ResearchPad - lipid-metabolism https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Association test using Copy Number Profile Curves (CONCUR) enhances power in rare copy number variant analysis]]> https://www.researchpad.co/article/elastic_article_14642 Copy number variants comprise a large proportion of variation in human genomes. Large rare CNVs, especially those disrupting genes or changing the dosages of genes, can carry relatively strong risks for neurodevelopmental and neuropsychiatric disorders. Kernel-based association methods have been developed for the analysis of rare CNVs and shown to be a valuable tool. Kernel methods model the collective effect of rare CNVs using flexible kernel functions that capture the characteristics of CNVs and measure CNV similarity of individual pairs. Typically kernels are created by summarizing similarity within an artificially defined “CNV locus” and then collapsing across all loci. In this work, we propose a new kernel-based test, CONCUR, that is based on the CNV location information contained in standard processing of the variants and which obviates the need for arbitrarily defined CNV loci. CONCUR quantifies similarity between individual pairs as the common area under their copy number profile curves and is designed to detect CNV dosage, length and dosage-length interaction effects. In simulation studies and real data analysis, we demonstrate the ability of the CONCUR test to detect CNV effects under diverse CNV architectures with power and robustness over existing methods.

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<![CDATA[Ablation of <i>Iah1</i>, a candidate gene for diet-induced fatty liver, does not affect liver lipid accumulation in mice]]> https://www.researchpad.co/article/elastic_article_14595 Nonalcoholic fatty liver disease (NAFLD) is a pathological condition caused by excess triglyceride deposition in the liver. The SMXA-5 severe fatty liver mouse model has been established from the SM/J and A/J strains. To explore the genetic factors involved in fatty liver development in SMXA-5 mice, we had previously performed quantitative trait locus (QTL) analysis, using (SM/J×SMXA-5)F2 intercross mice, and identified Fl1sa on chromosome 12 (centromere-53.06 Mb) as a significant QTL for fatty liver. Furthermore, isoamyl acetate-hydrolyzing esterase 1 homolog (Iah1) was selected as the most likely candidate gene for Fl1sa. Iah1 gene expression in fatty liver-resistant A/J-12SM mice was significantly higher than in fatty liver-susceptible A/J mice. These data indicated that the Iah1 gene might be associated with fatty liver development. However, the function of murine Iah1 remains unknown. Therefore, in this study, we created Iah1 knockout (KO) mice with two different backgrounds [C57BL/6N (B6) and A/J-12SM (A12)] to investigate the relationship between Iah1 and liver lipid accumulation. Liver triglyceride accumulation in Iah1-KO mice of B6 or A12 background did not differ from their respective Iah1-wild type mice under a high-fat diet. These results indicated that loss of Iah1 did not contribute to fatty liver. On the other hands, adipose tissue dysfunction causes lipid accumulation in ectopic tissues (liver, skeletal muscle, and pancreas). To investigate the effect of Iah1 deficiency on white adipose tissue, we performed DNA microarray analysis of epididymal fat in Iah1-KO mice of A12 background. This result showed that Iah1 deficiency might decrease adipokines Sfrp4 and Metrnl gene expression in epididymal fat. This study demonstrated that Iah1 deficiency did not cause liver lipid accumulation and that Iah1 was not a suitable candidate gene for Fl1sa.

