William S Blaner

Columbia University, New York, New York, United States

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Publications (220)1157.44 Total impact

  • Robin D Clugston · Madeleine A Gao · William S Blaner
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    ABSTRACT: 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.
    Current Molecular Pharmacology 08/2015;
  • Nuttaporn Wongsiriroj · William S Blaner
    08/2015; 4(4):220-1. DOI:10.3978/j.issn.2304-3881.2015.07.06
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    ABSTRACT: Diacylglycerol O-acyltransferase 1 (DGAT1) catalyzes the final step of triglyceride synthesis, transferring an acyl group from acyl-CoA to diacylglycerol. DGAT1 also catalyzes the acyl-CoA-dependent formation of retinyl esters in vitro and in mouse intestine and skin. Although DGAT1 is expressed in both hepatocytes and hepatic stellate cells (HSCs), we reported genetic and nutritional studies that established that DGAT1 does not contribute to retinyl ester formation in the liver. We now have explored in more depth the role(s) of DGAT1 in hepatic retinoid metabolism and storage. Our data show that DGAT1 affects the cellular distribution between hepatocytes and HSCs of stored and newly absorbed dietary retinol. For livers of Dgat1-deficient mice, a greater percentage of stored retinyl ester is present in HSCs at the expense of hepatocytes. This is also true for newly absorbed oral [(3)H]retinol. These differences are associated with significantly increased expression, by 2.8-fold, of cellular retinol-binding protein, type I (RBP1) in freshly isolated HSCs from Dgat1-deficient mice, raising the possibility that RBP1, which contributes to retinol uptake into cells and retinyl ester synthesis, accounts for the differences. We further show that the retinyl ester-containing lipid droplets in HSCs are affected in Dgat1-null mice, being fewer in number but, on average, larger than in wild type (WT) HSCs. Finally, we demonstrate that DGAT1 affects experimentally induced HSC activation in vivo but that this effect is independent of altered retinoic acid availability or effects on gene expression. Our studies establish that DGAT1 has a role in hepatic retinoid storage and metabolism, but this does not involve direct actions of DGAT1 in retinyl ester synthesis.
    06/2015; 4(3):184-96. DOI:10.3978/j.issn.2304-3881.2014.12.02
  • Robin D Clugston · Li-Shin Huang · William S Blaner
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    ABSTRACT: 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.-Clugston, R. D., Huang, L.-S., Blaner, W. S. Chronic alcohol consumption has a biphasic effect on hepatic retinoid loss. © FASEB.
    The FASEB Journal 05/2015; 29(9). DOI:10.1096/fj.14-266296 · 5.04 Impact Factor
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    ABSTRACT: β-Apo-carotenoids, including β-apo-13-carotenone and β-apo-14’-carotenal, are potent retinoic acid receptor (RAR) antagonists in transactivation assays. We asked how these influence RAR-dependent processes in living cells. Initially, we explored the effects of β-apo-13-carotenone and β-apo-14’-carotenal on P19 cells, a mouse embryonal carcinoma cell line that differentiates into neurons when treated with all-trans-retinoic acid. Treatment of P19 cells with either compound failed to block all-trans-retinoic acid induced differentiation. Liquid chromatography tandem mass spectrometry studies, however, established that neither of these β-apo-carotenoids accumulates in P19 cells. All-trans-retinoic acid accumulated to high levels in P19 cells. This suggests that the uptake and metabolism of β-apo-carotenoids by some cells does not involve the same processes used for retinoids and that these may be cell type specific. We also investigated the effects of two β-apo-carotenoids on 3T3-L1 adipocyte marker gene expression during adipocyte differentiation. Treatment of 3T3-L1 adipocytes with either β-apo-13-carotenone or β-apo-10’-carotenoic acid, which lacks RAR antagonist activity, stimulated adipocyte marker gene expression. Neither blocked the inhibitory effects of a relatively large dose of exogenous all-trans-retinoic acid on adipocyte differentiation. Our data suggest that in addition to acting as transcriptional antagonists, some β-apo-carotenoids act through other mechanisms to influence 3T3-L1 adipocyte differentiation.
