Lecithin:Retinol Acyltransferase Is Critical for Cellular Uptake of Vitamin A from Serum Retinol-binding Protein

Amengual, Jaume; Golczak, Marcin; Palczewski, Krzysztof; Lintig, Johannes von

doi:10.1074/jbc.m112.353979

Cited by 84 publications

(86 citation statements)

References 40 publications

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“…proposed to couple with STRA6 within the cell ( 95,100,101 ). von Lintig and colleagues have convincingly established that the functional coupling of LRAT with STRA6 increases cellular retinol uptake into tissues and have proposed that LRAT is a critical component of this process ( 101 ).…”

Section: Cellular Uptake Of Retinoidsmentioning

confidence: 99%

“…von Lintig and colleagues have convincingly established that the functional coupling of LRAT with STRA6 increases cellular retinol uptake into tissues and have proposed that LRAT is a critical component of this process ( 101 ). In vitro experiments have established that STRA6 facilitates effi cient retinol exchange between intercellular CRBPI and extracellular RBP4 ( 100 ).…”

Section: Cellular Uptake Of Retinoidsmentioning

confidence: 99%

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Retinol and retinyl esters: biochemistry and physiology

O’Byrne

Blaner

2013

Journal of Lipid Research

298

250

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The different retinoid forms present within the body (see Fig. 1 ) are generated by and large through modifi cations to the terminal polar end group of the molecule. Retinol and retinyl esters are the most abundant retinoid forms present in the body. All-trans -retinol is by defi nition vitamin A. When a fatty acyl group is esterifi ed to the hydroxyl terminus of retinol, a storage form of retinol, the retinyl ester, is formed. The most abundant retinyl esters present in the body are those of palmitic acid, oleic acid, stearic acid, and linoleic acid ( 6, 7 ). Although retinyl acetate can be found in supplements to foods and vitamin formulations, only long-chain acyl groups are esterifi ed to retinol by animals. Retinyl esters have no known biological activity aside from retinol storage and for serving as the substrate for the formation of the visual chromophore 11-cis -retinal, which must be formed from all-trans -retinyl ester through linked hydrolysis and isomerization reactions catalyzed by the enzyme RPE65 ( 3,4,8,9 ). Retinol is a transport form and a precursor form, which is enzymatically activated to retinoic acid via a two-step oxidation process. The primary role of retinal is in the eye where 11-cis -retinal is needed for visual pigment formation. In tissues, retinal serves as an intermediate in the synthesis of retinoic acid from retinol ( 6, 7 ). The literature also suggests a direct role for retinal in adipose tissue, where it was shown to inhibit adipogenesis and suppress peroxisome proliferator-activated receptor-␥ (PPAR ␥ ) and retinoid X receptor (RXR) responses in cell culture models and in mouse models fed high-fat diets ( 10 ).Abstract By defi nition, a vitamin is a substance that must be obtained regularly from the diet. Vitamin A must be acquired from the diet, but unlike most vitamins, it can also be stored within the body in relatively high levels. For humans living in developed nations or animals living in present-day vivariums, stored vitamin A concentrations can become relatively high, reaching levels that can protect against the adverse effects of insuffi cient vitamin A dietary intake for six months, or even much longer. The ability to accumulate vitamin A stores lessens the need for routinely consuming vitamin A in the diet, and this provides a selective advantage to the organism. The molecular processes that underlie this selective advantage include effi cient mechanisms to acquire vitamin A from the diet, effi cient and overlapping mechanisms for the transport of vitamin A in the circulation, a specifi c mechanism allowing for vitamin A storage, and a mechanism for mobilizing vitamin A from these stores in response to tissue needs. These processes are considered in this review. Since the identifi cation of fat-soluble A a century ago ( 1 ), retinoids (vitamin A and its natural and synthetic analogs) have been the most extensively studied of the fatsoluble vitamins. This research has identifi ed essential roles for retinoids in many different aspects of mammalian physiology, includ...

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Section: Cellular Uptake Of Retinoidsmentioning

confidence: 99%

Section: Cellular Uptake Of Retinoidsmentioning

confidence: 99%

Retinol and retinyl esters: biochemistry and physiology

O’Byrne

Blaner

2013

Journal of Lipid Research

298

250

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“…Visual functions of the eye, unlike any other tissue, depend on vitamin A. In fact, retinoids are preferentially taken up by the eye at the expense of other peripheral tissues (Amengual et al, 2012). This selectivity offers the opportunity of designing compounds that use vitamin A transport machinery and thus benefit from efficient and active uptake into the eye, low systemic toxicity, and dramatically improved pharmacokinetics .…”