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<![CDATA[OR17-02 Changes in Hepatokines and Apolipoproteins Are Associated with Metabolic Response to Metreleptin in Partial Lipodystrophy]]> https://www.researchpad.co/article/elastic_article_6708 Introduction Metreleptin treatment may improve the metabolic aspects of partial lipodystrophy; however, the treatment response is heterogeneous. This study aimed to explore changes in circulating apolipoprotein concentrations, as well as ANGPLT3, ANGPLT4, and IGF-1 levels in patients treated with Metreleptin as part of a clinical study investigating the efficacy of Metreleptin in nonalcoholic steatohepatitis (NASH) associated with partial lipodystrophy (ClinicalTrials.gov identifier: NCT01679197). Methods Serum samples of 18 patients with partial lipodystrophy who underwent a full metabolic evaluation and paired liver biopsies before and after Metreleptin were studied. Patients were tested at baseline, month (M) 3, M6, and M12. Glycemic response was defined as “more than 1% HbA1c reduction from baseline”. Lipid response was defined as “more than 30% decrease in triglycerides from baseline”. The hepatic response was defined as “a decrease of 2 points or more from baseline in NASH score, without an increase in fibrosis”. Patients with “any 2 of 3 above” at M12 were defined as metabolic responders. Results Metreleptin treatment resulted in significant reductions in triglycerides (346 mg/dL vs. 253 mg/dL; F: 8.474; p < 0.001), apo B (145.24 mg/dL vs. 111.09 mg/dL; F: 9.266: p < 0.001), apo CII (18.65 mg/dL vs. 15.95 mg/dL; F: 6.663: p = 0.001), apo CIII (62.95 mg/dL vs. 49.33 mg/dL; F: 5.640, p = 0.002), apo E (8.16 mg/dL vs. 6.52 mg/dL; F: 11.056, p < 0.001), and ANGPLT3 (14.36 ng/mL vs. 12.00 mg/dL; F: 4.348; p = 0.008) over time. IGF-1 levels significantly increased at M3 (134 ng/mL vs. 139 ng/mL; p = 0.001), however the difference was not significant over time. Metabolic responders had lower baseline leptin (12.4 ng/mL vs. 27.8 ng/mL; p = 0.024) and IGF-1 (95 ng/ml vs. 151 ng/mL; p = 0.008), and higher apo CII (39.06 mg/dL vs. 17.90 mg/dL; p = 0.011), apo CIII (173.57 mg/dL vs. 51.51 mg/dL; p = 0.015), apo E (18.41 mg/dL vs. 5.89 mg/dL; p = 0.002), and ANGPLT3 (17.33 ng/mL vs. 10.06 ng/mL; p = 0.04). Metabolic responders had a significant increase in IGF-1 (95 ng/mL vs. 134 ng/mL; p = 0.019), which was statistically distinguished from non-responders (p = 0.004). Responders also had a greater reduction in apo CII (20.51 mg/dL vs. -1.84 mg/dL; p = 0.001), apo CIII (32.59 mg/dL vs. -7.83 mg/dL; p = 0.007), apo E (8.17 mg/dL vs. 0.22 mg/dL; p = 0.001), and ANGPLT3 (6.08 ng/mL vs. -0.16 ng/mL; p = 0.005) early after treatment at M3. Conclusions Metreleptin treatment lowers levels of apolipoproteins associated with triglyceride metabolism as well as ANGPLT3 in patients with partial lipodystrophy. Metabolic response to Metreleptin appears to be correlated with early changes in these factors and an increase in IGF-1 levels.

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<![CDATA[OR17-01 Leptin Decreases De Novo Lipogenesis in Lipodystrophic Patients]]> https://www.researchpad.co/article/elastic_article_6288 De novo lipogenesis (DNL) plays a role in the development of hepatic steatosis and non-alcoholic fatty liver disease (NAFLD). In rodent models of both health and lipodystrophy (LD), leptin decreases DNL. In human patients with LD, reduced adipose tissue results in adipokine deficiencies, including lower plasma leptin, which contributes to insulin resistance, dyslipidemia and ectopic accumulation of triglycerides (TG). The mechanisms by which leptin regulates serum and hepatic-TG are not well elucidated. Studying patients with LD before and after leptin therapy provides an important clinical model for understanding leptin’s effect on DNL. We hypothesized that leptin treatment in lipodystrophic patients would decrease DNL by decreasing insulin resistance and glycemia, resulting in reduced circulating and hepatic-TG.