    Archives of Biochemistry and Biophysics 01/2015; 572. DOI:10.1016/j.abb.2015.01.009 · 3.02 Impact Factor
  • Shiva Raghuvanshi · Vanessa Reed · William S. Blaner · Earl H. Harrison
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    ABSTRACT: The intestine and liver are crucial organs for vitamin A uptake and storage. Liver accounts for 70% of total body retinoid stores. Vitamin A deficiency (VAD) is a major micronutrient deficiency around the world. The provitamin A carotenoid, β-carotene, is a significant source of vitamin A in the diet. β-Carotene 15,15′ oxygenase-1 (BCO1) and β-carotene 9′,10′ oxygenase-2 (BCO2) are the two known carotenoid cleavage enzymes in humans. BCO1 and BCO2 are highly expressed in liver and intestine. Hepatocytes and hepatic stellate cells are two main cell types involved in the hepatic metabolism of retinoids. Stellate-like cells in the intestine also show ability to store vitamin A. Liver is also known to accumulate carotenoids, however, their uptake, retention and metabolism in specific liver and intestinal cell types is still unknown. Hence, we studied the cellular and subcellular expression and localization of BCO1 and BCO2 proteins in rat liver and intestine. We demonstrate that both BCO1 and BCO2 proteins are localized in hepatocytes and mucosal epithelium. We also show that BCO1 is also highly expressed in hepatic stellate cells (HSC) and portal endothelial cells in liver. At the subcellular level in liver, BCO1 is found in cytosol, while BCO2 is found in mitochondria. In intestine, immunohistochemistry showed strong BCO1 immunoreactivity in the duodenum, particularly in Brunner’s glands. Both BCO1 and BCO2 showed diffuse presence along epithelia with strong immunoreactivity in endothelial cells and in certain epithelial cells which warrant further investigation as possible intestinal retinoid storage cells.
    Archives of Biochemistry and Biophysics 01/2015; 572. DOI:10.1016/j.abb.2014.12.024 · 3.02 Impact Factor
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    ABSTRACT: Unlabelled: Liver X receptors (LXRs) are determinants of hepatic stellate cell (HSC) activation and liver fibrosis. Freshly isolated HSCs from Lxrαβ(-/-) mice have increased lipid droplet (LD) size, but the functional consequences of this are unknown. Our aim was to determine whether LXRs link cholesterol to retinoid storage in HSCs and how this impacts activation. Primary HSCs from Lxrαβ(-/-) and wild-type mice were profiled by gene array during in vitro activation. Lipid content was quantified by high-performance liquid chromatography and mass spectroscopy. Primary HSCs were treated with nuclear receptor ligands, transfected with small interfering RNA and plasmid constructs, and analyzed by immunocytochemistry. Lxrαβ(-/-) HSCs have increased cholesterol and retinyl esters. The retinoid increase drives intrinsic retinoic acid receptor signaling, and activation occurs more rapidly in Lxrαβ(-/-) HSCs. We identify Rab18 as a novel retinoic acid-responsive, LD-associated protein that helps mediate stellate cell activation. Rab18 mRNA, protein, and membrane insertion increase during activation. Both Rab18 guanosine triphosphatase activity and isoprenylation are required for stellate cell LD loss and induction of activation markers. These phenomena are accelerated in Lxrαβ(-/-) HSCs, where there is greater retinoic acid flux. Conversely, Rab18 knockdown retards LD loss in culture and blocks activation, just like the functional mutants. Rab18 is also induced with acute liver injury in vivo. Conclusion: Retinoid and cholesterol metabolism are linked in stellate cells by the LD-associated protein Rab18. Retinoid overload helps explain the profibrotic phenotype of Lxrαβ(-/-) mice, and we establish a pivotal role for Rab18 GTPase activity and membrane insertion in wild-type stellate cell activation. Interference with Rab18 may have significant therapeutic benefit in ameliorating liver fibrosis. (Hepatology 2015;62:615-626.
