treated with rhLCAT (x 3 per week IV injection 30 mg/kg for 2 weeks) plasma LpX was eliminated and a normal mouse lipoprotein profile was observed and most notably HDL-C increased from 5.6 g/dL to 54.1 mg/dL. Treatment with rhLCAT decreased the albumin/creatinine ratio 5±1 fold. Conclusions: LCAT-Ko and SREBP1a mice on a PRCL diet can be used as efficient model for investigating potential therapies for LCAT deficiency. Results show the feasibility of rhLCAT treatment for preventing renal disease in patients with FLD.

Metabolic in Vivo Labeling Highlights Differences of Metabolically Active Microbes from the Mucosal Gastrointestinal Microbiome between High-Fat and Normal Chow Diet

2017 ◽  
Vol 16 (4) ◽  
pp. 1593-1604 ◽  
Author(s):  
Andreas Oberbach ◽  
Sven-Bastiaan Haange ◽  
Nadine Schlichting ◽  
Marco Heinrich ◽  
Stefanie Lehmann ◽  
...  
Keyword(s):  
Chow Diet ◽  
High Fat ◽  
Gastrointestinal Microbiome ◽  
In Vivo Labeling ◽  
Normal Chow ◽  
Normal Chow Diet

scholarly journals Estrogens Protect against High-Fat Diet-Induced Insulin Resistance and Glucose Intolerance in Mice

Endocrinology ◽  
2009 ◽  
Vol 150 (5) ◽  
pp. 2109-2117 ◽  
Author(s):  
Elodie Riant ◽  
Aurélie Waget ◽  
Haude Cogo ◽  
Jean-François Arnal ◽  
Rémy Burcelin ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Glucose Intolerance ◽  
High Fat Diet ◽  
Chow Diet ◽  
High Fat ◽  
Normal Chow ◽  
Visceral Adipose ◽  
Deficient Mice ◽  
Normal Chow Diet

Although corroborating data indicate that estrogens influence glucose metabolism through the activation of the estrogen receptor α (ERα), it has not been established whether this pathway could represent an effective therapeutic target to fight against metabolic disturbances induced by a high-fat diet (HFD). To this end, we first evaluated the influence of chronic 17β-estradiol (E2) administration in wild-type ovariectomized mice submitted to either a normal chow diet or a HFD. Whereas only a modest effect was observed in normal chow diet-fed mice, E2 administration exerted a protective effect against HFD-induced glucose intolerance, and this beneficial action was abolished in ERα-deficient mice. Furthermore, E2 treatment reduced HFD-induced insulin resistance by 50% during hyperinsulinemic euglycemic clamp studies and improved insulin signaling (Akt phosphorylation) in insulin-stimulated skeletal muscles. Unexpectedly, we found that E2 treatment enhanced cytokine (IL-6, TNF-α) and plasminogen activator inhibitor-1 mRNA expression induced by HFD in the liver and visceral adipose tissue. Interestingly, although the proinflammatory effect of E2 was abolished in visceral adipose tissue from chimeric mice grafted with bone marrow cells from ERα-deficient mice, the beneficial effect of the hormone on glucose tolerance was not altered, suggesting that the metabolic and inflammatory effects of estrogens can be dissociated. Eventually comparison of sham-operated with ovariectomized HFD-fed mice demonstrated that endogenous estrogens levels are sufficient to exert a full protective effect against insulin resistance and glucose intolerance. In conclusion, the regulation of the ERα pathway could represent an effective strategy to reduce the impact of high-fat diet-induced type 2 diabetes.

scholarly journals Effects of Diet Induced Weight Reduction on Cartilage Pathology and Inflammatory Mediators in the Joint Tissues

2021 ◽  
Vol 8 ◽  
Author(s):  
Antonia RuJia Sun ◽  
Xiaoxin Wu ◽  
Ross Crawford ◽  
Hongxing Li ◽  
Lin Mei ◽  
...  
Keyword(s):  
Weight Loss ◽  
Inflammatory Cytokines ◽  
Cartilage Degeneration ◽  
Normal Diet ◽  
The Body ◽  
Chow Diet ◽  
Normal Chow ◽  
Obesogenic Diet ◽  
Dietary Switch ◽  
Normal Chow Diet