Leptin-naïve patients with LD (n=11) were treated with recombinant leptin (metreleptin) for 6 months. All measurements were performed after an 8–12 hr fast. The % of TG in TG-rich lipoproteins (TRLP-TG) derived from DNL (% DNL) was measured using body water labeling (oral D2O) of TG and mass spectrometry analysis. Absolute DNL was calculated as the product of TRLP-TG and % DNL. HbA1c and serum-TG were measured biochemically, hepatic-TG by MRI, and total body and hepatic insulin sensitivity measured during a hyperinsulinemic-euglycemic clamp.

DNL decreased after metreleptin: % DNL from 22.8±6.8 to 9.1±5.1% (p=0.0008) and absolute DNL from 54.2±32.1 to 8.6±6.5 mg/dl (p=0.003). TRLP-TG decreased from (median [interquartile range]) 160 [107, 280] to 98 [66, 147] mg/dl (p=0.01). Total body and hepatic insulin sensitivity increased from 3.7 [3.0, 7.3] to 8.4 [5.1,10.6] mg/kgFFM/min (p=0.03) and from 61.0 [48.5, 69.3] to 84.7 [75.2, 107.6] % (p =0.01), respectively. HbA1c decreased from 8.6±1.8 to 7.1±1.4% (p=0.04), hepatic-TG decreased from 17.6±11.9 to 10.3±9.1% (p=0.02), and serum-TG from 386 [216, 686] to 223 [118, 497] mg/dl (p=0.06). DNL correlated negatively with insulin sensitivity both before (r=-0.73, p=0.03) and after (r=-0.85, p=0.004) metreleptin. DNL correlated positively with hepatic-TG before (r=0.70 p=0.03) and tended to correlate after metreleptin (r=0.65, p=0.06). The change in DNL correlated with change in serum-TG (r=0.77, p=0.04) but not the change in hepatic-TG (p=0.80).

We show here for the first time that 6 months of metreleptin treatment in humans with LD decreased DNL by 84% and was associated with reductions in glycemia and improved peripheral and hepatic insulin sensitivity. These data indicate a strong link between metreleptin’s effects to increase clearance of blood glucose by peripheral tissues and reduce hepatic carbohydrate flux, resulting in DNL reductions. This led to lowered hepatic steatosis and dyslipidemia and suggests treatments that target multi-organ insulin resistance may lead to decreased NAFLD and cardiovascular risk.

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<![CDATA[Microplastic-mediated transport of PCBs? A depuration study with Daphnia magna]]> https://www.researchpad.co/article/5c75ac14d5eed0c484d0811f

The role of microplastic (MP) as a carrier of persistent organic pollutants (POPs) to aquatic organisms has been a topic of debate. However, the reverse POP transport can occur if relative contaminant concentrations are higher in the organism than in the microplastic. We evaluated the effect of microplastic on the PCB removal in planktonic animals by exposing the cladoceran Daphnia magna with a high body burden of polychlorinated biphenyls (PCB 18, 40, 128 and 209) to a mixture of microplastic and algae; daphnids exposed to only algae served as the control. As the endpoints, we used PCB body burden, growth, fecundity and elemental composition (%C and %N) of the daphnids. In the daphnids fed with microplastic, PCB 209 was removed more efficiently, while there was no difference for any other congeners and ΣPCBs between the microplastic-exposed and control animals. Also, higher size-specific egg production in the animals carrying PCB and receiving food mixed with microplastics was observed. However, the effects of the microplastic exposure on fecundity were of low biological significance, because the PCB body burden and the microplastic exposure concentrations were greatly exceeding environmentally relevant concentrations.