    Hepatology 12/2014; 62(2). DOI:10.1002/hep.27645 · 11.06 Impact Factor
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    ABSTRACT: Retinoic acid signaling is required for maintaining a range of cellular processes, including cell differentiation, proliferation, and apoptosis. We investigated the actions of all-trans-retinoic acid (atRA) signaling in pancreatic β-cells of adult mice. atRA signaling was ablated in β-cells by overexpressing a dominant-negative retinoic acid receptor (RAR)-α mutant (RARdn) using an inducible Cre-Lox system under the control of the pancreas duodenal homeobox gene promoter. Our studies establish that hypomorphism for RAR in β-cells leads to an age-dependent decrease in plasma insulin in the fed state and in response to a glucose challenge. Glucose-stimulated insulin secretion was also impaired in islets isolated from mice expressing RARdn. Among genes that are atRA responsive, Glut2 and Gck mRNA levels were decreased in isolated islets from RARdn-expressing mice. Histologic analyses of RARdn-expressing pancreata revealed a decrease in β-cell mass and insulin per β-cell 1 mo after induction of the RARdn. Our results indicate that atRA signaling mediated by RARs is required in the adult pancreas for maintaining both β-cell function and mass, and provide insights into molecular mechanisms underlying these actions.-Brun, P.-J., Grijalva, A., Rausch, R., Watson, E., Yuen, J. J., Das, B. C., Shudo, K., Kagechika, H., Leibel, R. L., Blaner, W. S. Retinoic acid receptor signaling is required to maintain glucose-stimulated insulin secretion and β-cell mass.
    The FASEB Journal 11/2014; 29(2). DOI:10.1096/fj.14-256743 · 5.04 Impact Factor
  • Robin D Clugston · William S Blaner
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    ABSTRACT: 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. Zoo Biol. XX:XX-XX, 2014. © 2014 Wiley Periodicals, Inc.
    Zoo Biology 11/2014; 33(6). DOI:10.1002/zoo.21140 · 0.83 Impact Factor
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    ABSTRACT: Amphibian biology is intricate, and there are many inter-related factors that need to be understood before establishing successful Conservation Breeding Programs (CBPs). Nutritional needs of amphibians are highly integrated with disease and their husbandry needs, and the diversity of developmental stages, natural habitats, and feeding strategies result in many different recommendations for proper care and feeding. This review identifies several areas where there is substantial room for improvement in maintaining healthy ex situ amphibian populations specifically in the areas of obtaining and utilizing natural history data for both amphibians and their dietary items, achieving more appropriate environmental parameters, understanding stress and hormone production, and promoting better physical and population health. Using a scientific or research framework to answer questions about disease, nutrition, husbandry, genetics, and endocrinology of ex situ amphibians will improve specialists' understanding of the needs of these species. In general, there is a lack of baseline data and comparative information for most basic aspects of amphibian biology as well as standardized laboratory approaches. Instituting a formalized research approach in multiple scientific disciplines will be beneficial not only to the management of current ex situ populations, but also in moving forward with future conservation and reintroduction projects. This overview of gaps in knowledge concerning ex situ amphibian care should serve as a foundation for much needed future research in these areas. Zoo Biol. XX:XX-XX, 2014. © 2014 Wiley Periodicals, Inc.
    Zoo Biology 10/2014; 33(6). DOI:10.1002/zoo.21180 · 0.83 Impact Factor
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    ABSTRACT: Dietary carotenoids like β-carotene are converted within the body either to retinoid, via β-carotene-15,15'-dioxygenase (BCO1), or to β-apo-carotenoids, via β-carotene-9',10'-oxygenase 2 (BCO2). Some β-apo-carotenoids are potent antagonists of retinoic acid receptor (RAR)-mediated transcriptional regulation, which is required to assure normal heart development and functions. We established liquid chromatography tandem mass spectrometery (LC/MS/MS) methods for measuring concentrations of 10 β-apo-carotenoids in mouse plasma, liver and heart and assessed how these are influenced by Bco1-deficiency and β-carotene intake. Surprisingly, Bco1(-/-) mice had an increase in heart levels of retinol, nonesterified fatty acids, and ceramides and a decrease in heart triglycerides. These lipid changes were accompanied by elevations in levels of genes important to retinoid metabolism, specifically Rdh10 and Rbp4, as well as ones involved in lipid metabolism, including Pparg, Lpl, Cd36, Scd1 and Fas. We also obtained evidence of compromised heart function, as assessed by two-dimensional echocardiography, in Bco1(-/-) mice. However, the total absence of Bco1 did not substantially affect β-apo-carotenoid concentrations in heart. β-Carotene administration to matched Bco1-deficient and wild type mice elevated total β-apo-carotenal levels in heart, liver and plasma and total β-apo-carotenoic acid levels in liver. Thus, BCO1 modulates heart metabolism and function possibly by altering levels of cofactors required for the actions of nuclear hormone receptors.
