Joseph Napoli

Joseph Napoli
University of California, Berkeley | UCB · Department of Nutritional Science and Toxicology

PhD

About

243
Publications
15,921
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12,424
Citations
Additional affiliations
July 1999 - present
University of California, Berkeley
Position
  • Professor
July 1999 - present
University of Berkley
Position
  • Professor (Full)

Publications

Publications (243)
Article
Full-text available
This review addresses the fasting vs. re-feeding effects of retinoic acid (RA) biosynthesis and functions, and sexually dimorphic RA actions. It also discusses other understudied topics essential for understanding RA activities—especially interactions with energy-balance-regulating hormones, including insulin and glucagon, and sex hormones. This re...
Article
Full-text available
The retinol dehydrogenase Rdh10 catalyzes the rate-limiting reaction that converts retinol into retinoic acid (RA), an autacoid that regulates energy balance and reduces adiposity. Skeletal muscle contributes to preventing adiposity, by consuming nearly half the energy of a typical human. We report sexually dimorphic differences in energy metabolis...
Preprint
Among others, the retinol dehydrogenase Rdh10 catalyzes the rate-limiting reaction that converts retinol into retinoic acid (RA), an autacoid that regulates energy balance and suppresses adiposity. Relative to WT, Rdh10+/- males experienced reduced fatty-acid oxidation, glucose intolerance and insulin resistance. Running endurance decreased 40%. Rd...
Chapter
Cellular retinoid-binding proteins (BP) chaperone retinol through esterification, conversion of retinol into retinal, reduction of retinal, conversion of retinal into all-trans-retinoic acid (ATRA), and ATRA to catabolism. They also deliver ATRA to nuclear receptors and mediate non-genomic ATRA actions. These retinoid-specific binding-proteins incl...
Article
We report a high-performance liquid chromatography/tandem mass spectrometry (HPLC-MS/MS) assay to quantify without derivatizaton dehyroepiandrosterone (DHEA), 17β-estradiol (E2), testosterone (T), and their sulfates in serum and tissues. This assay functions well with multiple adipose depots, a previously unattained analysis. To delipidate and faci...
Article
Full-text available
RDH1 is one of the several enzymes that catalyze the first of the two reactions to convert retinol into all-trans-retinoic acid (atRA). Here, we show that Rdh1-null mice fed a low-fat diet gain more weight as adiposity (17% males, 13% females) than wild-type mice by 20 weeks old, despite neither consuming more calories nor decreasing activity. Gluc...
Article
Full-text available
The balance of effector versus regulatory T cells (Tregs) controls inflammation in numerous settings, including multiple sclerosis (MS). Here we show that memory phenotype CD4 ⁺ T cells infiltrating the central nervous system during experimental autoimmune encephalomyelitis (EAE), a widely studied animal model of MS, expressed high levels of mRNA f...
Article
Full-text available
Fluconazole-induced alopecia is a significant problem for patients receiving long-term therapy. We evaluated the hair-cycle changes of fluconazole in a rat model and investigated potential molecular mechanisms. Plasma and tissue levels of retinoic acid were not found causal. Human patients with alopecia attributed to fluconazole also underwent deta...
Article
Full-text available
Pharmacological dosing of all-trans-retinoic acid (atRA) controls adiposity in rodents by inhibiting adipogenesis and inducing fatty acid oxidation. Retinol dehydrogenases (Rdh) catalyze the first reaction that activate retinol into atRA. This study examined post-natal contributions of Rdh10 to atRA biosynthesis and physiological functions of endog...
Article
Full-text available
All-trans-retinoic acid (RA) inhibits adipogenesis in established preadipocyte cell lines. Dosing pharmacological amounts of RA reduces weight gain in mice fed a high-fat diet, i.e. counteracts diet-induced obesity (DIO). The aldehyde dehydrogenase Raldh1 (Aldh1a1) functions as one of three enzymes that converts the retinol metabolite retinal into...
