Fine Mapping of the Mouse Ath28 Locus Yields Three Atherosclerosis Modifying Sub-Regions

Genes ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 70
Author(s):  
Juying Han ◽  
Brian Ritchey ◽  
Emmanuel Opoku ◽  
Jonathan D. Smith
Keyword(s):  
Mouse Genome ◽  
Hdl Cholesterol ◽  
Genomic Region ◽  
Modifier Genes ◽  
Mouse Strains ◽  
Chromosome 2 ◽  
Lesion Area ◽  
Lesion Development ◽  
Congenic Lines ◽  
Cholesterol Levels

A mouse strain intercross between Apoe−/− AKR/J and DBA/2J mice identified three replicated atherosclerosis quantitative trait loci (QTLs). Our objective was to fine map mouse atherosclerosis modifier genes within a genomic region known to affect lesion development in apoE-deficient (Apoe−/−) mice. We dissected the Ath28 QTL on the distal end of chromosome 2 by breeding a panel of congenic strains and measuring aortic root lesion area in 16-week-old male and female mice fed regular laboratory diets. The parental congenic strain contained ~9.65 Mb of AKR/J DNA from chromosome 2 on the DBA/2J genetic background, which had lesions 55% and 47% smaller than female and male DBA/2J mice, respectively (p < 0.001). Seven additional congenic lines identified three separate regions associated with the lesion area, named Ath28.1, Ath28.2, and Ath28.3, where the AKR/J alleles were atherosclerosis-protective for two regions and atherosclerosis-promoting for the other region. These results were replicated in both sexes, and in combined analysis after adjusting for sex. The congenic lines did not greatly impact total and HDL cholesterol levels or body weight. Bioinformatic analyses identified all coding and non-coding genes in the Ath28.1 sub-region, as well as strain sequence differences that may be impactful. Even within a <10 Mb region of the mouse genome, evidence supports the presence of at least three atherosclerosis modifier genes that differ between the AKR/J and DBA/2J mouse strains, supporting the polygenic nature of atherosclerosis susceptibility.

Abstract 477: HDL Inhibition of Murine Atherosclerosis Lesion Development is Dependent on Strain Background

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Timothy J Sontag ◽  
Paulette A Krishack ◽  
Tapan K Biswas ◽  
Godfrey S Getz ◽  
Catherine A Reardon
Keyword(s):  
Inflammatory Cell ◽  
Innominate Artery ◽  
Ascending Aorta ◽  
Ldl Oxidation ◽  
Mouse Strains ◽  
Lesion Development ◽  
Cell Recruitment ◽  
Cholesterol Levels ◽  
Inflammatory Cell Recruitment ◽  
Time Point

Inbred mouse strains vary greatly in their relative atherosensitivity, with C57BL/6 (C57) being the most sensitive and hence the preferred strain for most atherosclerosis studies. Among the resistant strains, FVBN/J (FVB) has been relatively well studied. On the ApoE knockout (E°) background, both mouse strains develop atherosclerotic lesions which are exacerbated by feeding a high fat/high cholesterol western-type diet (WTD). However, the FVB-E° mouse exhibits nearly 10-fold smaller lesions than the C57-E°. Additionally, FVB mice have plasma HDL cholesterol levels that are twice as high as C57. Wild type FVB mice have been shown to have lower inflammatory cell recruitment to the peritoneum upon thioglycollate treatment than C57. Our lab has generated ApoE/ApoA-I double knockout mice (EA°, lacking HDL) on both C57 and FVB background to compare the effect of HDL deficiency on lesion development. We hypothesize that the loss of HDL will have a greater effect on the more lesion susceptible C57 than the resistant FVB. 8 week C57 and FVB E° and EA° mice were kept on a WTD for 6 or 10 weeks and lesions were quantified in the innominate artery, ascending aorta, and aortic root. In all cases mice in the C57 background displayed significantly greater lesion size than mice in the FVB background, except in the ascending aorta of the E° mice at the earlier time point, despite higher plasma cholesterol levels in the FVB mice. The presence of ApoA-I was protective (E° vs EA°) in the C57 strain in the ascending aorta at both time points and its protection became significant in the innominate artery at the 10 week time point. No additional protection was afforded by ApoA-I in the FVB strain. ApoA-I deficiency in FVB mice did not affect inflammatory cell recruitment to the peritoneal cavity or plasma markers of LDL oxidation as greatly as in C57 mice. Plasma monocyte counts both before and after 6 weeks on WTD were higher in C57 mice with no effect of ApoA-I in either strain. In conclusion, the FVB strain is less sensitive than C57 to lesion development at 3 major arterial sites with no protection afforded by HDL/ApoA-I, whereas HDL/ApoA-I is significantly protective in the C57 strain. This protection may result from the anti-inflammatory/anti-oxidative nature of C57 HDL that is not observed in FVB mice.