    AJP Heart and Circulatory Physiology 09/2014; 307(11). DOI:10.1152/ajpheart.00548.2014 · 3.84 Impact Factor
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    ABSTRACT: Diacylglycerol acyltransferase 1 (DGAT1) catalyzes the final step in triglyceride synthesis, the conversion of diacylglycerol (DAG) to triglyceride. Dgat1−/− mice exhibit a number of beneficial metabolic effects including reduced obesity and improved insulin sensitivity and no known cardiac dysfunction. In contrast, failing human hearts have severely reduced DGAT1 expression associated with accumulation of DAGs and ceramides. To test whether DGAT1 loss alone affects heart function, we created cardiomyocyte-specific DGAT1 knock-out (hDgat1−/−) mice. hDgat1−/− mouse hearts had 95% increased DAG and 85% increased ceramides compared with floxed controls. 50% of these mice died by 9 months of age. The heart failure marker brain natriuretic peptide increased 5-fold in hDgat1−/− hearts, and fractional shortening (FS) was reduced. This was associated with increased expression of peroxisome proliferator-activated receptor α and cluster of differentiation 36. We crossed hDgat1−/− mice with previously described enterocyte-specific Dgat1 knock-out mice (hiDgat1−/−). This corrected the early mortality, improved FS, and reduced cardiac ceramide and DAG content. Treatment of hDgat1−/− mice with the glucagon-like peptide 1 receptor agonist exenatide also improved FS and reduced heart DAG and ceramide content. Increased fatty acid uptake into hDgat1−/− hearts was normalized by exenatide. Reduced activation of protein kinase Cα (PKCα), which is increased by DAG and ceramides, paralleled the reductions in these lipids. Our mouse studies show that loss of DGAT1 reproduces the lipid abnormalities seen in severe human heart failure.
    Journal of Biological Chemistry 08/2014; 289(43). DOI:10.1074/jbc.M114.601864 · 4.57 Impact Factor
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    ABSTRACT: The hepatic circadian clock plays a pivotal role in regulating major aspects of energy homeostasis and lipid metabolism. In this study, we show that RORγ robustly regulates the rhythmic expression of several lipid metabolic genes, including the insulin-induced gene 2a, Insig2a, elongation of very long chain fatty acids-like 3, Elovl3 and sterol 12α-hydroxylase, Cyp8b1, by enhancing their expression at ZT20-4. The time-dependent increase in their expression correlates with the rhythmic expression pattern of RORγ. The enhanced recruitment of RORγ to ROREs in their promoter region, increased histone acetylation, and reporter and mutation analysis support the concept that RORγ regulates the transcription of several lipid metabolic genes directly by binding ROREs in their promoter regulatory region. Consistent with the disrupted expression of a number of lipid metabolic genes, loss of RORγ reduced the level of several lipids in liver and blood in a ZT-preferred manner. Particularly the whole-body bile acid pool size was considerably reduced in RORγ−/− mice in part through its regulation of several Cyp genes. Similar observations were made in liver-specific RORγ-deficient mice. Altogether, our study indicates that RORγ functions as an important link between the circadian clock and the transcriptional regulation of several metabolic genes.
    Nucleic Acids Research 08/2014; 42(16). DOI:10.1093/nar/gku766 · 9.11 Impact Factor
  • Yang Li · Nuttaporn Wongsiriroj · William S Blaner
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    ABSTRACT: Since their discovery over a century ago, retinoids have been the most studied of the fat-soluble vitamins. Unlike most vitamins, retinoids are stored at relatively high concentrations in the body to buffer against nutritional insufficiency. Until recently, it was thought that the sole important retinoid delivery pathway to tissues involved retinol bound to retinol-binding protein (RBP4). More recent findings, however, indicate that retinoids can be delivered to tissues through multiple overlapping delivery pathways, involving chylomicrons, very low density lipoprotein (VLDL) and low density lipoprotein (LDL), retinoic acid bound to albumin, water soluble β-glucuronides of retinol and retinoic acid, and provitamin A carotenoids. This review will focus on explaining this evolving understanding of retinoid metabolism and transport within the body.
