Publications by authors named "Robin Clugston"

37 Publications

Low maternal vitamin A intake increases the incidence of teratogen induced congenital diaphragmatic hernia in mice.

Pediatr Res 2021 Mar 2. Epub 2021 Mar 2.

Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.

Background: Congenital diaphragmatic hernia (CDH) is a severe birth defect associated with high perinatal mortality and long-term morbidity. The etiology of CDH is poorly understood although abnormal retinoid signaling has been proposed to contribute to abnormal diaphragm development. Existing epidemiological data suggest that inadequate dietary vitamin A intake is a risk factor for developing CDH.

Methods: Using a mouse model of teratogen-induced CDH, the objective of this study was to test the hypothesis that low maternal vitamin A intake contributes to abnormal diaphragm development. To test this hypothesis, we optimized a model of altered maternal dietary vitamin A intake and a teratogenic model of CDH in mice that recapitulates the hallmark features of posterolateral diaphragmatic hernia in humans.

Results: Our data uniquely show that low maternal dietary vitamin A intake and marginal vitamin A status increases the incidence of teratogen-induced CDH in mice.

Conclusion: Low dietary vitamin A intake and marginal vitamin A status lead to an increased incidence of teratogen-induced CDH in mice, highlighting the importance of adequate dietary vitamin A intake and CDH risk.

Impact: This study describes and validates a mouse model of altered maternal and fetal vitamin A status. This study links existing epidemiological data with a mouse model of teratogen-induced congenital diaphragmatic hernia, highlighting the importance of low maternal vitamin A intake as a risk factor for the development of congenital diaphragmatic hernia. This study supports the Retinoid Hypothesis, which posits that the etiology of congenital diaphragmatic hernia is linked to abnormal retinoid signaling in the developing diaphragm.
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http://dx.doi.org/10.1038/s41390-021-01409-6DOI Listing
March 2021

Absence of CD36 alters systemic vitamin A homeostasis.

Sci Rep 2020 11 23;10(1):20386. Epub 2020 Nov 23.

Department of Physiology, University of Alberta, 7-49 Medical Sciences Building, Edmonton, AB, T6G 2H7, Canada.

Fatty acid translocase (CD36) is a scavenger receptor with multiple ligands and diverse physiological actions. We recently reported that alcohol-induced hepatic retinoid mobilization is impaired in Cd36 mice, leading us to hypothesize that CD36 has a novel role in hepatic vitamin A mobilization. Given the central role of the liver in systemic vitamin A homeostasis we also postulated that absence of CD36 would affect whole-body vitamin A homeostasis. We tested this hypothesis in aging wild type and Cd36 mice, as well as mice fed a vitamin A-deficient diet. In agreement with our hypothesis, Cd36 mice accumulated hepatic retinyl ester stores with age to a greater extent than wild type mice. However, contrary to expectations, Cd36 mice consuming a vitamin A-deficient diet mobilized hepatic retinoid similar to wild type mice. Interestingly, we observed that Cd36 mice had significantly reduced white adipose tissue retinoid levels compared to wild type mice. In conclusion, we demonstrate that the absence of CD36 alters whole-body vitamin A homeostasis and suggest that this phenotype is secondary to the impaired chylomicron metabolism previously reported in these mice.
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http://dx.doi.org/10.1038/s41598-020-77411-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683526PMC
November 2020

Carotenoids and fatty liver disease: Current knowledge and research gaps.

Authors:
Robin D Clugston

Biochim Biophys Acta Mol Cell Biol Lipids 2020 11 2;1865(11):158597. Epub 2020 Jan 2.

Department of Physiology, University of Alberta, Edmonton T6G 2H7, AB, Canada. Electronic address:

Carotenoids form an important part of the human diet, consumption of which has been associated with many health benefits. With the growing global burden of liver disease, increasing attention has been paid on the possible beneficial role that carotenoids may play in the liver. This review focuses on carotenoid actions in non-alcoholic fatty liver disease (NAFLD), and alcoholic liver disease (ALD). Indeed, many human studies have suggested an association between decreased circulating levels of carotenoids and increased incidence of NAFLD and ALD. The literature describing supplementation of individual carotenoids in rodent models of NAFLD and ALD is reviewed, with particular attention paid to β-carotene and lycopene, but also including β-cryptoxanthin, lutein, zeaxanthin, and astaxanthin. The effect of beta-carotene oxygenase 1 and 2 knock-out mice on hepatic lipid metabolism is also discussed. In general, there is evidence to suggest that carotenoids have beneficial effects in animal models of both NAFLD and ALD. Mechanistically, these benefits may occur via three possible modes of action: 1) improved hepatic antioxidative status broadly attributed to carotenoids in general, 2) the generation of vitamin A from β-carotene and β-cryptoxanthin, leading to improved hepatic retinoid signaling, and 3) the generation of apocarotenoid metabolites from β-carotene and lycopene, that may regulate hepatic signaling pathways. Gaps in our knowledge regarding carotenoid mechanisms of action in the liver are highlighted throughout, and the review ends by emphasizing the importance of dose effects, mode of delivery, and mechanism of action as important areas for further study. This article is part of a Special Issue entitled Carotenoids recent advances in cell and molecular biology edited by Johannes von Lintig and Loredana Quadro.
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http://dx.doi.org/10.1016/j.bbalip.2019.158597DOI Listing
November 2020

The role of adipose triglyceride lipase in lipid and glucose homeostasis: lessons from transgenic mice.

Lipids Health Dis 2019 Nov 22;18(1):204. Epub 2019 Nov 22.

Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, T6G 2H7, Canada.