scholarly journals Genetic contributors to lipoprotein cholesterol levels in an intercross of 129S1/SvImJ and RIIIS/J inbred mice

2004 ◽  
Vol 17 (2) ◽  
pp. 114-121 ◽  
Author(s):  
Malcolm A. Lyons ◽  
Ron Korstanje ◽  
Renhua Li ◽  
Kenneth A. Walsh ◽  
Gary A. Churchill ◽  
...  
Keyword(s):  
Total Cholesterol ◽  
Inbred Mice ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Lipoprotein Cholesterol ◽  
Mouse Strains ◽  
High Cholesterol ◽  
Significant Qtls ◽  
Cholesterol Levels ◽  
Trait Locus

To determine the genetic contribution to variation among lipoprotein cholesterol levels, we performed quantitative trait locus (QTL) analyses on an intercross between mouse strains RIIIS/J and 129S1/SvImJ. Male mice of the parental strains and the reciprocal F1 and F2 populations were fed a high-cholesterol, cholic acid-containing diet for 8–12 wk. At the end of the feeding period, plasma total, high-density lipoprotein (HDL), and non-HDL cholesterol were determined. For HDL cholesterol, we identified three significant QTLs on chromosomes (Chrs) 1 ( D1Mit507, 88 cM, 72–105 cM, 4.8 LOD), 9 ( D11Mit149, 14 cM, 10–25 cM, 9.4 LOD), and 12 ( D12Mit60, 20 cM, 0–50 cM, 5.0 LOD). These QTLs were considered identical to QTLs previously named Hdlq5, Hdlq17, and Hdlq18, respectively, in crosses sharing strain 129. For total cholesterol, we identified two significant QTLs on Chrs 1 and 9, which were named Chol10 ( D1Mit507, 88 cM, 10–105 cM, 3.9 LOD) and Chol11 ( D11Mit149, 14 cM, 0–30 cM, 4.4 LOD), respectively. In addition, for total cholesterol, we identified two suggestive QTLs on Chrs 12 (distal) and 17, which remain unnamed. For non-HDL cholesterol, we identified and named one new QTL on Chr 17, Nhdlq3 ( D17Mit221, 58 cM, 45–60 cM, 3.4 LOD). Nhdlq3 colocalized with orthologous human QTLs for lipoprotein phenotypes, and with Abcg5 and Abcg8. Overall, we detected eight QTLs for lipoprotein cholesterol concentrations on Chrs 1, 9, 12, and 17 (each two per chromosome), including a new QTL for non-HDL cholesterol, Nhdlq3, on Chr 17.

The Effects of L-Carnitine Supplementation on Serum Lipids: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

2019 ◽  
Vol 25 (30) ◽  
pp. 3266-3281 ◽  
Author(s):  
Hadis Fathizadeh ◽  
Alireza Milajerdi ◽  
Željko Reiner ◽  
Fariba Kolahdooz ◽  
Maryam Chamani ◽  
...  
Keyword(s):  
Serum Lipids ◽  
Ldl Cholesterol ◽  
Meta Analysis ◽  
Hdl Cholesterol ◽  
Health Conditions ◽  
Carnitine Supplementation ◽  
Randomized Controlled ◽  
Cholesterol Levels ◽  
Vldl Cholesterol ◽  
Subgroup Analyses