    06/2014; 3(3):126-39. DOI:10.3978/j.issn.2304-3881.2014.05.04
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    ABSTRACT: Background: Lipolysis regulates energy homeostasis through the hydrolysis of intracellular triglycerides and the release of fatty acids for use as energy substrates or lipid mediators in cellular processes. Genes encoding proteins that regulate energy homeostasis through lipolysis are thus likely to play an important role in determining susceptibility to metabolic disorders. Methods: We sequenced 12 lipolytic-pathway genes in Old Order Amish participants whose fasting serum triglyceride levels were at the extremes of the distribution and identified a novel 19-bp frameshift deletion in exon 9 of LIPE, encoding hormone-sensitive lipase (HSL), a key enzyme for lipolysis. We genotyped the deletion in DNA from 2738 Amish participants and performed association analyses to determine the effects of the deletion on metabolic traits. We also obtained biopsy specimens of abdominal subcutaneous adipose tissue from 2 study participants who were homozygous for the deletion (DD genotype), 10 who were heterozygous (ID genotype), and 7 who were noncarriers (II genotype) for assessment of adipose histologic characteristics, lipolysis, enzyme activity, cytokine release, and messenger RNA (mRNA) and protein levels. Results: Carriers of the mutation had dyslipidemia, hepatic steatosis, systemic insulin resistance, and diabetes. In adipose tissue from study participants with the DD genotype, the mutation resulted in the absence of HSL protein, small adipocytes, impaired lipolysis, insulin resistance, and inflammation. Transcription factors responsive to peroxisome-proliferator-activated receptor γ (PPAR-γ) and downstream target genes were down-regulated in adipose tissue from participants with the DD genotype, altering the regulation of pathways influencing adipogenesis, insulin sensitivity, and lipid metabolism. Conclusions: These findings indicate the physiological significance of HSL in adipocyte function and the regulation of systemic lipid and glucose homeostasis and underscore the severe metabolic consequences of impaired lipolysis. (Funded by the National Institutes of Health and others).
    New England Journal of Medicine 05/2014; 370(24). DOI:10.1056/NEJMoa1315496 · 55.87 Impact Factor
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    ABSTRACT: Insulin signaling in osteoblasts has been shown recently to contribute to whole-body glucose homeostasis in animals fed a normal diet; however, it is unknown whether bone contributes to the insulin resistance that develops in animals challenged by a high-fat diet (HFD). Here, we evaluated the consequences of osteoblast-specific overexpression of or loss of insulin receptor in HFD-fed mice. We determined that the severity of glucose intolerance and insulin resistance that mice develop when fed a HFD is in part a consequence of osteoblast-dependent insulin resistance. Insulin resistance in osteoblasts led to a decrease in circulating levels of the active form of osteocalcin, thereby decreasing insulin sensitivity in skeletal muscle. Insulin resistance developed in osteoblasts as the result of increased levels of free saturated fatty acids, which promote insulin receptor ubiquitination and subsequent degradation. Together, these results underscore the involvement of bone, among other tissues, in the disruption of whole-body glucose homeostasis resulting from a HFD and the involvement of insulin and osteocalcin cross-talk in glucose intolerance. Furthermore, our data indicate that insulin resistance develops in bone as the result of lipotoxicity-associated loss of insulin receptors.
