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The adverse effects of alcohol on vitamin A metabolism.

Clugston RD, Blaner WS - Nutrients (2012)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine and Institute of Human Nutrition, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. rdc2132@columbia.edu

ABSTRACT
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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Related in: MedlinePlus

A simplified overview of retinoid metabolism in a hypothetical cell. This scheme reflects retinoid metabolism in a hypothetical cell. The reader should note that these processes do not typically occur within all cells in vivo, but have been grouped here for simplicity. Similarly, multiple isoforms exist for many of the binding proteins and enzymes presented below; for a complete review of retinoid metabolism, please refer to the recent review by D’Ambrosio et al. [55]. In the cytoplasm, retinol is bound to a cellular retinol-binding protein (CRBP), from this point there are three possible pathways for retinol to take. First, retinol can be transferred to retinol-binding protein (RBP), which itself is bound to transthyretin (TTR), and secreted into the circulation. Second, it can be esterified into retinyl ester by lecithin:retinol acyltransferase (LRAT), and stored in cytoplasmic lipid droplets. Third, it can be metabolized into retinaldehyde and subsequently converted into retinoic acid. Retinoic acid may be bound by a cellular retinoic acid binding protein (CRABP), which can direct it toward the nucleus where it can signal through the nuclear transcription factors retinoic acid receptor (RAR) and retinoid X receptor (RXR), or it can be directed toward catabolism into polar metabolites by various members of the cytochrome P450 family (CYP). Catalytic enzymes are shown in red text; binding proteins are in blue text. ADH: alcohol dehydrogenase; RALDH: retinaldehyde dehydrogenase; RDH: retinol dehydrogenase; REH: retinyl ester hydrolase.
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nutrients-04-00356-f002: A simplified overview of retinoid metabolism in a hypothetical cell. This scheme reflects retinoid metabolism in a hypothetical cell. The reader should note that these processes do not typically occur within all cells in vivo, but have been grouped here for simplicity. Similarly, multiple isoforms exist for many of the binding proteins and enzymes presented below; for a complete review of retinoid metabolism, please refer to the recent review by D’Ambrosio et al. [55]. In the cytoplasm, retinol is bound to a cellular retinol-binding protein (CRBP), from this point there are three possible pathways for retinol to take. First, retinol can be transferred to retinol-binding protein (RBP), which itself is bound to transthyretin (TTR), and secreted into the circulation. Second, it can be esterified into retinyl ester by lecithin:retinol acyltransferase (LRAT), and stored in cytoplasmic lipid droplets. Third, it can be metabolized into retinaldehyde and subsequently converted into retinoic acid. Retinoic acid may be bound by a cellular retinoic acid binding protein (CRABP), which can direct it toward the nucleus where it can signal through the nuclear transcription factors retinoic acid receptor (RAR) and retinoid X receptor (RXR), or it can be directed toward catabolism into polar metabolites by various members of the cytochrome P450 family (CYP). Catalytic enzymes are shown in red text; binding proteins are in blue text. ADH: alcohol dehydrogenase; RALDH: retinaldehyde dehydrogenase; RDH: retinol dehydrogenase; REH: retinyl ester hydrolase.

Mentions: The studies discussed above provide compelling evidence that chronic alcohol consumption leads to a depletion of hepatic retinoid stores; however, the mechanism to explain this phenomenon remains elusive. Early nutritional studies established that the drop in hepatic retinoid content occurred independently of dietary vitamin A intake, and that malabsorption from the intestine was not responsible. Two hypotheses to explain alcohol’s effect subsequently emerged; (1) that alcohol stimulates mobilization of hepatic retinoid stores to extra-hepatic tissues; and (2) that alcohol stimulates retinoid catabolism [18]. Other posited explanations include reduced uptake of vitamin A into the liver from chylomicron remnants, reduced transfer of retinol from hepatocytes to HSCs, and reduced storage capacity of HSCs [30]. The next section of this review contains a detailed dissection of alcohol’s interaction with the retinoid metabolic pathway, providing a biochemical basis for understanding alcohol’s effect on tissue retinoid levels; a general overview of retinoid metabolism is provided in Figure 2 for the reader’s orientation.