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<![CDATA[Epidermal growth factor receptor inhibition attenuates non-alcoholic fatty liver disease in diet-induced obese mice]]> https://www.researchpad.co/article/5c673077d5eed0c484f37b8e

Non-alcoholic fatty liver disease (NAFLD) is one of the main causes of chronic liver disease. NAFLD begins with excessive lipid accumulation in the liver and progresses to nonalcoholic steatohepatitis (NASH) and cirrhosis. NAFLD is closely linked to dysregulated hepatic lipid metabolism. Although recent studies have reported that epidermal growth factor receptor (EGFR) signaling regulates lipid metabolism, the roles of EGFR and EGFR inhibitors as modulators of lipid metabolism are largely unknown. Here, we investigated whether inhibiting EGFR using the EGFR tyrosine kinase inhibitor (TKI) PD153035 improves NAFLD. Our results demonstrate that EGFR was activated in liver tissues from high fat diet (HFD)-induced NAFLD mice. Inhibiting EGFR using PD153035 significantly reduced phosphatidylinositol-3-kinase/protein kinase B signaling and sterol responsive elementary binding protein 1 and 2 expression, which prevented HFD-induced hepatic steatosis and hypercholesterolemia by reducing de novo lipogenesis and cholesterol synthesis and enhancing fatty acid oxidation. Additionally, inhibiting EGFR improved HFD-induced glucose intolerance. In conclusion, these results indicate that EGFR plays an important role in NAFLD and is a potential therapeutic target.

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<![CDATA[Tofu and fish oil independently modulate serum lipid profiles in rats: Analyses of 10 class lipoprotein profiles and the global hepatic transcriptome]]> https://www.researchpad.co/article/5c605a43d5eed0c4847ccc8f

Soy protein and fish oil are food components that decrease the risk of cardiovascular disease. Previous studies demonstrated that these food components reduced serum cholesterol levels and suppressed hepatic lipogenesis. However, the underlying mechanisms of action of these food components remain unclear. Ten classes of serum lipoprotein profiles showed that dietary tofu, a soybean curd, suppressed cholesterol absorption, while fish oil reduced most of the lipoprotein classes in rats. Tofu and fish oil both halved the level of the lipoprotein class LAC1 (LDL-anti-protease complex), a 15-nm LDL-anti-protease complex, which is speculated to be a cause of atherosclerosis. Moreover, a global transcriptome analysis revealed that tofu inhibited the mRNA expression of genes involved in hepatic lipogenesis, while fish oil stimulated that of genes related to fatty acid degradation. Therefore, tofu and fish oil independently regulate lipid metabolism. The decrease observed in LAC1 may have been due to reduced cholesterol absorption in the tofu diet group and the interference of lipogenesis via the activation of polyunsaturated fatty acid detoxification in the fish oil group.

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<![CDATA[Changes in hepato-renal gene expression in microminipigs following a single exposure to a mixture of perfluoroalkyl acids]]> https://www.researchpad.co/article/5c390b92d5eed0c48491d4a6

It is evident that some perfluoroalkyl acids (PFAAs), a group of globally dispersed pollutants, have long biological half-lives in humans and farm animals. However, the effects of PFAAs in domestic animals have not been fully elucidated. The present study investigated how exposure to a single dose of a mixture of 10 PFAAs influenced hepatic and renal gene expression and histopathology, as well as plasma clinical biochemistry, in microminipigs (MMPigs) over 21 days. In animals treated with PFAAs, the mRNA expression of twelve genes related to fatty acid metabolism was upregulated in the kidney, while only few of these genes were induced in the liver. The expression of several kidney injury-associated genes such as, IGFBP1, IGFBP6, GCLC X2, GCLC X3, MSGT1, OLR1 was upregulated in the kidney. Interestingly, the expression of IGFBP-genes was differentially altered in the liver and kidney. Our findings thus identified hepato-renal gene expression changes in MMPigs that were associated with various molecular pathways including peroxisome proliferation, lipid metabolism, kidney injury, and apoptosis. Furthermore, serum HDL levels were significantly decreased following exposure to PFAAs, whereas no significant histopathological changes were detected, as compared to the vehicle group. Taken together, the present study provided the first indication that a single exposure to a mixture of PFAAs can produce changes in MMPig renal gene expression that were observed three weeks post exposure, suggesting that more attention should be paid to the kidney as a primary target organ of PFAAs.