The ability of mammals to store and draw on fat reserves has been a driving force throughout evolution in an environment with intermittent nutrient availability. The discovery of adipose triglyceride lipase (ATGL) as a triglyceride lipase provided a heightened understanding of the mechanisms governing mobilization of fat reserves from adipose tissue. ATGL catalyses the initial step in adipose triglyceride lipolysis, working in concert with other enzymes to mobilize triglyceride for energy production. In addition to the role of ATGL in adipose tissue triglyceride mobilization, ATGL plays crucial roles in regulating lipid homeostasis in other tissues. These roles have been characterized primarily using transgenic mice with tissue-specific ATGL ablation. For example, the global ATGL knockout induces a severe cardiac defect that results in premature mortality that is mimicked by inducible cardiomyocyte-specific ATGL knockout. Global- and adipose-specific ATGL ablation induces a whole-body shift from lipid metabolism to glucose metabolism to satisfy metabolic demand primarily facilitated by an increase in glucose uptake by skeletal muscle. Generation of liver-specific ATGL knockouts has implicated hepatic lipolysis as a critical component of normal liver function. Analysis of β-cell ATGL knockouts implicates the necessity of pancreatic ATGL in insulin secretion. The objective of this review is to discuss the contributions of ATGL to systemic lipid- and glucose-homeostasis discovered through the study of transgenic mice.
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http://dx.doi.org/10.1186/s12944-019-1151-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874817PMC
November 2019

Correction: Gene ontology enrichment analysis of congenital diaphragmatic hernia-associated genes.

Pediatr Res 2019 Nov;86(5):676

Department of Physiology, and Women and Children's Health Research Institute, University of Alberta, Edmonton, AB, Canada.

A correction to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41390-019-0536-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848021PMC
November 2019

Vitamin E alleviates non-alcoholic fatty liver disease in phosphatidylethanolamine N-methyltransferase deficient mice.

Biochim Biophys Acta Mol Basis Dis 2019 01 6;1865(1):14-25. Epub 2018 Oct 6.

Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, AB, Canada; Department of Biochemistry, University of Alberta, Edmonton, AB, Canada. Electronic address:

Phosphatidylethanolamine N-methyltransferase (PEMT) converts phosphatidylethanolamine (PE) to phosphatidylcholine (PC), mainly in the liver. Pemt mice are protected from high-fat diet (HFD)-induced obesity and insulin resistance, but develop severe non-alcoholic fatty liver disease (NAFLD) when fed a HFD, mostly due to impaired VLDL secretion. Oxidative stress is thought to be an essential factor in the progression from simple steatosis to steatohepatitis. Vitamin E is an antioxidant that has been clinically used to improve NAFLD pathology. Our aim was to determine whether supplementation of the diet with vitamin E could attenuate HFD-induced hepatic steatosis and its progression to NASH in Pemt mice. Treatment with vitamin E (0.5 g/kg) for 3 weeks improved VLDL-TG secretion and normalized cholesterol metabolism, but failed to reduce hepatic TG content. Moreover, vitamin E treatment was able to reduce hepatic oxidative stress, inflammation and fibrosis. We also observed abnormal ceramide metabolism in Pemt mice fed a HFD, with elevation of ceramides and other sphingolipids and higher expression of mRNAs for acid ceramidase (Asah1) and ceramide kinase (Cerk). Interestingly, vitamin E supplementation restored Asah1 and Cerk mRNA and sphingolipid levels. Together this study shows that vitamin E treatment efficiently prevented the progression from simple steatosis to steatohepatitis in mice lacking PEMT.
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http://dx.doi.org/10.1016/j.bbadis.2018.10.010DOI Listing
January 2019

Gene ontology enrichment analysis of congenital diaphragmatic hernia-associated genes.

Pediatr Res 2019 01 25;85(1):13-19. Epub 2018 Sep 25.

Department of Physiology, and Women and Children's Health Research Institute, University of Alberta, Edmonton, AB, Canada.

Congenital diaphragmatic hernia (CDH) is a commonly occurring major congenital anomaly with a profound impact on neonatal mortality. The etiology of CDH is poorly understood and is complicated by multiple clinical presentations, reflecting the location and type of diaphragm defect. With the increased power of genetic screening, more genes are being associated with CDH, creating a knowledge gap between CDH-associated genes and their contribution to diaphragm embryogenesis. Our goal was to investigate CDH-associated genes and identify common pathways that may lead to abnormal diaphragm development. A comprehensive list of CDH-associated genes was identified from the literature and categorized according to multiple factors, including type of CDH. We undertook a large-scale gene function analysis using gene ontology to identify significantly enriched biological pathways and molecular functions associated with our gene set. We identified 218 CDH-associated genes. Our gene ontology analysis showed that genes representing distinct biological pathways are significantly enriched in relation to different clinical presentations of CDH. This includes retinoic acid signaling in Bochdalek CDH, myogenesis in diaphragm eventration, and angiogenesis in central tendon defects. We have identified unique genotype-phenotype relationships highlighting the major genetic drivers of the different types of CDH.
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http://dx.doi.org/10.1038/s41390-018-0192-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760551PMC
January 2019

Dietary Macronutrient Composition Determines the Contribution of DGAT1 to Alcoholic Steatosis.

Alcohol Clin Exp Res 2018 12 3;42(12):2298-2312. Epub 2018 Oct 3.

Department of Physiology, University of Alberta, Edmonton, AB, Canada.

Background: The first stage of alcoholic liver disease is hepatic steatosis. While alcohol is known to profoundly impact hepatic lipid metabolism, gaps in our knowledge remain regarding the mechanisms leading to alcohol-induced hepatic triglyceride (TG) accumulation. As the sole enzymes catalyzing the final step in TG synthesis, diacylglycerol O-acyltransferase (DGAT) 1 and 2 are potentially important contributors to alcoholic steatosis. Our goal was to study the effects of dietary fat content on alcohol-induced hepatic TG accumulation, and the relative contribution of DGAT1 and DGAT2 to alcoholic steatosis.