Obesogenic diets contribute to the pathology of osteoarthritis (OA) by altering systemic and local metabolic inflammation. Yet, it remains unclear how quickly and reproducibly the body responds to weight loss strategies and improve OA. In this study we tested whether switching obese diet to a normal chow diet can mitigate the detrimental effects of inflammatory pathways that contribute to OA pathology. Male C57BL/6 mice were first fed with obesogenic diet (high fat diet) and switched to normal chow diet (obese diet → normal diet) or continued obese diet or normal diet throughout the experiment. A mouse model of OA was induced by surgical destabilization of the medial meniscus (DMM) model into the knee joint. Outcome measures included changes in metabolic factors such as glucose, insulin, lipid, and serum cytokines levels. Inflammation in synovial biopsies was scored and inflammation was determined using FACs sorted macrophages. Cartilage degeneration was monitored using histopathology. Our results indicate, dietary switching (obese diet → normal diet) reduced body weight and restored metabolic parameters and showed less synovial tissue inflammation. Systemic blood concentrations of pro-inflammatory cytokines IL-1α, IL-6, IL-12p40, and IL-17 were decreased, and anti-inflammatory cytokines IL-4 and IL-13 were increased in dietary switch group compared to mice that were fed with obesogenic diet continuously. Although obese diet worsens the cartilage degeneration in DMM OA model, weight loss induced by dietary switch does not promote the histopathological changes of OA during this study period. Collectively, these data demonstrate that switching obesogenic diet to normal improved metabolic syndrome symptoms and can modulate both systemic and synovium inflammation levels.

Abstract 374: Interleukin-19: A Novel Pro-Angiogenic and Anti-Inflammatory Adipokine

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Christine Vrakas ◽  
Sheri E Keleman ◽  
Rosario Scalia ◽  
Michael V Autieri
Keyword(s):  
Adipose Tissue ◽  
Visceral Fat ◽  
Subcutaneous Fat ◽  
Chow Diet ◽  
Vascular Cells ◽  
Regulatory Factor ◽  
Normal Chow ◽  
Gene Regulatory ◽  
Anti Inflammatory ◽  
Normal Chow Diet

Uncontrolled inflammation leads to many of the chronic diseases associated with obesity. Due to a lack of oxygen in the tissue, expanding adipose tissue becomes hypoxic and pro-inflammatory. Adipocytes release pro-angiogenic factors in an effort to restore blood flow to the tissue. Presently, little is known about the potential for endogenously expressed anti-inflammatory cytokines to attenuate inflammation and also provide pro-angiogenic effects. IL-19 is uniquely anti-inflammatory, pro-angiogenic and is both expressed by and targets various cells types. IL-19 expression in adipocytes and stromal vascular cells is increased in visceral compared to subcutaneous fat, and is also increased in visceral fat on high fat diet (HFD) compared to normal chow diet. There is no known mechanism to explain the role of IL-19 in adipose tissue expansion, and we hypothesized that IL-19 may have pro-angiogenic and anti-inflammatory properties in expanding adipose tissue. We have identified a gene regulatory factor, Interleukin Enhancer-Binding Factor 3 (ILF3) that is induced in adipocytes and stromal vascular cells by HFD and IL-19 treatment. We found that both IL-19 and VEGF induce ILF3 expression in cultured human endothelial cells (hECs). Proliferation is significantly reduced when ILF3 is knocked down using siRNA in hECs. Furthermore, when ILF3 is knocked down and hECs are stimulated with VEGF several angiogenic cytokines are also decreased. Through immunohistochemistry we found that ILF3 translocates from the nucleus to the cytoplasm in visceral fat of C57BL/6 mice fed a HFD, and remains in the nucleus when fed a normal chow diet. In summary IL-19 may be a unique HFD responsive adipokine functioning to reduce inflammation and increase angiogenesis in expanding adipose tissue. The angiogenic function of IL-19 may work through induction of the gene regulatory factor, ILF3.