Section: Rdh8mentioning

confidence: 99%

Expansion of First-in-Class Drug Candidates That Sequester Toxic All-Trans-Retinal and Prevent Light-Induced Retinal Degeneration

et al. 2014

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All-trans-retinal, a retinoid metabolite naturally produced upon photoreceptor light activation, is cytotoxic when present at elevated levels in the retina. To lower its toxicity, two experimentally validated methods have been developed involving inhibition of the retinoid cycle and sequestration of excess of all-trans-retinal by drugs containing a primary amine group. We identified the first-in-class drug candidates that transiently sequester this metabolite or slow down its production by inhibiting regeneration of the visual chromophore, 11-cis-retinal. Two enzymes are critical for retinoid recycling in the eye. Lecithin:retinol acyltransferase (LRAT) is the enzyme that traps vitamin A (all-trans-retinol) from the circulation and photoreceptor cells to produce the esterified substrate for retinoid isomerase (RPE65), which converts all-trans-retinyl ester into 11-cis-retinol. Here we investigated retinylamine and its derivatives to assess their inhibitor/substrate specificities for RPE65 and LRAT, mechanisms of action, potency, retention in the eye, and protection against acute light-induced retinal degeneration in mice. We correlated levels of visual cycle inhibition with retinal protective effects and outlined chemical boundaries for LRAT substrates and RPE65 inhibitors to obtain critical insights into therapeutic properties needed for retinal preservation.

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“…Mutations in Stra6 cause a wide range of defects that include anophthalmia, pulmonary agenesis, diaphragmatic hernia, pancreatic malformations, mental retardation, and congenital heart defects (Golzio et al, 2007;Pasutto et al, 2007). Lrat is an enzyme that converts intracellular retinol to retinyl esters; such esters are a storage form of retinoids in the cell (Amengual et al, 2012;Batten et al, 2004;Guo and Gudas, 1998;Liu and Gudas, 2005;O'Byrne et al, 2005;Zolfaghari and Ross, 2000). Crabp2 is involved in transporting RA from the cytoplasm into the nucleus (Noy, 2000), and Cyp26a1 metabolizes RA into polar metabolites in ES cells (Langton and Gudas, 2008;White et al, 1997).…”

Section: Identification Of Differentially Expressed Genes In Wt and Rmentioning

confidence: 99%

RARγ is Essential for Retinoic Acid Induced Chromatin Remodeling and Transcriptional Activation in Embryonic Stem Cells

Kashyap

Laursen

Brenet

et al. 2012

Journal of Cell Science

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SummaryWe have utilized retinoic acid receptor c (gamma) knockout (RARc 2/2 ) embryonic stem (ES) cells as a model system to analyze RARc mediated transcriptional regulation of stem cell differentiation. Most of the transcripts regulated by all-trans retinoic acid (RA) in ES cells are dependent upon functional RARc signaling. Notably, many of these RA-RARc target genes are implicated in retinoid uptake and metabolism. For instance, Lrat (lecithin:retinol acyltransferase), Stra6 (stimulated by retinoic acid 6), Crabp2 (cellular retinoic acid binding protein 2), and Cyp26a1 (cytochrome p450 26a1) transcripts are induced in wild type (WT), but not in RARc 2/2 cells. Transcripts for the transcription factors Pbx1 (pre-B cell leukemia homeobox-1), Wt1 (Wilm's tumor gene-1), and Meis1 (myeloid ecotropic viral integration site-1) increase upon RA treatment of WT, but not RARc 2/2 cells. In contrast, Stra8, Dleu7, Leftb, Pitx2, and Cdx1 mRNAs are induced by RA even in the absence of RARc. Mapping of the epigenetic signature of Meis1 revealed that RA induces a rapid increase in the H3K9/ K14ac epigenetic mark at the proximal promoter and at two sites downstream of the transcription start site in WT, but not in RARc 2/2 cells. Thus, RA-associated increases in H3K9/K14ac epigenetic marks require RARc and are associated with increased Meis1 transcript levels, whereas H3K4me3 is present at the Meis1 proximal promoter even in the absence of RARc. In contrast, at the Lrat proximal promoter primarily the H3K4me3 mark, and not the H3K9/K14ac mark, increases in response to RA, independently of the presence of RARc. Our data show major epigenetic changes associated with addition of the RARc agonist RA in ES cells.

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Lecithin:Retinol Acyltransferase Is Critical for Cellular Uptake of Vitamin A from Serum Retinol-binding Protein

Cited by 84 publications

References 40 publications

Retinol and retinyl esters: biochemistry and physiology

Retinol and retinyl esters: biochemistry and physiology

Expansion of First-in-Class Drug Candidates That Sequester Toxic All-Trans-Retinal and Prevent Light-Induced Retinal Degeneration

RARγ is Essential for Retinoic Acid Induced Chromatin Remodeling and Transcriptional Activation in Embryonic Stem Cells

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