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<![CDATA[Parental high dietary arachidonic acid levels modulated the hepatic transcriptome of adult zebrafish (Danio rerio) progeny]]> https://www.researchpad.co/article/5b6da1c4463d7e4dccc5faf6

Disproportionate high intake of n-6 polyunsaturated fatty acids (PUFAs) in the diet is considered as a major human health concern. The present study examines changes in the hepatic gene expression pattern of adult male zebrafish progeny associated with high levels of the n-6 PUFA arachidonic acid (ARA) in the parental diet. The parental generation (F0) was fed a diet which was either low (control) or high in ARA (high ARA). Progenies of both groups (F1) were given the control diet. No differences in body weight were found between the diet groups within adult stages of either F0 or F1 generation. Few differentially expressed genes were observed between the two dietary groups in the F0 in contrast to the F1 generation. Several links were found between the previous metabolic analysis of the parental fish and the gene expression analysis in their adult progeny. Main gene expression differences in the progeny were observed related to lipid and retinoid metabolism by PPARα/RXRα playing a central role in mediating changes to lipid and long-chain fatty acid metabolism. The enrichment of genes involved in β-oxidation observed in the progeny, corresponded to the increase in peroxisomal β-oxidative degradation of long-chain fatty acids in the parental fish metabolomics data. Similar links between the F0 and F1 generation were identified for the methionine cycle and transsulfuration pathway in the high ARA group. In addition, estrogen signalling was found to be affected by parental high dietary ARA levels, where gene expression was opposite directed in F1 compared to F0. This study shows that the dietary n-3/n-6 PUFA ratio can alter gene expression patterns in the adult progeny. Whether the effect is mediated by permanent epigenetic mechanisms regulating gene expression in developing gametes needs to be further investigated.

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<![CDATA[Regulation of protein-coding gene and long noncoding RNA pairs in liver of conventional and germ-free mice following oral PBDE exposure]]> https://www.researchpad.co/article/5b6d94b7463d7e2f79286cbf

Gut microbiome communicates with the host liver to modify hepatic xenobiotic biotransformation and nutrient homeostasis. Polybrominated diphenyl ethers (PBDEs) are persistent environmental contaminants that are detected in fatty food, household dust, and human breast milk at worrisome levels. Recently, long noncoding RNAs (lncRNAs) have been recognized as novel biomarkers for toxicological responses and may regulate the transcriptional/translational output of protein-coding genes (PCGs). However, very little is known regarding to what extent the interactions between PBDEs and gut microbiome modulate hepatic lncRNAs and PCGs, and what critical signaling pathways are impacted at the transcriptomic scale. In this study, we performed RNA-Seq in livers of nine-week-old male conventional (CV) and germ-free (GF) mice orally exposed to the most prevalent PBDE congeners BDE-47 and BDE-99 (100 μmol/kg once daily for 4-days; vehicle: corn oil, 10 ml/kg), and unveiled key molecular pathways and PCG-lncRNA pairs targeted by PBDE-gut microbiome interactions. Lack of gut microbiome profoundly altered the PBDE-mediated transcriptomic response in liver, with the most prominent effect observed in BDE-99-exposed GF mice. The top pathways up-regulated by PBDEs were related to xenobiotic metabolism, whereas the top pathways down-regulated by PBDEs were in lipid metabolism and protein synthesis in both enterotypes. Genomic annotation of the differentially regulated lncRNAs revealed that majority of these lncRNAs overlapped with introns and 3’-UTRs of PCGs. Lack of gut microbiome profoundly increased the percentage of PBDE-regulated lncRNAs mapped to the 3’-UTRs of PCGs, suggesting the potential involvement of lncRNAs in increasing the translational efficiency of PCGs by preventing miRNA-3’-UTR binding, as a compensatory mechanism following toxic exposure to PBDEs. Pathway analysis of PCGs paired with lncRNAs revealed that in CV mice, BDE-47 regulated nucleic acid and retinol metabolism, as well as circadian rhythm; whereas BDE-99 regulated fatty acid metabolism. In GF mice, BDE-47 differentially regulated 19 lncRNA-PCG pairs that were associated with glutathione conjugation and transcriptional regulation. In contrast, BDE-99 up-regulated the xenobiotic-metabolizing Cyp3a genes, but down-regulated the fatty acid-metabolizing Cyp4 genes. Taken together, the present study reveals common and unique lncRNAs and PCG targets of PBDEs in mouse liver, and is among the first to show that lack of gut microbiome sensitizes the liver to toxic exposure of BDE-99 but not BDE-47. Therefore, lncRNAs may serve as specific biomarkers that differentiate various PBDE congeners as well as environmental chemical-mediated dysbiosis. Coordinate regulation of PCG-lncRNA pairs may serve as a more efficient molecular mechanism to combat against xenobiotic insult, and especially during dysbiosis-induced increase in the internal dose of toxicants.