Methods: These studies were carried out in wild-type (WT) mice fed alcohol-containing high-fat or low-fat formulations of Lieber-DeCarli liquid diets, as well as follow-up studies in Dgat1 mice.

Results: A direct comparison of the low-fat and high-fat liquid diet in WT mice revealed surprisingly similar levels of alcoholic steatosis, although there were underlying differences in the pattern of hepatic lipid accumulation and expression of genes involved in hepatic lipid metabolism. Follow-up studies in Dgat1 mice revealed that these animals are protected from alcoholic steatosis when consumed as part of a high-fat diet, but not a low-fat diet.

Conclusions: Dietary macronutrient composition influences the relative contribution of DGAT1 and DGAT2 to alcoholic steatosis, such that in the context of alcohol and a high-fat diet, DGAT1 predominates.
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http://dx.doi.org/10.1111/acer.13881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286229PMC
December 2018

Poor Vitamin Status is Associated with Skeletal Muscle Loss and Mucositis in Head and Neck Cancer Patients.

Nutrients 2018 Sep 5;10(9). Epub 2018 Sep 5.

Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB T6G 2E1, Canada.

Mucositis and muscle wasting are two common toxicity effects of cancer treatment in head and neck cancer (HNC). There is limited data evaluating cancer treatment toxicities in relation to vitamin status. This study aimed to assess changes in vitamin status during HNC treatment in relation to body composition, inflammation and mucositis. In this prospective cohort study, dietary intakes (3-day food record), plasma levels of vitamins and C-reactive protein (CRP) were assessed at baseline (at diagnosis) and post-treatment (after 6⁻8 weeks of radiation therapy with or without chemotherapy). Computed tomography images were used to quantify body composition. Mucositis information was collected from health records of patients. Twenty-eight HNC patients (age 60 ± 10 years) completed both study time points. Patients who developed mucositis had significantly lower dietary intake of vitamins and plasma 25-hydroxy vitamin D (25-OHD) and retinol levels ( < 0.02). Patients lost a considerable amount of muscle mass (3.4 kg) and fat mass (3.6 kg) over the course of treatment. There was a trend toward greater muscle loss in patients with 25-OHD < 50 nmol/L compared to patients with 25-OHD ≥ 50 nmol/L ( = 0.07). A significant negative correlation was found between plasma retinol and CRP level at the end of treatment ( = 0.03). Poor vitamin status could be a contributing factor in developing treatment-induced toxicities.
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http://dx.doi.org/10.3390/nu10091236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165496PMC
September 2018

-Expressing Interneurons Regulate Left-Right Alternation during Mammalian Locomotor Activity.

J Neurosci 2018 06 22;38(25):5666-5676. Epub 2018 May 22.

Neuroscience and Mental Health Institute and

The basic pattern of activity underlying stepping in mammals is generated by a neural network located in the caudal spinal cord. Within this network, the specific circuitry coordinating left-right alternation has been shown to involve several groups of molecularly defined interneurons. Here we characterize a population of spinal neurons that express the Wilms' tumor 1 () gene and investigate their role during locomotor activity in mice of both sexes. We demonstrate that -expressing cells are located in the ventromedial region of the spinal cord of mice and are also present in the human spinal cord. In the mouse, these cells are inhibitory, project axons to the contralateral spinal cord, terminate in close proximity to other commissural interneuron subtypes, and are essential for appropriate left-right alternation during locomotion. In addition to identifying -expressing interneurons as a key component of the locomotor circuitry, this study provides insight into the manner in which several populations of molecularly defined interneurons are interconnected to generate coordinated motor activity on either side of the body during stepping. In this study, we characterize -expressing spinal interneurons in mice and demonstrate that they are commissurally projecting and inhibitory. Silencing of this neuronal population during a locomotor task results in a complete breakdown of left-right alternation, whereas flexor-extensor alternation was not significantly affected. Axons of neurons are shown to terminate nearby commissural interneurons, which coordinate motoneuron activity during locomotion, and presumably regulate their activity. Finally, the gene is shown to be present in the spinal cord of humans, raising the possibility of functional homology between these species. This study not only identifies a key component of the locomotor circuitry but also begins to unravel the connectivity among the growing number of molecularly defined interneurons that comprise this neural network.
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http://dx.doi.org/10.1523/JNEUROSCI.0328-18.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595980PMC
June 2018

Comment on "Lung and Liver growth and retinoic acid status in human fetuses with congenital diaphragmatic hernia".

Early Hum Dev 2018 01 24;116:93. Epub 2017 Nov 24.

Department of Physiology, University of Alberta, Edmonton, Alberta, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.earlhumdev.2017.11.006DOI Listing
January 2018

knockout mice are protected against lithogenic diet-induced gallstones.

J Lipid Res 2017 08 20;58(8):1692-1701. Epub 2017 Jun 20.

Gastroenterology Division, Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO

The scavenger receptor and multiligand transporter CD36 functions to promote cellular free fatty acid uptake and regulates aspects of both hepatic and intestinal cholesterol metabolism. However, the role of CD36 in regulating canalicular and biliary cholesterol transport and secretion is unknown. Here, we show that germline knockout (KO) mice are protected against lithogenic diet (LD)-induced gallstones compared with congenic (C57BL6/J) controls. KO mice crossed into congenic KO mice (DKO mice) demonstrated protection against LD-induced gallstones, reversing the susceptibility phenotype observed in KO mice. DKO mice demonstrated reduced biliary cholesterol secretion and a shift into more hydrophophilic bile acid species, without changes in either BA pool size or fecal excretion. In addition, we found that the mean and maximum force of gallbladder contraction was increased in germline KO mice, and gallbladder lipid content was reduced compared with wild-type controls. Finally, whereas germline KO mice were protected against LD-induced gallstones, neither liver- nor intestine-specific KO mice were protected. Taken together, our findings show that CD36 plays an important role in modifying gallstone susceptibility in mice, at least in part by altering biliary lipid composition, but also by promoting gallbladder contractility.
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http://dx.doi.org/10.1194/jlr.M077479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538290PMC
August 2017

Chronic alcohol consumption decreases brown adipose tissue mass and disrupts thermoregulation: a possible role for altered retinoid signaling.