The adverse effects of alcohol on vitamin A metabolism.

Clugston RD, Blaner WS - Nutrients (2012)

A simplified overview of retinoid metabolism in a hypothetical cell. This scheme reflects retinoid metabolism in a hypothetical cell. The reader should note that these processes do not typically occur within all cells in vivo, but have been grouped here for simplicity. Similarly, multiple isoforms exist for many of the binding proteins and enzymes presented below; for a complete review of retinoid metabolism, please refer to the recent review by D’Ambrosio et al. [55]. In the cytoplasm, retinol is bound to a cellular retinol-binding protein (CRBP), from this point there are three possible pathways for retinol to take. First, retinol can be transferred to retinol-binding protein (RBP), which itself is bound to transthyretin (TTR), and secreted into the circulation. Second, it can be esterified into retinyl ester by lecithin:retinol acyltransferase (LRAT), and stored in cytoplasmic lipid droplets. Third, it can be metabolized into retinaldehyde and subsequently converted into retinoic acid. Retinoic acid may be bound by a cellular retinoic acid binding protein (CRABP), which can direct it toward the nucleus where it can signal through the nuclear transcription factors retinoic acid receptor (RAR) and retinoid X receptor (RXR), or it can be directed toward catabolism into polar metabolites by various members of the cytochrome P450 family (CYP). Catalytic enzymes are shown in red text; binding proteins are in blue text. ADH: alcohol dehydrogenase; RALDH: retinaldehyde dehydrogenase; RDH: retinol dehydrogenase; REH: retinyl ester hydrolase.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3367262&req=5

nutrients-04-00356-f002: A simplified overview of retinoid metabolism in a hypothetical cell. This scheme reflects retinoid metabolism in a hypothetical cell. The reader should note that these processes do not typically occur within all cells in vivo, but have been grouped here for simplicity. Similarly, multiple isoforms exist for many of the binding proteins and enzymes presented below; for a complete review of retinoid metabolism, please refer to the recent review by D’Ambrosio et al. [55]. In the cytoplasm, retinol is bound to a cellular retinol-binding protein (CRBP), from this point there are three possible pathways for retinol to take. First, retinol can be transferred to retinol-binding protein (RBP), which itself is bound to transthyretin (TTR), and secreted into the circulation. Second, it can be esterified into retinyl ester by lecithin:retinol acyltransferase (LRAT), and stored in cytoplasmic lipid droplets. Third, it can be metabolized into retinaldehyde and subsequently converted into retinoic acid. Retinoic acid may be bound by a cellular retinoic acid binding protein (CRABP), which can direct it toward the nucleus where it can signal through the nuclear transcription factors retinoic acid receptor (RAR) and retinoid X receptor (RXR), or it can be directed toward catabolism into polar metabolites by various members of the cytochrome P450 family (CYP). Catalytic enzymes are shown in red text; binding proteins are in blue text. ADH: alcohol dehydrogenase; RALDH: retinaldehyde dehydrogenase; RDH: retinol dehydrogenase; REH: retinyl ester hydrolase.
Mentions: The studies discussed above provide compelling evidence that chronic alcohol consumption leads to a depletion of hepatic retinoid stores; however, the mechanism to explain this phenomenon remains elusive. Early nutritional studies established that the drop in hepatic retinoid content occurred independently of dietary vitamin A intake, and that malabsorption from the intestine was not responsible. Two hypotheses to explain alcohol’s effect subsequently emerged; (1) that alcohol stimulates mobilization of hepatic retinoid stores to extra-hepatic tissues; and (2) that alcohol stimulates retinoid catabolism [18]. Other posited explanations include reduced uptake of vitamin A into the liver from chylomicron remnants, reduced transfer of retinol from hepatocytes to HSCs, and reduced storage capacity of HSCs [30]. The next section of this review contains a detailed dissection of alcohol’s interaction with the retinoid metabolic pathway, providing a biochemical basis for understanding alcohol’s effect on tissue retinoid levels; a general overview of retinoid metabolism is provided in Figure 2 for the reader’s orientation.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine and Institute of Human Nutrition, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. rdc2132@columbia.edu

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus