Vitamin A inhibits pancreatic stellate cell activation: implications for treatment of pancreatic fibrosis

McCarroll, Joshua A.; Phillips, Phoebe A.; Santucci, Nicole; Pirola, Romano C.; Wilson, Jeremy S.; Apte, Minoti V.

doi:10.1136/gut.2005.064543

Cited by 132 publications

(86 citation statements)

References 40 publications

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“…Also uncertain is the contribution of impaired glucose tolerance to diminished pancreatic β-cell function and mass associated with type 2 diabetes (5). GSIS relies on the pancreas, and pancreas development, islet formation, and function require normal vitamin A nutriture (6)(7)(8). Vitamin A restriction during development impairs islet development and promotes glucose intolerance in adult rodents.…”

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confidence: 99%

Identification of 9- cis -retinoic acid as a pancreas-specific autacoid that attenuates glucose-stimulated insulin secretion

Kane

Folias

Pingitore

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

100

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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 not been detected in serum or multiple tissues with analytically validated assays. Here, we identify 9cRA in mouse pancreas by liquid chromatography/tandem mass spectrometry (LC/MS/MS), and show that 9cRA decreases with feeding and after glucose dosing and varies inversely with serum insulin. 9cRA reduces glucose-stimulated insulin secretion (GSIS) in mouse islets and in the rat β-cell line 832/13 within 15 min by reducing glucose transporter type 2 (Glut2) and glucokinase (GK) activities. 9cRA also reduces Pdx-1 and HNF4α mRNA expression, ∼8-and 80-fold, respectively: defects in Pdx-1 or HNF4α cause maturity onset diabetes of the young (MODY4 and 1, respectively), as does a defective GK gene (MODY2). Pancreas β-cells generate 9cRA, and mouse models of reduced β-cell number, heterozygous Akita mice, and streptozotocin-treated mice have reduced 9cRA. 9cRA is abnormally high in glucose-intolerant mice, which have β-cell hypertropy, including mice with diet-induced obesity (DIO) and ob/ob and db/db mice. These data establish 9cRA as a pancreas-specific autacoid with multiple mechanisms of action and provide unique insight into GSIS.retinol | vitamin A | rexinoids I mpaired glucose-stimulated insulin secretion (GSIS) develops through multiple mechanisms, including actions of metabolic hormones and inflammatory cytokines, products of metabolic overload, and endoplasmic reticulum stress; however, mechanisms of GSIS and impaired glucose tolerance remain incompletely understood (1-4). Also uncertain is the contribution of impaired glucose tolerance to diminished pancreatic β-cell function and mass associated with type 2 diabetes (5). GSIS relies on the pancreas, and pancreas development, islet formation, and function require normal vitamin A nutriture (6-8). Vitamin A restriction during development impairs islet development and promotes glucose intolerance in adult rodents. On the other hand, restricting vitamin A in mature diabetes-prone rats reduces diabetes and insulitis, possibly through enhancing glucose sensing and metabolism. Alltrans-retinoic acid (atRA), an activated metabolite of vitamin A, regulates pancreas development, and atRA does not enhance the incidence of diabetes in diabetes-prone rats fed a vitamin Adeficient diet (7, 9, 10). Although the contribution of vitamin A to pancreas development through atRA seems clear, mechanisms whereby vitamin A affects mature pancreas function have not been determined in depth, nor have the specific vitamin A metabolites been identified that contribute to GSIS control.atRA induces differentiation and regulates cell processes by activating the nuclear receptors RAR α, -β, and -γ, which regulate transcription and translation (11...

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confidence: 99%

Identification of 9- cis -retinoic acid as a pancreas-specific autacoid that attenuates glucose-stimulated insulin secretion

Kane

Folias

Pingitore

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

100

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“…It is currently known that antioxidants can be used as a treatment strategy in various pathologies, including ethanol consumption. It has been found that activation of pancreatic stellate cells is inhibited when these are incubated with antioxidants (Apte et al, 2000;McCarroll et al, 2006). This is why vitamin A, an antioxidant, may represent a potential treatment strategy for the damage produced by ethanol.…”

Section: Introductionmentioning

confidence: 99%

Ethanol Intake and Toxicity: In Search of New Treatments

et al. 2017

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SANDOVAL, C.; VÁSQUEZ, B.; MANDARIM-DE-LACERDA, C. & DEL SOL, M.Ethanol intake and toxicity: In search of new treatments. Int. J. Morphol., 35(3):942-949, 2017. SUMMARY:Prolonged alcohol consumption has consequences on the liver, producing necrotic precipitates and fibrosis, on the pancreas, causing the pancreatic acini to atrophy and destroying insulin-producing cells, and on the central nervous system (CNS), causing the gray and white matter in the frontal lobes of the brain and cerebellum to atrophy. Generally, alcohol is metabolized via oxidative pathways, where the enzymes alcohol dehydrogenase and aldehyde dehydrogenase participate during its metabolization in the liver and CNS, or via nonoxidative pathways during its metabolization in the pancreas. Ethanol metabolism can produce oxidative stress and tissue damage mediated by free radicals, causing morphological and functional alterations in the liver. In the pancreas, it can cause progressive and irreversible damage affecting the endocrine and exocrine functions, a result of the activation of the stellate cells, which are activated directly by alcohol, causing pancreatic fibrosis. In the CNS ethanol can bind directly to proteins, nucleic acids and phospholipids to develop its pathogenesis. The effects produced by alcohol can be counteracted by supplementation with antioxidants, which reduce the inflammation and areas of focal necrosis in the liver, inhibit the activation of pancreatic stellate cells, and reduce oxidative stress in the CNS. Additionally, in order to reduce the negative effects associated with alcohol consumption, recent studies have suggested the administration of antioxidants as a treatment strategy.

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“…This vitamin A-storage might not only be a mere feature of quiescent PSC, but functionally contribute to the maintenance of this state. McCarroll et al [20] showed that retinol and its metabolites (all-trans retinoic acid and 9-retinoic acid) inhibited the induction of a-SMA expression in PSCs. Retinol and its metabolites induced quiescence in culture-activated PSCs, in association with a significant decrease in the activation of mitogen-activated protein (MAP) kinases [20].…”

Section: Activation Of Pscsmentioning

confidence: 99%

“…McCarroll et al [20] showed that retinol and its metabolites (all-trans retinoic acid and 9-retinoic acid) inhibited the induction of a-SMA expression in PSCs. Retinol and its metabolites induced quiescence in culture-activated PSCs, in association with a significant decrease in the activation of mitogen-activated protein (MAP) kinases [20]. It is, therefore, tempting to speculate that retinoic acids are involved in the maintenance of a quiescent phenotype, through the binding to their nuclear receptors and the regulation of gene expression.…”

Section: Activation Of Pscsmentioning

confidence: 99%