Sci Rep 2017 03 6;7:43474. Epub 2017 Mar 6.

Department of Medicine, Columbia University, New York, NY, USA.

Retinoic acid, an active metabolite of dietary vitamin A, acts as a ligand for nuclear receptor transcription factors with more than 500 known target genes. It is becoming increasingly clear that alcohol has a significant impact on cellular retinoic acid metabolism, with resultant effects on its function. Here, we test the hypothesis that chronic alcohol consumption impairs retinoic acid signaling in brown adipose tissue (BAT), leading to impaired BAT function and thermoregulation. All studies were conducted in age-matched, male mice consuming alcohol-containing liquid diets. Alcohol's effect on BAT was assessed by histology, qPCR, HPLC, LC/MS and measures of core body temperature. Our data show that chronic alcohol consumption decreases BAT mass, with a resultant effect on thermoregulation. Follow-up mechanistic studies reveal a decreased triglyceride content in BAT, as well as impaired retinoic acid homeostasis, associated with decreased BAT levels of retinoic acid in alcohol-consuming mice. Our work highlights a hitherto uncharacterized effect of alcohol on BAT function, with possible implications for thermoregulation and energy metabolism in drinkers. Our data indicate that alcohol's effects on brown adipose tissue may be mediated through altered retinoic acid signaling.
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http://dx.doi.org/10.1038/srep43474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5337954PMC
March 2017

Vitamin A Absorption, Storage and Mobilization.

Subcell Biochem 2016;81:95-125

Department of Medicine, College of Physicians and Surgeons, Columbia University, 650 W 168th St., New York, NY, 10032, USA.

It is well established that chylomicron remnant (dietary) vitamin A is taken up from the circulation by hepatocytes, but more than 80 % of the vitamin A in the liver is stored in hepatic stellate cells (HSC). It presently is not known how vitamin A is transferred from hepatocytes to HSCs for storage. Since retinol-binding protein 4 (RBP4), a protein that is required for mobilizing stored vitamin A, is synthesized solely by hepatocytes and not HSCs, it similarly is not known how vitamin A is transferred from HSCs to hepatocytes. Although it has long been thought that RBP4 is absolutely essential for delivering vitamin A to tissues, recent research has proven that this notion is incorrect since total RBP4-deficiency is not lethal. In addition to RBP4, vitamin A is also found in the circulation bound to lipoproteins and as retinoic acid bound to albumin. It is not known how these different circulating pools of vitamin A contribute to the vitamin A needs of different tissues. In our view, better insight into these three issues is required to better understand vitamin A absorption, storage and mobilization. Here, we provide an up to date synthesis of current knowledge regarding the intestinal uptake of dietary vitamin A, the storage of vitamin A within the liver, and the mobilization of hepatic vitamin A stores, and summarize areas where our understanding of these processes is incomplete.
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http://dx.doi.org/10.1007/978-94-024-0945-1_4DOI Listing
November 2017

Long-term Diet and Biomarker Changes after a Short-term Intervention among Hispanic Breast Cancer Survivors: The ¡Cocinar Para Su Salud! Randomized Controlled Trial.

Cancer Epidemiol Biomarkers Prev 2016 11 26;25(11):1491-1502. Epub 2016 Jul 26.

Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York.

Background: Among Hispanic breast cancer survivors, we examined the long-term effects of a short-term culturally based dietary intervention on increasing fruits/vegetables (F/V), decreasing fat, and changing biomarkers associated with breast cancer recurrence risk.

Methods: Spanish-speaking women (n = 70) with a history of stage 0-III breast cancer who completed treatment were randomized to ¡Cocinar Para Su Salud! (n = 34), a culturally based 9-session program (24 hours over 12 weeks, including nutrition education, cooking classes, and food-shopping field trips), or a control group (n = 36, written dietary recommendations for breast cancer survivors). Diet recalls, fasting blood, and anthropometric measures were collected at baseline, 6, and 12 months. We report changes between groups at 12 months in dietary intake and biomarkers using 2-sample Wilcoxon t tests and generalized estimating equation (GEE) models.

Results: At 12 months, the intervention group compared with the control group reported higher increases in mean daily F/V servings (total: +2.0 vs. -0.4; P < 0.01), and nonsignificant decreases in the percentage of calories from fat (-2.2% vs. -1.1%; P = 0.69) and weight (-2.6 kg vs. -1.5 kg; P = 0.56). Compared with controls, participants in the intervention group had higher increases in plasma lutein (+20.4% vs. -11.5%; P < 0.01), and borderline significant increases in global DNA methylation (+0.8% vs. -0.5%; P = 0.06).

Conclusions: The short-term ¡Cocinar Para Su Salud! program was effective at increasing long-term F/V intake in Hispanic breast cancer survivors and changed biomarkers associated with breast cancer recurrence risk.

Impact: It is possible for short-term behavioral interventions to have long-term effects on behaviors and biomarkers in minority cancer patient populations. Results can inform future study designs. Cancer Epidemiol Biomarkers Prev; 25(11); 1491-502. ©2016 AACR.
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http://dx.doi.org/10.1158/1055-9965.EPI-15-1334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501703PMC
November 2016

The Hepatic Lipidome: A Gateway to Understanding the Pathogenes is of Alcohol-Induced Fatty Liver.

Curr Mol Pharmacol 2017 ;10(3):195-206

Department of Medicine, Columbia University, New York, NY, 10032. United States.