scholarly journals Cardiac mTOR rescues the detrimental effects of diet-induced obesity in the heart after ischemia-reperfusion

2015 ◽  
Vol 308 (12) ◽  
pp. H1530-H1539 ◽  
Author(s):  
Toshinori Aoyagi ◽  
Jason K. Higa ◽  
Hiroko Aoyagi ◽  
Naaiko Yorichika ◽  
Briana K. Shimada ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Chow Diet ◽  
In Vivo Models ◽  
Myocardial Scarring ◽  
Diet Induced Obesity ◽  
Normal Chow ◽  
Normal Chow Diet

Diet-induced obesity deteriorates the recovery of cardiac function after ischemia-reperfusion (I/R) injury. While mechanistic target of rapamycin (mTOR) is a key mediator of energy metabolism, the effects of cardiac mTOR in ischemic injury under metabolic syndrome remains undefined. Using cardiac-specific transgenic mice overexpressing mTOR (mTOR-Tg mice), we studied the effect of mTOR on cardiac function in both ex vivo and in vivo models of I/R injury in high-fat diet (HFD)-induced obese mice. mTOR-Tg and wild-type (WT) mice were fed a HFD (60% fat by calories) for 12 wk. Glucose intolerance and insulin resistance induced by the HFD were comparable between WT HFD-fed and mTOR-Tg HFD-fed mice. Functional recovery after I/R in the ex vivo Langendorff perfusion model was significantly lower in HFD-fed mice than normal chow diet-fed mice. mTOR-Tg mice demonstrated better cardiac function recovery and had less of the necrotic markers creatine kinase and lactate dehydrogenase in both feeding conditions. Additionally, mTOR overexpression suppressed expression of proinflammatory cytokines, including IL-6 and TNF-α, in both feeding conditions after I/R injury. In vivo I/R models showed that at 1 wk after I/R, HFD-fed mice exhibited worse cardiac function and larger myocardial scarring along myofibers compared with normal chow diet-fed mice. In both feeding conditions, mTOR overexpression preserved cardiac function and prevented myocardial scarring. These findings suggest that cardiac mTOR overexpression is sufficient to prevent the detrimental effects of diet-induced obesity on the heart after I/R, by reducing cardiac dysfunction and myocardial scarring.

Independent and combined effects of airway remodelling and allergy on airway responsiveness

2018 ◽  
Vol 132 (3) ◽  
pp. 327-338 ◽  
Author(s):  
Kimberley C.W. Wang ◽  
Timothy D. Le Cras ◽  
Alexander N. Larcombe ◽  
Graeme R. Zosky ◽  
John G. Elliot ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Airway Responsiveness ◽  
Wall Structure ◽  
Control Group ◽  
Chow Diet ◽  
Airway Remodelling ◽  
Combined Effects ◽  
Specific Expression ◽  
Normal Chow ◽  
Normal Chow Diet

Airway remodelling and allergic inflammation are key features of airway hyperresponsiveness (AHR) in asthma; however, their interrelationships are unclear. The present study investigated the separate and combined effects of increased airway smooth muscle (ASM) layer thickness and allergy on AHR. We integrated a protocol of ovalbumin (OVA)-induced allergy into a non-inflammatory mouse model of ASM remodelling induced by conditional and airway-specific expression of transforming growth factor-α (TGF-α) in early growth response-1 (Egr-1)-deficient transgenic mice, which produced thickening of the ASM layer following ingestion of doxycycline. Mice were sensitised to OVA and assigned to one of four treatment groups: Allergy – normal chow diet and OVA challenge; Remodelling – doxycycline in chow and saline challenge; Allergy and Remodelling – doxycycline in chow and OVA challenge; and Control – normal chow diet and saline challenge. Airway responsiveness to methacholine (MCh) and histology were assessed. Compared with the Control group, airway responsiveness to MCh was increased in the Allergy group, independent of changes in wall structure, whereas airway responsiveness in the Remodelling group was increased independent of exposure to aeroallergen. The combined effects of allergy and remodelling on airway responsiveness were greater than either of them alone. There was a positive relationship between the thickness of the ASM layer with airway responsiveness, which was shifted upward in the presence of allergy. These findings support allergy and airway remodelling as independent causes of variable and excessive airway narrowing.