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<![CDATA[Illuminating pathogen–host intimacy through optogenetics]]> https://www.researchpad.co/article/5b5ff78f463d7e28ade495c3

The birth and subsequent evolution of optogenetics has resulted in an unprecedented advancement in our understanding of the brain. Its outstanding success does usher wider applications; however, the tool remains still largely relegated to neuroscience. Here, we introduce selected aspects of optogenetics with potential applications in infection biology that will not only answer long-standing questions about intracellular pathogens (parasites, bacteria, viruses) but also broaden the dimension of current research in entwined models. In this essay, we illustrate how a judicious integration of optogenetics with routine methods can illuminate the host–pathogen interactions in a way that has not been feasible otherwise.

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<![CDATA[Partial Inhibition of Adipose Tissue Lipolysis Improves Glucose Metabolism and Insulin Sensitivity Without Alteration of Fat Mass]]> https://www.researchpad.co/article/5989da54ab0ee8fa60b8e8ac

Partial inhibition of adipose tissue lipolysis does not increase fat mass but improves glucose metabolism and insulin sensitivity through modulation of fatty acid turnover and induction of fat cell de novo lipogenesis.

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<![CDATA[OR17-07 Retinol Binding Protein 4 Predicts Functional Vascular Disease in Early Postmenopausal Women]]> https://www.researchpad.co/article/Nee192a07-5f9f-4c48-8408-345e4961a5cd <![CDATA[OR17-06 Transglutaminase 2 Inhibition Reduces Aortic Stiffness in Western Diet-Fed Female Mice]]> https://www.researchpad.co/article/Nf90e835e-ac01-4966-b321-97ad029f2a75 <![CDATA[OR17-05 Hypospadias Is a Predictor of Adverse Cardiometabolic Risk in Adulthood - a Case-Control Study]]> https://www.researchpad.co/article/Ncde9b8f3-e6af-43c6-86b3-b29fb7334ba1 <![CDATA[Combination Treatment of Rosuvastatin or Atorvastatin, with Regular Exercise Improves Arterial Wall Stiffness in Patients with Coronary Artery Disease]]> https://www.researchpad.co/article/5989da16ab0ee8fa60b7b619

Objective

Statin- and exercise-therapy are both clinically beneficial by preventing cardiovascular events in patients with coronary artery disease (CAD). However, there is no information on the vascular effects of the combination of statins and exercise on arterial wall stiffness in CAD patients.

Methods

The present study is a sub-analysis of PRESET study that determined the effects of 20-week treatment with statins (rosuvastatin, n = 14, atorvastatin, n = 14) combined with regular exercise on arterial wall stiffness assessed by measurement of brachial and ankle pulse wave velocity (baPWV) in CAD patients.