Background: The findings of trials investigating the effects of L-carnitine administration on serum lipids are inconsistent. This meta-analysis of randomized controlled trials (RCTs) was performed to summarize the effects of L-carnitine intake on serum lipids in patients and healthy individuals. Methods: Two authors independently searched electronic databases including MEDLINE, EMBASE, Cochrane Library, Web of Science, PubMed and Google Scholar from 1990 until August 1, 2019, in order to find relevant RCTs. The quality of selected RCTs was evaluated using the Cochrane Collaboration risk of bias tool. Cochrane’s Q test and I-square (I2) statistic were used to determine the heterogeneity across included trials. Weight mean difference (SMD) and 95% CI between the two intervention groups were used to determine pooled effect sizes. Subgroup analyses were performed to evaluate the source of heterogeneity based on suspected variables such as, participant’s health conditions, age, dosage of L-carnitine, duration of study, sample size, and study location between primary RCTs. Results: Out of 3460 potential papers selected based on keywords search, 67 studies met the inclusion criteria and were eligible for the meta-analysis. The pooled results indicated that L-carnitine administration led to a significant decrease in triglycerides (WMD: -10.35; 95% CI: -16.43, -4.27), total cholesterol (WMD: -9.47; 95% CI: - 13.23, -5.70) and LDL-cholesterol (LDL-C) concentrations (WMD: -6.25; 95% CI: -9.30, -3.21), and a significant increase in HDL-cholesterol (HDL-C) levels (WMD: 1.39; 95% CI: 0.21, 2.57). L-carnitine supplementation did not influence VLDL-cholesterol concentrations. When we stratified studies for the predefined factors such as dosage, and age, no significant effects of the intervention on triglycerides, LDL-C, and HDL-C levels were found. Conclusion: This meta-analysis demonstrated that L-carnitine administration significantly reduced triglycerides, total cholesterol and LDL-cholesterol levels, and significantly increased HDL-cholesterol levels in the pooled analyses, but did not affect VLDL-cholesterol levels; however, these findings were not confirmed in our subgroup analyses by participant’s health conditions, age, dosage of L-carnitine, duration of study, sample size, and study location.

Ser447stopMutation in Lipoprotein Lipase Is Associated With Elevated HDL Cholesterol Levels in Normolipidemic Males

1997 ◽  
Vol 17 (3) ◽  
pp. 595-599 ◽  
Author(s):  
Jan Albert Kuivenhoven ◽  
Björn E. Groenemeyer ◽  
Jolanda M. A. Boer ◽  
Paul W. A. Reymer ◽  
Riteke Berghuis ◽  
...  
Keyword(s):  
Lipoprotein Lipase ◽  
Hdl Cholesterol ◽  
Cholesterol Levels

Passive Cigarette Smoking and Reduced HDL Cholesterol Levels in Children With High-Risk Lipid Profiles

Circulation ◽  
1997 ◽  
Vol 96 (5) ◽  
pp. 1403-1407 ◽  
Author(s):  
Ellis J. Neufeld ◽  
Michele Mietus-Snyder ◽  
Alexa S. Beiser ◽  
Annette L. Baker ◽  
Jane W. Newburger
Keyword(s):  
High Risk ◽  
Cigarette Smoking ◽  
Hdl Cholesterol ◽  
Lipid Profiles ◽  
Cholesterol Levels

scholarly journals N-Acetyl Cysteine Overdose Inducing Hepatic Steatosis and Systemic Inflammation in Both Propacetamol-Induced Hepatotoxic and Normal Mice

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 442
Author(s):  
Gunn-Guang Liou ◽  
Cheng-Chi Hsieh ◽  
Yi-Ju Lee ◽  
Pin-Hung Li ◽  
Ming-Shiun Tsai ◽  
...  
Keyword(s):  
Inbred Mouse ◽  
Serum Triglyceride ◽  
Mouse Strains ◽  
High Dose ◽  
Therapeutic Effects ◽  
Protein Nitration ◽  
Cholesterol Levels ◽  
Antioxidative Enzyme Activities ◽  
Acetyl Cysteine ◽  
Dose Dependent