scholarly journals Comparison of serum and urinary biomarker panels with albumin/creatinine ratio in the prediction of renal function decline in type 1 diabetes

Diabetologia ◽  
2020 ◽  
Vol 63 (4) ◽  
pp. 788-798 ◽  
Author(s):  
Marco Colombo ◽  
◽  
Stuart J. McGurnaghan ◽  
Luke A. K. Blackbourn ◽  
R. Neil Dalton ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Renal Disease ◽  
Disease Progression ◽  
Serum Biomarkers ◽  
Research Network ◽  
Creatinine Ratio ◽  
Renal Disease Progression ◽  
Albumin Creatinine Ratio ◽  
Urine Biomarkers

Abstract Aims/hypothesis We examined whether candidate biomarkers in serum or urine can improve the prediction of renal disease progression in type 1 diabetes beyond prior eGFR, comparing their performance with urinary albumin/creatinine ratio (ACR). Methods From the population-representative Scottish Diabetes Research Network Type 1 Bioresource (SDRNT1BIO) we sampled 50% and 25% of those with starting eGFR below and above 75 ml min−1 [1.73 m]−2, respectively (N = 1629), and with median 5.1 years of follow-up. Multiplexed ELISAs and single molecule array technology were used to measure nine serum biomarkers and 13 urine biomarkers based on our and others’ prior work using large discovery and candidate studies. Associations with final eGFR and with progression to <30 ml min−1 [1.73] m−2, both adjusted for baseline eGFR, were tested using linear and logistic regression models. Parsimonious biomarker panels were identified using a penalised Bayesian approach, and their performance was evaluated through tenfold cross-validation and compared with using urinary ACR and other clinical record data. Results Seven serum and seven urine biomarkers were strongly associated with either final eGFR or progression to <30 ml min−1 [1.73 m]−2, adjusting for baseline eGFR and other covariates (all at p<2.3 × 10−3). Of these, associations of four serum biomarkers were independent of ACR for both outcomes. The strongest associations with both final eGFR and progression to <30 ml min−1 [1.73 m]−2 were for serum TNF receptor 1, kidney injury molecule 1, CD27 antigen, α-1-microglobulin and syndecan-1. These serum associations were also significant in normoalbuminuric participants for both outcomes. On top of baseline covariates, the r2 for prediction of final eGFR increased from 0.702 to 0.743 for serum biomarkers, and from 0.702 to 0.721 for ACR alone. The area under the receiver operating characteristic curve for progression to <30 ml min−1 [1.73 m]−2 increased from 0.876 to 0.953 for serum biomarkers, and to 0.911 for ACR alone. Other urinary biomarkers did not outperform ACR. Conclusions/interpretation A parsimonious panel of serum biomarkers easily measurable along with serum creatinine may outperform ACR for predicting renal disease progression in type 1 diabetes, potentially obviating the need for urine testing.

scholarly journals Correlation between albumin creatinine ratio and hypertension in type 2 diabetes

2020 ◽  
Vol 4 (1) ◽  
Author(s):  
Vitasari Indriani ◽  
Wahyu Siswandari ◽  
Pugud Samudro ◽  
Nor Sri Inayati
Keyword(s):  
Risk Factors ◽  
Blood Pressure ◽  
Type 2 Diabetes ◽  
Type Diabetes ◽  
Diabetic Patients ◽  
Creatinine Ratio ◽  
Kidney Dysfunction ◽  
Albumin Creatinine Ratio ◽  
Diabetes Patients

Hypertension is often found in patients with type 2 diabetes. Albumin Creatinine Ratio (ACR) is used to detect early symptoms of kidney disease in patients with type 2 diabetes. The aim of this study is to determine the correlation between ACR and hypertension, as well as its relationship with other risk factors in type diabetes patients 2. Data were collected from 112 diabetic patients at PROLANIS FKTP Banyumas to see ACR and blood pressure. The results showed that poor glycemic control could be one of the risk factors. It can be concluded that detecting kidney dysfunction through ACR and starting treatment as early as possible can avoid the worst possibilities in type 2 diabetes patients.