    The Journal of clinical investigation 03/2014; 124(4). DOI:10.1172/JCI72323 · 13.22 Impact Factor
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    ABSTRACT: The literature indicates that retinoids can influence the metabolism and actions of xenobiotics and conversely that xenobiotics can influence the metabolism and actions of retinoids. We were interested in understanding the degree to which hepatic retinoid stores, accumulated over a lifetime, affect xenobiotic metabolism and actions. To investigate this, we induced liver injury through administration of the hepatotoxin thioacetamide (TAA) to chow fed wild type (WT) mice and lecithin:retinol acyltransferase-deficient (Lrat(-/-)) mice that are genetically unable to accumulate hepatic retinoid stores. Within 48 h of TAA-treatment, WT mice develop liver injury as evidenced by focal necrotic areas and increases in serum ALT activity and myeloperoxidase activity in hepatic parenchyma. Simultaneously, features of hepatic encephalopathy develop, as evidenced by a 25% increase in blood ammonia and a 3-fold reduction of blood glucose levels. This is accompanied by reduced hepatic glutathione, and increased thiobarbituric acid reactive substances (TBARS), protein carbonyl and sulfhydryl groups, and increased cytochrome P450-catalyzed hydroxylation activity and flavin-containing monooxygenase (FMO) activity in microsomes prepared from WT liver. Strikingly, none of these TAA-induced effects were observed for matched Lrat(-/-) mice. To confirm that TAA hepatotoxicity depends on retinoid availability, we administered, over 48 h, 4 oral doses of 3,000 IU retinyl acetate each to the mice. This led to the development of hepatotoxicity in Lrat(-/-) mice that was similar in extent to that observed in WT mice. Our findings establish that endogenous hepatic retinoid stores can modulate the toxicity of TAA in mice.
    Toxicological Sciences 03/2014; 139(2). DOI:10.1093/toxsci/kfu045 · 3.85 Impact Factor
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    ABSTRACT: CD36 is a scavenger receptor with multiple ligands and cellular functions, including facilitating cellular uptake of free fatty acids (FFA). Chronic alcohol consumption increases hepatic CD36 expression, leading to the hypothesis that this promotes uptake of circulating FFA, 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 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.
    The Journal of Lipid Research 11/2013; 55(2). DOI:10.1194/jlr.M041863 · 4.42 Impact Factor
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    ABSTRACT: Approximately 80-90% of all retinoid in the body is stored as retinyl ester (RE) in liver. Adipose too contributes significantly to RE storage. Employing genetic and nutritional interventions we explored factors that regulate RE accumulation in liver and adipose and how these influence levels of retinoic acid (RA) and RA-responsive gene expression. Our data establish that an acyl-CoA:retinol acyltransferase (ARAT) activity is not involved in RE synthesis in the liver, even when mice are stressed nutritionally upon feeding of a 25-fold excess retinol diet or upon ablation of cellular retinol-binding protein, type I (CRBPI). Unlike liver, where lecithin:retinol acyltransferase (LRAT) is responsible for all RE synthesis, this is not true for adipose where Lrat-deficient mice display elevated RE concentrations. However, when CrbpI is also absent, these resemble wild type levels, suggesting a role for CrbpI in RE accumulation in adipose. Although expression of several RA-responsive genes is elevated in Lrat-deficient liver, employing a sensitive liquid chromatography tandem mass spectrometry protocol, we did not detect elevated concentrations of all-trans-retinoic acid. The elevated RA-responsive gene expression was associated with elevated hepatic triglyceride levels and decreased expression of Pparδ and its Pdk4 target, suggesting a role for RA in these processes in vivo.
    The Journal of Lipid Research 11/2013; 55(1). DOI:10.1194/jlr.M043844 · 4.42 Impact Factor
  • Cancer Research 08/2013; 73(8 Supplement):181-181. DOI:10.1158/1538-7445.AM2013-181 · 9.33 Impact Factor

Publication Stats

8k Citations
1,157.44 Total Impact Points


  • 1982–2015
    • Columbia University
      • • Department of Medicine
      • • College of Physicians and Surgeons
      • • Institute of Human Nutrition
      • • Division of Digestive and Liver Disease
      New York, New York, United States
  • 1985–2014
    • CUNY Graduate Center
      New York City, New York, United States
  • 2007–2012
    • Case Western Reserve University
      • Department of Pharmacology
      Cleveland, OH, United States
  • 2005
    • Mount Sinai School of Medicine
      • Department of Medicine
      Manhattan, New York, United States
  • 2001
    • Karolinska Institutet
      • Institute of Environmental Medicine - IMM
      Сольна, Stockholm, Sweden
  • 1986–1988
    • New York Medical College
      • Department of Medicine
      New York City, New York, United States
    • Kaiser Permanente
      Oakland, California, United States
  • 1987
    • University of Hawaiʻi at Mānoa
      Honolulu, Hawaii, United States