Chronic alcohol consumption can lead to the development of alcoholic fatty liver disease. The underlying pathogenic mechanisms however, have not been fully elucidated. Here, we review the current state of the art regarding the application of lipidomics to study alcohol's effect on hepatic lipids. It is clear that alcohol has a profound effect on the hepatic lipidome, with documented changes in the major lipid categories (i.e. fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, sterol lipids and prenol lipids). Alcohol's most striking effect is the marked change in the hepatic fatty acyl pool. This effect includes increased levels of 18-carbon fatty acyl chains incorporated into multiple lipid species, as well as a general shift toward increased unsaturation of fatty acyl moieties. In addition to our literature review, we also make several recommendations to consider when designing lipidomic studies into alcohol's effects. These recommendations include integration of lipidomic data with other measures of lipid metabolism, inclusion of multiple experimental time points, and presentation of quantitative data. We believe rigorous analysis of the hepatic lipidome can yield new insight into the pathogenesis of alcohol-induced fatty liver. While the existing literature has been largely descriptive, the field is poised to apply lipidomics to yield a new level of understanding on alcohol's effects on hepatic lipid metabolism.
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http://dx.doi.org/10.2174/1874467208666150817111419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4757511PMC
February 2019

Chronic alcohol consumption has a biphasic effect on hepatic retinoid loss.

FASEB J 2015 Sep 18;29(9):3654-67. Epub 2015 May 18.

Department of Medicine, Columbia University, New York, New York, USA.

The alcohol-induced depletion of hepatic retinoid stores correlates with the progression of liver injury; however, the mechanisms underlying alcohol's effects have not been fully elucidated. Our goal was to gain a mechanistic understanding of alcohol-induced hepatic retinoid depletion. Wild-type and mutant mice were continuously fed alcohol through Lieber-DeCarli liquid diets, with matched control animals pair fed an isocaloric alcohol-free diet to ensure equal nutrient and calorie intake between groups. A systematic analysis of tissue retinol and retinyl ester levels was performed with HPLC, complemented by gene and protein expression analyses. Our results delineated 2 phases of alcohol-induced depletion of hepatic retinoid. Initially, ∼15% of hepatic retinoid content was mobilized from the liver, causing extrahepatic tissue retinoid levels to increase. Subsequently, there was a precipitous drop in hepatic retinoid content (>60%), without further retinoid accumulation in the periphery. Follow-up studies in mutant mice revealed roles for RBP, CRBP1, and CD36 in retinoid mobilization and extrahepatic retinoid uptake, as well as a role for CYP2E1 in the catabolism of hepatic retinoid. In summary, alcohol has a biphasic effect on hepatic retinoid stores, characterized by an initial phase of rapid mobilization to extrahepatic tissues followed by extensive catabolism within the liver.
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http://dx.doi.org/10.1096/fj.14-266296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4550375PMC
September 2015

Vitamin A (retinoid) metabolism and actions: What we know and what we need to know about amphibians.

Zoo Biol 2014 Nov-Dec;33(6):527-35. Epub 2014 Jun 24.

Department of Medicine, Columbia University, New York, New York.

Vitamin A status is an important consideration in the health of both wild and captive amphibians. Data concerning whole body vitamin A homeostasis in amphibians are scarce, although these animals have been used as experimental models to study the actions of vitamin A in vision, limb regeneration and embryogenesis. The available data suggest that many aspects of vitamin A biology in amphibians are similar to the canonical characteristics of vitamin A metabolism and actions established in mammals. This is consistent with the evolutionary conservation of these important biological processes. Amphibians must obtain vitamin A in their diet, with captive animals being prone to vitamin A deficiency. There is still much to be learned about vitamin A biology in amphibians that can only be achieved through rigorous scientific research. Improved understanding of amphibian vitamin A biology will aid the conservation of endangered amphibians in the wild, as well as the successful maintenance of ex situ populations.
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http://dx.doi.org/10.1002/zoo.21140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4685470PMC
August 2015

Heparan sulfate deficiency disrupts developmental angiogenesis and causes congenital diaphragmatic hernia.

J Clin Invest 2014 Jan 20;124(1):209-21. Epub 2013 Dec 20.

Congenital diaphragmatic hernia (CDH) is a common birth malformation with a heterogeneous etiology. In this study, we report that ablation of the heparan sulfate biosynthetic enzyme NDST1 in murine endothelium (Ndst1ECKO mice) disrupted vascular development in the diaphragm, which led to hypoxia as well as subsequent diaphragm hypoplasia and CDH. Intriguingly, the phenotypes displayed in Ndst1ECKO mice resembled the developmental defects observed in slit homolog 3 (Slit3) knockout mice. Furthermore, introduction of a heterozygous mutation in roundabout homolog 4 (Robo4), the gene encoding the cognate receptor of SLIT3, aggravated the defect in vascular development in the diaphragm and CDH. NDST1 deficiency diminished SLIT3, but not ROBO4, binding to endothelial heparan sulfate and attenuated EC migration and in vivo neovascularization normally elicited by SLIT3-ROBO4 signaling. Together, these data suggest that heparan sulfate presentation of SLIT3 to ROBO4 facilitates initiation of this signaling cascade. Thus, our results demonstrate that loss of NDST1 causes defective diaphragm vascular development and CDH and that heparan sulfate facilitates angiogenic SLIT3-ROBO4 signaling during vascular development.
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http://dx.doi.org/10.1172/JCI71090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3871243PMC
January 2014

CD36-deficient mice are resistant to alcohol- and high-carbohydrate-induced hepatic steatosis.

J Lipid Res 2014 Feb 26;55(2):239-46. Epub 2013 Nov 26.

Department of Medicine, Columbia University, New York, NY 10032.