Results

The combination of statins and regular exercise significantly improved exercise capacity, lipid profile, including low- and high-density lipoprotein cholesterol, and high-sensitivity C-reactive protein (hs-CRP), baPWV (baseline: 1747±355, at 20 weeks of treatment: 1627±271 cm/s, p = 0.008), and basophil count (baseline: 42±32, 20 weeks: 26±15 cells/µL, p = 0.007), but had no effect on blood pressure (baseline: 125±22, 20 weeks: 121±16 mmHg). Changes in baPWV correlated significantly with changes in basophil count (r = 0.488, p = 0.008), but not with age, lipids profile, exercise capacity, or hs-CRP.

Conclusion

In CAD patients, the combination treatment with statins and exercise resulted in significant amelioration of arterial wall stiffness, at least in part, through reduction of circulating basophils.

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<![CDATA[Alcohol Facilitates CD1d Loading, Subsequent Activation of NKT Cells, and Reduces the Incidence of Diabetes in NOD Mice]]> https://www.researchpad.co/article/5989dae2ab0ee8fa60bbc2a6

Background

Ethanol (‘alcohol’) is a partly hydrophobic detergent that may affect the accessibility of glycolipids thereby influencing immunological effects of these molecules.

Methods

The study included cellular in vitro tests using α-galactosylceramide (αGalCer), and in vivo NOD mice experiments detecting diabetes incidence and performing behavioural and bacterial analyses.

Results

Alcohol in concentrations from 0.6% to 2.5% increased IL-2 production from NKT cells stimulated with αGalCer by 60% (p<0.05). CD1d expressed on HeLa cells contained significantly increasing amounts of αGalCer with increasing concentrations of alcohol, suggesting that alcohol facilitated the passive loading of αGalCer to CD1d. NOD mice were found to tolerate 5% ethanol in their drinking water without signs of impairment in liver function. Giving this treatment, the diabetes incidence declined significantly. Higher numbers of CD3+CD49b+ NKT cells were found in spleen and liver of the alcohol treated compared to the control mice (p<0.05), whereas the amount of CD4+Foxp3+ regulator T cells did not differ. Increased concentrations of IFN-γ were detected in 24-hour blood samples of alcohol treated mice. Behavioural studies showed no change in attitude of the ethanol-consuming mice, and bacterial composition of caecum samples was not affected by alcohol, disqualifying these as protective mechanisms.

Conclusion

Alcohol facilitates the uptake of glycolipids and the stimulation of NKT cells, which are known to counteract Type 1 diabetes development. We propose that this is the acting mechanism by which treatment with alcohol reduces the incidence of diabetes in NOD mice. This is corroborated by epidemiology showing beneficial effect of alcohol to reduce the severity of atherosclerosis and related diseases.

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<![CDATA[Chardonnay Grape Seed Flour Ameliorates Hepatic Steatosis and Insulin Resistance via Altered Hepatic Gene Expression for Oxidative Stress, Inflammation, and Lipid and Ceramide Synthesis in Diet-Induced Obese Mice]]> https://www.researchpad.co/article/5989db37ab0ee8fa60bd3827

To identify differentially expressed hepatic genes contributing to the improvement of high-fat (HF) diet-induced hepatic steatosis and insulin resistance following supplementation of partially defatted flavonoid-rich Chardonnay grape seed flour (ChrSd), diet-induced obese (DIO) mice were fed HF diets containing either ChrSd or microcrystalline cellulose (MCC, control) for 5 weeks. The 2-h insulin area under the curve was significantly lowered by ChrSd, indicating that ChrSd improved insulin sensitivity. ChrSd intake also significantly reduced body weight gain, liver and adipose tissue weight, hepatic lipid content, and plasma low-density lipoprotein (LDL)-cholesterol, despite a significant increase in food intake. Exon microarray analysis of hepatic gene expression revealed down-regulation of genes related to triglyceride and ceramide synthesis, immune response, oxidative stress, and inflammation and upregulation of genes related to fatty acid oxidation, cholesterol, and bile acid synthesis. In conclusion, the effects of ChrSd supplementation in a HF diet on weight gain, insulin resistance, and progression of hepatic steatosis in DIO mice were associated with modulation of hepatic genes related to oxidative stress, inflammation, ceramide synthesis, and lipid and cholesterol metabolism.