Acetaminophen (APAP) overdose induces acute liver damage and even death. The standard therapeutic dose of N-acetyl cysteine (NAC) cannot be applied to every patient, especially those with high-dose APAP poisoning. There is insufficient evidence to prove that increasing NAC dose can treat patients who failed in standard treatment. This study explores the toxicity of NAC overdose in both APAP poisoning and normal mice. Two inbred mouse strains with different sensitivities to propacetamol-induced hepatotoxicity (PIH) were treated with different NAC doses. NAC therapy decreased PIH by reducing lipid oxidation, protein nitration and inflammation, and increasing glutathione (GSH) levels and antioxidative enzyme activities. However, the therapeutic effects of NAC on PIH were dose-dependent from 125 (N125) to 275 mg/kg (N275). Elevated doses of NAC (400 and 800 mg/kg, N400 and N800) caused additional deaths in both propacetamol-treated and normal mice. N800 treatments significantly decreased hepatic GSH levels and induced inflammatory cytokines and hepatic microvesicular steatosis in both propacetamol-treated and normal mice. Furthermore, both N275 and N400 treatments decreased serum triglyceride (TG) and induced hepatic TG, whereas N800 treatment significantly increased interleukin-6, hepatic TG, and total cholesterol levels. In conclusion, NAC overdose induces hepatic and systemic inflammations and interferes with fatty acid metabolism.

scholarly journals Low levels of soluble TWEAK, indicating on-going inflammation, were associated with depression in type 1 diabetes: a cross-sectional study

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Eva O. Melin ◽  
Jonatan Dereke ◽  
Magnus Hillman
Keyword(s):  
Cardiovascular Disease ◽  
Type 1 Diabetes ◽  
Goodness Of Fit ◽  
Hdl Cholesterol ◽  
Cross Sectional ◽  
Cholesterol Levels ◽  
Increased Risk ◽  
Galectin 3 ◽  
Low Levels

Abstract Background Low levels of the soluble tumour necrosis factor-like weak inducer of apoptosis (sTWEAK) and depression are linked to cardiovascular disease. Galectin-3, inadequate glycemic control and low high-density lipoprotein (HDL)-cholesterol levels were previously linked to depression in these patients with type 1 diabetes mellitus (T1DM). The main aim was to explore whether sTWEAK was associated with depression. A secondary aim was to explore diabetes related variables associated with low sTWEAK. Methods Cross-sectional design. T1DM patients (n = 283, men 56%, age18–59 years) were consecutively recruited from one specialist diabetes clinic. Depression was defined as Hospital Anxiety and Depression Scale-Depression sub scale ≥8 points. Blood samples, anthropometrics and blood pressure were collected, supplemented with data from electronic health records. Enzyme linked immunosorbent assays were used to measure sTWEAK and galectin-3. Low sTWEAK was defined as < 7.2 ng/ml and high galectin-3 as ≥2.6 ng/ml. Multiple logistic regression analyses were performed, calibrated and validated for goodness of fit. We adjusted for age, sex, diabetes duration, galectin-3, metabolic variables, serum-creatinine, smoking, physical inactivity, medication, and cardiovascular complications. Results For 29 depressed versus 254 non-depressed patients the prevalence rates were for low sTWEAK: 93 and 68% (p = 0.003) and for high galectin-3: 34 and 13% (p = 0.005) respectively. HDL-cholesterol levels were lower for the depressed (p = 0.015). Patients with low sTWEAK versus high sTWEAK had lower usage of continuous subcutaneous insulin infusion (CSII) (6% versus 17%, p = 0.005). Low sTWEAK (adjusted odds ratio (AOR) 9.0, p = 0.006), high galectin-3 (AOR 6.3, p = 0.001), HDL-cholesterol (per mmol/l) (AOR 0.1, p = 0.006), use of antidepressants (AOR 8.4, p < 0.001), and age (per year) (AOR 1.05, p = 0.027) were associated with depression. CSII (AOR 0.3, p = 0.003) and depression (AOR 7.1, p = 0.009) were associated with low sTWEAK. Conclusions Lower levels of sTWEAK and HDL-cholesterol and higher levels of galectin-3 were independently associated with depression in T1DM. These factors might all contribute to the increased risk for cardiovascular disease and mortality previously demonstrated in patients with depression. CSII (inversely) and depression were independently associated with low sTWEAK levels.

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