CD36 is a scavenger receptor with multiple ligands and cellular functions, including facilitating cellular uptake of free fatty acids (FFAs). Chronic alcohol consumption increases hepatic CD36 expression, leading to the hypothesis that this promotes uptake of circulating FFAs, which then serve as a substrate for triglyceride (TG) synthesis and the development of alcoholic steatosis. We investigated this hypothesis in alcohol-fed wild-type and Cd36-deficient (Cd36(-/-)) mice using low-fat/high-carbohydrate Lieber-DeCarli liquid diets, positing that Cd36(-/-) mice would be resistant to alcoholic steatosis. Our data show that the livers of Cd36(-/-) mice are resistant to the lipogenic effect of consuming high-carbohydrate liquid diets. These mice also do not further develop alcoholic steatosis when chronically fed alcohol. Surprisingly, we did not detect an effect of alcohol or CD36 deficiency on hepatic FFA uptake; however, the lower baseline levels of hepatic TG in Cd36(-/-) mice fed a liquid diet were associated with decreased expression of genes in the de novo lipogenesis pathway and a lower rate of hepatic de novo lipogenesis. In conclusion, Cd36(-/-) mice are resistant to hepatic steatosis when fed a high-carbohydrate liquid diet, and they are also resistant to alcoholic steatosis. These studies highlight an important role for CD36 in hepatic lipid homeostasis that is not associated with hepatic fatty acid uptake.
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http://dx.doi.org/10.1194/jlr.M041863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3886662PMC
February 2014

Altered hepatic retinyl ester concentration and acyl composition in response to alcohol consumption.

Biochim Biophys Acta 2013 Jul;1831(7):1276-86

Department of Medicine, Columbia University, New York, NY 10032, USA.

Retinoids (vitamin A and its metabolites) are essential micronutrients that regulate many cellular processes. Greater than 70% of the body's retinoid reserves are stored in the liver as retinyl ester (RE). Chronic alcohol consumption induces depletion of hepatic retinoid stores, and the extent of this has been correlated with advancing stages of alcoholic liver disease. The goal of this study was to analyze the mechanisms responsible for depletion of hepatic RE stores by alcohol consumption A change in the fatty-acyl composition of RE in alcohol-fed mice was observed within two weeks after the start of alcohol consumption. Specifically, alcohol-feeding was associated with a significant decline in hepatic retinyl palmitate levels; however, total RE levels were maintained by a compensatory increase in levels of usually minor RE species, particularly retinyl oleate. Our data suggests that alcohol feeding initially stimulates a futile cycle of RE hydrolysis and synthesis, and that the change in RE acyl composition is associated with a change in the acyl composition of hepatic phosphatidylcholine. The alcohol-induced change in RE acyl composition was specific to the liver, and was not seen in lung or white adipose tissue. This shift in hepatic RE fatty acyl composition is a sensitive indicator of alcohol consumption and may be an early biomarker for events associated with the development of alcoholic liver disease.
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July 2013

Altered hepatic retinyl ester concentration and acyl composition in response to alcohol consumption.

Biochim Biophys Acta 2012 Jul 12;1831(7):1276-86. Epub 2013 Apr 12.

Department of Medicine, Columbia University, New York, NY, 10032, USA.

Retinoids (vitamin A and its metabolites) are essential micronutrients that regulate many cellular processes. Greater than 70% of the body's retinoid reserves are stored in the liver as retinyl ester (RE). Chronic alcohol consumption induces depletion of hepatic retinoid stores, and the extent of this has been correlated with advancing stages of alcoholic liver disease. The goal of this study was to analyze the mechanisms responsible for depletion of hepatic RE stores by alcohol consumption. A change in the fatty-acyl composition of RE in alcohol-fed mice was observed within two weeks after the start of alcohol consumption. Specifically, alcohol-feeding was associated with a significant decline in hepatic retinyl palmitate levels; however, total RE levels were maintained by a compensatory increase in levels of usually minor RE species, particularly retinyl oleate. Our data suggests that alcohol feeding initially stimulates a futile cycle of RE hydrolysis and synthesis, and that the change in RE acyl composition is associated with a change in the acyl composition of hepatic phosphatidylcholine. The alcohol-induced change in RE acyl composition was specific to the liver, and was not seen in lung or white adipose tissue. This shift in hepatic RE fatty acyl composition is a sensitive indicator of alcohol consumption and may be an early biomarker for events associated with the development of alcoholic liver disease.
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http://dx.doi.org/10.1016/j.bbalip.2013.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3786403PMC
July 2012

Chronic ethanol consumption increases cardiomyocyte fatty acid uptake and decreases ventricular contractile function in C57BL/6J mice.

J Mol Cell Cardiol 2013 Jun 16;59:30-40. Epub 2013 Feb 16.

The Department of Medicine, Division of Digestive & Liver Disease, Columbia University College of Physicians & Surgeons, New York, NY 10032, USA.

Alcohol, a major cause of human cardiomyopathy, decreases cardiac contractility in both animals and man. However, key features of alcohol-related human heart disease are not consistently reproduced in animal models. Accordingly, we studied cardiac histology, contractile function, cardiomyocyte long chain fatty acid (LCFA) uptake, and gene expression in male C57BL/6J mice consuming 0, 10, 14, or 18% ethanol in drinking water for 3months. At sacrifice, all EtOH groups had mildly decreased body and increased heart weights, dose-dependent increases in cardiac triglycerides and a marked increase in cardiac fatty acid ethyl esters. [(3)H]-oleic acid uptake kinetics demonstrated increased facilitated cardiomyocyte LCFA uptake, associated with increased expression of genes encoding the LCFA transporters CD36 and Slc27a1 (FATP1) in EtOH-fed animals. Although SCD-1 expression was increased, lipidomic analysis did not indicate significantly increased de novo LCFA synthesis. By echocardiography, ejection fraction (EF) and the related fractional shortening (FS) of left ventricular diameter during systole were reduced and negatively correlated with cardiac triglycerides. Expression of myocardial PGC-1α and multiple downstream target genes in the oxidative phosphorylation pathway, including several in the electron transport and ATP synthase complexes of the inner mitochondrial membrane, were down-regulated. Cardiac ATP was correspondingly reduced. The data suggest that decreased expression of PGC-1α and its target genes result in decreased cardiac ATP levels, which may explain the decrease in myocardial contractile function caused by chronic EtOH intake. This model recapitulates important features of human alcoholic cardiomyopathy and illustrates a potentially important pathophysiologic link between cardiac lipid metabolism and function.
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http://dx.doi.org/10.1016/j.yjmcc.2013.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3647020PMC
June 2013

The adverse effects of alcohol on vitamin A metabolism.