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<![CDATA[Metabolite Profiles Reveal Energy Failure and Impaired Beta-Oxidation in Liver of Mice with Complex III Deficiency Due to a BCS1L Mutation]]> https://www.researchpad.co/article/5989db08ab0ee8fa60bc92bf

Background & Aims

Liver is a target organ in many mitochondrial disorders, especially if the complex III assembly factor BCS1L is mutated. To reveal disease mechanism due to such mutations, we have produced a transgenic mouse model with c.232A>G mutation in Bcs1l, the causative mutation for GRACILE syndrome. The homozygous mice develop mitochondrial hepatopathy with steatosis and fibrosis after weaning. Our aim was to assess cellular mechanisms for disease onset and progression using metabolomics.

Methods

With mass spectrometry we analyzed metabolite patterns in liver samples obtained from homozygotes and littermate controls of three ages. As oxidative stress might be a mechanism for mitochondrial hepatopathy, we also assessed H2O2 production and expression of antioxidants.

Results

Homozygotes had a similar metabolic profile at 14 days of age as controls, with the exception of slightly decreased AMP. At 24 days, when hepatocytes display first histopathological signs, increases in succinate, fumarate and AMP were found associated with impaired glucose turnover and beta-oxidation. At end stage disease after 30 days, these changes were pronounced with decreased carbohydrates, high levels of acylcarnitines and amino acids, and elevated biogenic amines, especially putrescine. Signs of oxidative stress were present in end-stage disease.

Conclusions

The findings suggest an early Krebs cycle defect with increases of its intermediates, which might play a role in disease onset. During disease progression, carbohydrate and fatty acid metabolism deteriorate leading to a starvation-like condition. The mouse model is valuable for further investigations on mechanisms in mitochondrial hepatopathy and for interventions.

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<![CDATA[Enteric Microbiome Metabolites Correlate with Response to Simvastatin Treatment]]> https://www.researchpad.co/article/5989dae2ab0ee8fa60bbc399

Although statins are widely prescribed medications, there remains considerable variability in therapeutic response. Genetics can explain only part of this variability. Metabolomics is a global biochemical approach that provides powerful tools for mapping pathways implicated in disease and in response to treatment. Metabolomics captures net interactions between genome, microbiome and the environment. In this study, we used a targeted GC-MS metabolomics platform to measure a panel of metabolites within cholesterol synthesis, dietary sterol absorption, and bile acid formation to determine metabolite signatures that may predict variation in statin LDL-C lowering efficacy. Measurements were performed in two subsets of the total study population in the Cholesterol and Pharmacogenetics (CAP) study: Full Range of Response (FR), and Good and Poor Responders (GPR) were 100 individuals randomly selected from across the entire range of LDL-C responses in CAP. GPR were 48 individuals, 24 each from the top and bottom 10% of the LDL-C response distribution matched for body mass index, race, and gender. We identified three secondary, bacterial-derived bile acids that contribute to predicting the magnitude of statin-induced LDL-C lowering in good responders. Bile acids and statins share transporters in the liver and intestine; we observed that increased plasma concentration of simvastatin positively correlates with higher levels of several secondary bile acids. Genetic analysis of these subjects identified associations between levels of seven bile acids and a single nucleotide polymorphism (SNP), rs4149056, in the gene encoding the organic anion transporter SLCO1B1. These findings, along with recently published results that the gut microbiome plays an important role in cardiovascular disease, indicate that interactions between genome, gut microbiome and environmental influences should be considered in the study and management of cardiovascular disease. Metabolic profiles could provide valuable information about treatment outcomes and could contribute to a more personalized approach to therapy.

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