scholarly journals Pinealectomy increases thermogenesis and decreases lipogenesis

2019 ◽  
Author(s):  
Mikyung Kim ◽  
So Min Lee ◽  
Jeeyoun Jung ◽  
Yun Jin Kim ◽  
Kyo Chul Moon ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Lipid Droplets ◽  
Melatonin Receptors ◽  
Chow Diet ◽  
High Fat ◽  
Adipose Tissues ◽  
Lipogenic Genes ◽  
Sham Surgery ◽  
Normal Chow ◽  
Normal Chow Diet

AbstractThis study was designed to determine the effects of pineal gland-derived melatonin on obesity by employing rat pinealectomy (Pnx) model. After 10 weeks of high-fat diet (HFD) feeding, rats received sham or Pnx surgery followed by 10 weeks normal chow diet (NCD) feeding. Pnx decreased expressions of melatonin receptors, MTNR1A and MTNR1B, in brown (BAT) and white adipose tissues (WAT). Pnx rats showed increased insulin sensitivity compared with those that received sham surgery. Leptin levels were significantly decreased in the serum of Pnx group. In addition, Pnx stimulated thermogenic genes in BAT whereas attenuated lipogenic genes in WAT and the liver. Histologic analyses revealed marked decreased in the size of lipid droplets and increased expressions of UCP1 in BAT and attenuated lipid droplets in the sized and the number in the liver of Pnx group. In conclusion, these results in the current study suggest that Pnx increases thermogenesis in BAT and decreases lipogenesis in WAT and the liver.

scholarly journals Evaluation of methods for rapid microalbuminuria screening in kidney diseased patients

2012 ◽  
Vol 140 (3-4) ◽  
pp. 173-178
Author(s):  
Marijana Dajak ◽  
Ana Bontic ◽  
Svetlana Ignjatovic ◽  
Jelena Pavlovic ◽  
Nada Majkic-Singh ◽  
...  
Keyword(s):  
Positive Predictive Value ◽  
Kidney Function ◽  
Predictive Value ◽  
Kidney Diseases ◽  
Test Strip ◽  
Urine Specimen ◽  
Albumin Concentration ◽  
Creatinine Ratio ◽  
Albumin Creatinine Ratio ◽  
Spot Urine

Introduction. One of the criteria for chronic kidney disease detection is determination of microalbuminuria. Objective. This analysis was performed to evaluate accuracy of three useful methods for microalbuminuria detection in 24h urine collection and in the morning urine specimen calculated from urine albumin creatinine ratio, or with a dipstick in patients with different kidney diseases or kidney function. Methods. Microalbuminuria was detected in 74 patients referred to the Outpatient Nephrology Department for kidney function determination or regular nephrology checking. Albumin concentration determined using immunonephelometry was lower than 300 mg/day. Discriminates cutoff values for spot urine test strip and albumin creatinin ratio in predicting 24 h protein ?threshold? excretion were determined using ROC analysis. Results. Mean value of 24 h microalbuminuria was 80.3 mg/24 h, and value >30 mg/24 h was present in 71.8% of patient. Correlation coefficients between dipstick microalbuminuria or albumin/creatinine ratio in a spot urine specimen and 24 h microalbuminuria were 0.709 and 0.598 (p<0.0001). For pathological value of 24 h microalbuminuria >30 mg/24 h, the coresponding dipstick microalbuminuria value was ?20 mg/L (AUC 0.849, specificity 95%, positive predictive value 97.3%), and ?3.55 mg albumin/mmol creatinine ratio (AUC 0.914, specificity 90% and positive predictive value 95.5%). No difference was found between dipstick mikroalbuminuria and albumin/creatinine ratio value. In addition, albumin/creatinine ratio value from 24 h urine was similar to the value obtained from the spot urine sample. Conclusion. Obtained results indicated that albuminuria could be determined accurately in spot urine either with the Micral test strip or with albumin creatinine ratio.

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