Nutrients 2012 05 7;4(5):356-71. Epub 2012 May 7.

Department of Medicine and Institute of Human Nutrition, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.

The objective of this review is to explore the relationship between alcohol and the metabolism of the essential micronutrient, vitamin A; as well as the impact this interaction has on alcohol-induced disease in adults. Depleted hepatic vitamin A content has been reported in human alcoholics, an observation that has been confirmed in animal models of chronic alcohol consumption. Indeed, alcohol consumption has been associated with declines in hepatic levels of retinol (vitamin A), as well as retinyl ester and retinoic acid; collectively referred to as retinoids. Through the use of animal models, the complex interplay between alcohol metabolism and vitamin A homeostasis has been studied; the reviewed research supports the notion that chronic alcohol consumption precipitates a decline in hepatic retinoid levels through increased breakdown, as well as increased export to extra-hepatic tissues. While the precise biochemical mechanisms governing alcohol's effect remain to be elucidated, its profound effect on hepatic retinoid status is irrefutable. In addition to a review of the literature related to studies on tissue retinoid levels and the metabolic interactions between alcohol and retinoids, the significance of altered hepatic retinoid metabolism in the context of alcoholic liver disease is also considered.
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http://dx.doi.org/10.3390/nu4050356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3367262PMC
May 2012

Structural and functional development of the respiratory system in a newborn marsupial with cutaneous gas exchange.

Physiol Biochem Zool 2011 Nov-Dec;84(6):634-49. Epub 2011 Oct 14.

Adaptational and Evolutionary Respiratory Physiology Laboratory, School of Zoology, University of Tasmania, Hobart, Tasmania 7005, Australia.

Marsupials are born with structurally immature lungs and rely, to varying degrees, on cutaneous gas exchange. With a gestation of 13 d and a birth weight of 13 mg, the fat-tailed dunnart (Sminthopsis crassicaudata) is one of the smallest and most immature marsupial newborns. We determined that the skin is almost solely responsible for gas exchange in the early neonatal period. Indeed, fewer than 35% of newborn dunnarts were observed to make any respiratory effort on the day of birth, with pulmonary ventilation alone not meeting the demand for oxygen until approximately 35 d postpartum. Despite the lack of pulmonary ventilation, the phrenic nerve had made contact with the diaphragm, and the respiratory epithelium was sufficiently developed to support gas exchange on the day of birth. Both type I and type II (surfactant-producing) alveolar epithelial cells were present, with fewer than 7% of the cells resembling undifferentiated alveolar epithelial precursor cells. The type I epithelial cells did, however, display thickened cytoplasmic extensions, leading to a high diffusion distance for oxygen. In addition, the architecture of the lung was immature, resembling the early canalicular stage, with alveolarization not commencing until 45 d postpartum. The pulmonary vasculature was also immature, with a centrally positioned single-capillary layer not evident until 100 d postbirth. These structural limitations may impede efficient pulmonary gas exchange, forcing the neonatal fat-tailed dunnart to rely predominately on its skin, a phenomenon supported by a low metabolic rate and small size.
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http://dx.doi.org/10.1086/662557DOI Listing
May 2012

Distinct populations of hepatic stellate cells in the mouse liver have different capacities for retinoid and lipid storage.

PLoS One 2011 16;6(9):e24993. Epub 2011 Sep 16.

Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America.

Unlabelled: Hepatic stellate cell (HSC) lipid droplets are specialized organelles for the storage of retinoid, accounting for 50-60% of all retinoid present in the body. When HSCs activate, retinyl ester levels progressively decrease and the lipid droplets are lost. The objective of this study was to determine if the HSC population in a healthy, uninjured liver demonstrates heterogeneity in its capacity for retinoid and lipid storage in lipid droplets. To this end, we utilized two methods of HSC isolation, which leverage distinct properties of these cells, including their vitamin A content and collagen expression. HSCs were isolated either from wild type (WT) mice in the C57BL/6 genetic background by flotation in a Nycodenz density gradient, followed by fluorescence activated cell sorting (FACS) based on vitamin A autofluorescence, or from collagen-green fluorescent protein (GFP) mice by FACS based on GFP expression from a GFP transgene driven by the collagen I promoter. We show that GFP-HSCs have: (i) increased expression of typical markers of HSC activation; (ii) decreased retinyl ester levels, accompanied by reduced expression of the enzyme needed for hepatic retinyl ester synthesis (LRAT); (iii) decreased triglyceride levels; (iv) increased expression of genes associated with lipid catabolism; and (v) an increase in expression of the retinoid-catabolizing cytochrome, CYP2S1.

Conclusion: Our observations suggest that the HSC population in a healthy, uninjured liver is heterogeneous. One subset of the total HSC population, which expresses early markers of HSC activation, may be "primed" and ready for rapid response to acute liver injury.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0024993PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3174979PMC
February 2012

Altered hepatic lipid metabolism in C57BL/6 mice fed alcohol: a targeted lipidomic and gene expression study.