Article
Cellular binding-proteins (BP), including CRBP1, CRBP2, CRABP1, CRABP2, and FABP5, shepherd the poorly aqueous soluble retinoids during uptake, metabolism and function. Holo-BP promote efficient use of retinol, a scarce but essential nutrient throughout evolution, by sheltering it and its major metabolite all-trans-retinoic acid from adventitious i...
Chapter
Multiple binding and transport proteins facilitate many aspects of retinoid biology through effects on retinoid transport, cellular uptake, metabolism, and nuclear delivery. These include the serum retinol binding protein sRBP (aka Rbp4), the plasma membrane sRBP receptor Stra6, and the intracellular retinoid binding-proteins such as cellular retin...
Article
Rationale: Immune-modulating drugs that target myeloid-derived suppressor cells or stimulate Natural Killer T-cells have been shown to reduce mycobacterial loads in tuberculosis. Objectives: We aimed to determine if a combination of these drugs as adjunct immunotherapy to conventional antibiotic treatment could also increase therapeutic efficacy...
Article
Chronic intestinal inflammation accompanies familial adenomatous polyposis (FAP) and is a major risk factor for colorectal cancer in patients with this disease, but the cause of such inflammation is unknown. Since retinoic acid (RA) plays a critical role in maintaining immune homeostasis in the intestine, we hypothesized that altered RA metabolism...
Article
Although all-trans-retinoic acid (atRA) is a key regulator of intestinal immunity, its role in colorectal cancer (CRC) is unknown. We found that mice with colitis-associated CRC had a marked deficiency in colonic atRA due to alterations in atRA metabolism mediated by microbiota-induced intestinal inflammation. Human ulcerative colitis (UC), UC-asso...
Chapter
This chapter discusses newly detected retinoid metabolic processes in lipid droplets (LDs) and presents models of potential retinoid metabolons in LDs, which remain to be tested. LDs can serve as one intracellular site of activating retinol into the autacoid (locally-acting molecule, or "local hormone") retinoic acid (RA). The possible function of...
Article
We report an UHPLC-MS/MS to quantify all-trans-retinal in biological samples of limited size (15-35 mg), which is especially advantageous for use with adipose. To facilitate recovery, retinal and the internal standard 3,4-didehydroretinal were derivatized in situ into their O-ethyloximes. UHPLC resolution combined with high sensitivity and specific...
Article
Full-text available
All-trans-retinoic acid (atRA), an autocoid derived from retinol (vitamin A), regulates energy balance and reduces adiposity. We show that energy status regulates atRA biosynthesis at the rate-limiting step, catalyzed by retinol dehydrogenases (Rdh). Six hr after re-feeding, Rdh1 expression decreased 80-90% in liver and brown adipose tissue and Rdh...
Article
Full-text available
Brown adipose tissue (BAT) possesses the inherent ability to dissipate metabolic energy as heat through uncoupled mitochondrial respiration. An essential component of the mitochondrial electron transport chain is coenzyme Q (CoQ). While cells synthesize CoQ mostly endogenously, exogenous supplementation with CoQ has been successful as a therapy for...
Article
The vitamin A metabolite retinoic acid (RA) has been reported to suppress Th1 responses and enhance Th2 responses. Here we investigated whether differences in vitamin A metabolism could underlie the differences between C57BL/6 and BALB/c mice, which are reportedly seen as Th1 and Th2 responders, respectively. BALB/c mice were shown to have higher i...
Article
Full-text available
To determine the metabolic effects of grapefruit juice consumption we established a model in which C57Bl/6 mice drank 25-50% sweetened GFJ, clarified of larger insoluble particles by centrifugation (cGFJ), ad libitum as their sole source of liquid or isocaloric and sweetened water. cGFJ and control groups consumed similar amounts of liquids and cal...
Article
Full-text available
Endometriosis is characterized by the presence of endometrial glands and stroma in extra-uterine sites. Our objective was to determine if endometriotic lesions (EL) from women with endometriosis have altered retinoid levels in comparison to their eutopic endometrium, and to test the hypothesis that defects in all-trans retinoic acid (ATRA) biosynth...