J Lipid Res 2011 Nov 19;52(11):2021-31. Epub 2011 Aug 19.

Department of Medicine, Columbia University, New York, NY 10032, USA.

Chronic alcohol consumption is associated with fatty liver disease in mammals. The object of this study was to gain an understanding of dysregulated lipid metabolism in alcohol-fed C57BL/6 mice using a targeted lipidomic approach. Liquid chromatography tandem mass spectrometry was used to analyze several lipid classes, including free fatty acids, fatty acyl-CoAs, fatty acid ethyl esters, sphingolipids, ceramides, and endocannabinoids, in plasma and liver samples from control and alcohol-fed mice. The interpretation of lipidomic data was augmented by gene expression analyses for important metabolic enzymes in the lipid pathways studied. Alcohol feeding was associated with i) increased hepatic free fatty acid levels and decreased fatty acyl-CoA levels associated with decreased mitochondrial fatty acid oxidation and decreased fatty acyl-CoA synthesis, respectively; ii) increased hepatic ceramide levels associated with higher levels of the precursor molecules sphingosine and sphinganine; and iii) increased hepatic levels of the endocannabinoid anandamide associated with decreased expression of its catabolic enzyme fatty acid amide hydrolase. The unique combination of lipidomic and gene expression analyses allows for a better mechanistic understanding of dysregulated lipid metabolism in the development of alcoholic fatty liver disease.
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http://dx.doi.org/10.1194/jlr.M017368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3196234PMC
November 2011

Hepatic metabolism of retinoids and disease associations.

Biochim Biophys Acta 2012 Jan 1;1821(1):124-36. Epub 2011 Jul 1.

Department of Medicine, College of Physcians and Surgeons, Columbia University, 630 W, 168th St, New York, NY 10032, USA.

The liver is the most important tissue site in the body for uptake of postprandial retinoid, as well as for retinoid storage. Within the liver, both hepatocytes and hepatic stellate cells (HSCs) are importantly involved in retinoid metabolism. Hepatocytes play an indispensable role in uptake and processing of dietary retinoid into the liver, and in synthesis and secretion of retinol-binding protein (RBP), which is required for mobilizing hepatic retinoid stores. HSCs are the central cellular site for retinoid storage in the healthy animal, accounting for as much as 50-60% of the total retinoid present in the entire body. The liver is also an important target organ for retinoid actions. Retinoic acid is synthesized in the liver and can interact with retinoid receptors which control expression of a large number of genes involved in hepatic processes. Altered retinoid metabolism and the accompanying dysregulation of retinoid signaling in the liver contribute to hepatic disease. This is related to HSCs, which contribute significantly to the development of hepatic disease when they undergo a process of cellular activation. HSC activation results in the loss of HSC retinoid stores and changes in extracellular matrix deposition leading to the onset of liver fibrosis. An association between hepatic disease progression and decreased hepatic retinoid storage has been demonstrated. In this review article, we summarize the essential role of the liver in retinoid metabolism and consider briefly associations between hepatic retinoid metabolism and disease. This article is part of a Special Issue entitled Retinoid and Lipid Metabolism.
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http://dx.doi.org/10.1016/j.bbalip.2011.06.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3488285PMC
January 2012

Vitamin A metabolism: an update.

Nutrients 2011 01;3(1):63-103

Department of Medicine and Institute of Human Nutrition, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.

Retinoids are required for maintaining many essential physiological processes in the body, including normal growth and development, normal vision, a healthy immune system, normal reproduction, and healthy skin and barrier functions. In excess of 500 genes are thought to be regulated by retinoic acid. 11-cis-retinal serves as the visual chromophore in vision. The body must acquire retinoid from the diet in order to maintain these essential physiological processes. Retinoid metabolism is complex and involves many different retinoid forms, including retinyl esters, retinol, retinal, retinoic acid and oxidized and conjugated metabolites of both retinol and retinoic acid. In addition, retinoid metabolism involves many carrier proteins and enzymes that are specific to retinoid metabolism, as well as other proteins which may be involved in mediating also triglyceride and/or cholesterol metabolism. This review will focus on recent advances for understanding retinoid metabolism that have taken place in the last ten to fifteen years.
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http://dx.doi.org/10.3390/nu3010063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3042718PMC
January 2011

Early development of the primordial mammalian diaphragm and cellular mechanisms of nitrofen-induced congenital diaphragmatic hernia.

Birth Defects Res A Clin Mol Teratol 2010 Jan;88(1):15-24

Department of Physiology, University of Alberta, Edmonton, Canada.

Congenital diaphragmatic hernia (CDH) is a frequently occurring cause of neonatal respiratory distress and is associated with high mortality and long-term morbidity. Evidence from animal models suggests that CDH has its origins in the malformation of the pleuroperitoneal fold (PPF), a key structure in embryonic diaphragm formation. The aims of this study were to characterize the embryogenesis of the PPF in rats and humans, and to determine the potential mechanism that leads to abnormal PPF development in the nitrofen model of CDH. Analysis of rat embryos, and archived human embryo sections, allowed the timeframe of PPF formation to be determined for both species, thus delineating a critical period of diaphragm development in relation to CDH. Experiments on nitrofen-exposed NIH 3T3 cells in vitro led us to hypothesize that nitrofen might cause diaphragmatic hernia in vivo by two possible mechanisms: through decreased cell proliferation or by inducing apoptosis. Data from nitrofen-exposed rat embryos indicates that the primary mechanism of nitrofen teratogenesis in the PPF is through decreased cell proliferation. This study provides novel insight into the embryogenesis of the PPF in rats and humans, and it indicates that impaired cell proliferation might contribute to abnormal diaphragm development in the nitrofen model of CDH.
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http://dx.doi.org/10.1002/bdra.20613DOI Listing
January 2010