Article
Full-text available
The relationship between dietary vitamin A and all-trans-retinoic acid levels in serum and tissues had not been quantified. We determined the impact of dietary vitamin A on retinoid levels in serum, liver, kidney, testis, and epididymal white adipose of five mouse strains: AKR/J; BALB/cByJ; C3H/HeJ; C57BL/6J; 129S1/SvImJ. Retinoids were quantified...
Article
Full-text available
Host conditioning with total body irradiation (TBI) can potently augment adoptive T cell (ACT) immunotherapies by removal of sinks for homeostatic cytokines such as IL-7 and IL-15, depletion of CD4+ Tregs, and liberation of endogenous toll like-receptor agonists. Clinically, TBI-conditioning prior to ACT has been associated with durable complete re...
Article
Full-text available
Dendritic cells (DCs) comprise distinct populations with specialized immune-regulatory functions. However, the environmental factors that determine the differentiation of these subsets remain poorly defined. Here, we report that retinoic acid (RA), a vitamin A derivative, controls the homeostasis of pre-DC (precursor of DC)-derived splenic CD11b(+)...
Article
Retinol (ROL) and its biologically active metabolite, all-trans retinoic acid (ATRA), are essential for a number of reproductive processes. However, there is a paucity of information regarding their roles in ovarian folliculogenesis, oocyte maturation, and early embryogenesis. The objectives of this study were to quantify and compare peripheral pla...
Article
Full-text available
Rdh10 catalyzes the first step of all-trans-retinoic acid biogenesis physiologically, conversion of retinol into retinal. We show that Rdh10 associates with mitochondria/MAM in the absence of lipid droplet biosynthesis, but relocates to lipid droplets during acyl ester biosynthesis. Targeting to lipid droplets requires the thirty-two N-terminal res...
Article
Full-text available
Alopecia areata (AA) is an autoimmune disease that attacks anagen hair follicles. Gene array in graft-induced C3H/HeJ mice revealed that genes involved in retinoic acid (RA) synthesis were increased, whereas RA degradation genes were decreased in AA compared with sham controls. This was confirmed by immunohistochemistry in biopsies from patients wi...
Article
Full-text available
While vitamin A has been implicated in host resistance to infectious disease, little is known about the role of vitamin A and its active metabolite, retinoic acid (RA) in host defenses against cancer. Here, we show that local RA production within the tumor microenvironment (TME) is increased up to 5-fold as compared with naïve surrounding tissue, w...
Article
Retinoic acid (RA) signaling is necessary for proper patterning and morphogenesis during embryonic development. Tissue-specific RA signaling requires precise spatial and temporal synthesis of RA from retinal by retinaldehyde dehydrogenases (Raldh) and the conversion of retinol to retinal by retinol dehydrogenases (Rdh) of the short-chain dehydrogen...
Article
Cellular retinol-binding protein, type 1 (Crbp1), chaperones retinyl ester (RE) biosynthesis catalyzed by lecithin:retinol acyltransferase (LRAT). We monitored the subcellular loci of LRAT and Crbp1 before and during RE biosynthesis, and compared the results to diacylglycerol:acyltransferase type 2 (DGAT2) during triacylglycerol biosynthesis in thr...
Article
All-trans-retinoic acid (atRA) has been implicated in the local regulation of scleral proteoglycan synthesis in vivo. The purpose of the present study was to identify the enzymes involved in the synthesis of atRA during visually guided ocular growth, the cells involved in modulation of atRA biosynthesis in the choroid, and the effect of choroid-der...
Article
All-trans-retinoic acid (atRA) serves essential functions during embryogenesis and throughout postnatal vertebrate life. Insufficient or excess atRA causes teratogenic and/or toxic effects in the developing embryo: interference with atRA biosynthesis or signaling likely underlies some forms of cancer. Many symptoms of vitamin A (atRA precursor) def...
Chapter
Use of retinoid binding proteins as substrates for identifying enzymes of retinoid metabolism has revealed compelling new candidates (e.g. lecitin:retinol acyltransferase [LRAT], intestinal microsomal retinal reductase, retinol dehydrogenase [RDH]), and has redirected attention away from historical candidates (intestinal cytosolic retinal reductase...
Article
Full-text available
Cellular retinol-binding protein type I (CrbpI), encoded by Rpb1, serves as a chaperone of retinol homeostasis, but its physiological effects remain incompletely understood. We show here that the Rbp1−/− mouse has disrupted retinoid homeostasis in multiple tissues, with abnormally high 9-cis-retinoic acid (9cRA), a pancreas autacoid that attenuates...
Article
All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes. Epithelial differentiation and its relationship to cancer, and embryogenesis have typified intense areas of interest into atRA function. Recently, however, interest in atRA action in the nervous system, the immune system, energy bala...
Article
Gut-associated dendritic cells (DC) metabolize vitamin A into all-trans retinoic acid (RA), which is required to induce lymphocytes to localize to the gastrointestinal tract and promotes the differentiation of Foxp3+ regulatory T cells and IgA antibody-secreting cells. We investigated whether RA functions in a positive-feedback loop in DC to induce...
Article
Cellular retinol binding-protein I (CRBPI) and cellular retinol binding-protein II (CRBPII) serve as intracellular retinoid chaperones that bind retinol and retinal with high affinity and facilitate substrate delivery to select enzymes that catalyze retinoic acid (RA) and retinyl ester biosynthesis. Recently, 9-cis-RA has been identified in vivo in...
Article
Full-text available
All-trans-retinoic acid (atRA) stimulates neurogenesis, dendritic growth of hippocampal neurons, and higher cognitive functions, such as spatial learning and memory formation. Although astrocyte-derived atRA has been considered a key factor in neurogenesis, little direct evidence identifies hippocampus cell types and the enzymes that biosynthesize...
Article
Full-text available
All-trans retinoic acid protects against the development of HIV-associated nephropathy (HIVAN) in HIV-1 transgenic mice (Tg26). In vitro, all-trans retinoic acid inhibits HIV-induced podocyte proliferation and restores podocyte differentiation markers by activating its receptor-α (RARα). Here, we report that Am580, a water-soluble RARα-specific ago...
Article
Full-text available
The growth plate contains resting and proliferating chondrocytes in its upper zones (UGP) and maturing and hypertrophic chondrocytes in its lower zones (LGP), but the mechanisms by which it operates to sustain skeletal growth are not fully clear. Retinoid signaling was previously found to be nearly absent in UGP, but to be much stronger in LGP coin...
Article
Full-text available
The all-trans-retinoic acid (atRA) isomer, 9-cis-retinoic acid (9cRA), activates retinoic acid receptors (RARs) and retinoid X receptors (RXRs) in vitro. RARs control multiple genes, whereas RXRs serve as partners for RARs and other nuclear receptors that regulate metabolism. Physiological function has not been determined for 9cRA, because it has n...
Data
Low magnification image of a renal coronal section. Paraffin-embedded 5-µm cross sections were obtained through the mid-line of the kidney at the level of the renal pelvis. This image is a composite of three Hematoxylin & Eosin stained images from the surface of the kidney to the outer portion of the renal medulla. 100×. (2.18 MB EPS)
Data
Peptide Annotation Data (6.92 MB XLS)
Article
Full-text available
Background: Numerous metabolic pathways have been implicated in diabetes-induced renal injury, yet few studies have utilized unbiased systems biology approaches for mapping the interconnectivity of diabetes-dysregulated proteins that are involved. We utilized a global, quantitative, differential proteomic approach to identify a novel retinoic acid...
Article
Numerous physiological processes require retinoids, including development, nervous system function, immune responsiveness, proliferation, differentiation, and all aspects of reproduction. Reliable retinoid quantification requires suitable handling and, in some cases, resolution of geometric isomers that have different biological activities. Here we...
Article
Hirschsprung disease is a serious disorder of enteric nervous system (ENS) development caused by the failure of ENS precursor migration into the distal bowel. We now demonstrate that retinoic acid (RA) is crucial for GDNF-induced ENS precursor migration, cell polarization and lamellipodia formation, and that vitamin A depletion causes distal bowel...
Article
All-trans-retinoic acid (atRA) supports embryonic development, central nervous system function, and the immune response. atRA initiates neurogenesis and dendritic growth in the hippocampus and is required for spatial memory; superphysiological atRA inhibits neurogenesis, causes teratology and/or embryo toxicity, and alters cognitive function and be...
Article
Vascular endothelial growth factor (VEGF) and endometrial angiogenesis play a critical role in successful embryonic implantation. Despite many studies of the effects of estrogen and progesterone on VEGF expression, its focal regulation at the site of implantation is unknown. Retinoic acid (RA) has been reported to regulate VEGF in a variety of cell...
Article
Extrinsic signals controlling generation of neocortical neurons during embryonic life have been difficult to identify. In this study we demonstrate that the dorsal forebrain meninges communicate with the adjacent radial glial endfeet and influence cortical development. We took advantage of Foxc1 mutant mice with defects in forebrain meningeal forma...
Article
Full-text available
RDH12 mutations are responsible for early-onset autosomal recessive retinal dystrophy, which results in profound retinal pathology and severe visual handicap in patients. To investigate the function of RDH12 within the network of retinoid dehydrogenases/reductases (RDHs) present in retina, we studied the retinal phenotype of Rdh12-deficient mice. I...
Article
Full-text available
The retinoic acid receptors alpha, beta and gamma (RARalpha, RARbeta and RARgamma) are nuclear hormone receptors that regulate fundamental processes during embryogenesis, but their roles in skeletal development and growth remain unclear. To study skeletal-specific RAR function, we created conditional mouse mutants deficient in RAR expression in car...
Article
Full-text available
Retinoic acid (RA) is a potent signaling molecule that is essential for many biological processes, and its levels are tightly regulated by mechanisms that are only partially understood. The synthesis of RA from its precursor retinol (vitamin A) is an important regulatory mechanism. Therefore, the esterification of retinol with fatty acyl moieties t...
Article
Full-text available
All-trans-retinoic acid stimulates dendritic growth in hippocampal neurons within minutes by activating mitogen-activated protein kinase and mTOR and increasing dendritic translation of calcium calmodulin-dependent protein kinase II alpha and the alpha-amino-3-hydroxyl-5-methyl-4-isoxazole propionate receptor subunit GluR1. Hippocampal neurons expr...
Article
We report robust HPLC/UV methods for quantifying retinyl esters (RE), retinol (ROL), and retinal (RAL) applicable to diverse biological samples with lower limits of detection of 0.7, 0.2, and 0.2 pmol, respectively, and linear ranges greater than 3 orders of magnitude. These assays function well with small, complex biological samples (10-20mg tissu...
Article
We report an improved tandem mass spectrometric assay for retinoic acid (RA) applicable to in vitro and in vivo biological samples. This liquid chromatography tandem mass spectrometric (LC/MS/MS) assay for direct RA quantification is the most sensitive to date, with a 62.5 attomol lower limit of detection and a linear range spanning greater than 4...
Article
Differentiation and patterning in the developing nervous system require the vitamin A metabolite all-trans-retinoic acid (atRA). Recent data suggest that higher cognitive functions, such as creation of hippocampal memory, also require atRA and its receptors, RAR, through affecting synaptic plasticity. Here we show that within 30 min atRA increased...
Article
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), one of the most widely studied environmental contaminants, causes a variety of adverse health effects including teratogenesis and altered development which may be related to disruptions in retinoid homeostasis. The purpose of this study was to determine the effect that gestational administration of TCDD h...
Article
Rat RoDH performs efficiently (V(m)/K(m)) in a pathway of all-trans-retinoic acid biosynthesis in cells and recognizes the physiological form of vitamin A, i.e., retinol bound with cellular retinol binding-protein, type I. Here we report that mouse embryo (e7.5 to e18.5) and liver (e12.5 to P2M) display inversely related mRNA expression of an Rodh...