Retinoid metabolism during development of liver cirrhosis

Natarajan, Sathish Kumar; Thomas, Simmy; Anup, R.; Pulimood, Anna; Balasubramanian, K.A.

doi:10.1016/j.abb.2005.09.008

Cited by 24 publications

(26 citation statements)

References 32 publications

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“…Accordingly, loss of total retinoid but increased RA in liver during injury may have implications for stellate cell function (440). These observations differ from changes observed in vitamin-A deficient animals, in whom expression of lecithin:acyl transferase (LRAT), the enzyme responsible for esterifying retinol, is downregulated rapidly along with a retinoic acid responsive cytochrome P-450, Cyp26 (551).…”

Section: Effects Of Retinoids On Stellate Cellscontrasting

confidence: 53%

Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver

Friedman

2008

Physiological Reviews

2,356

2,549

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The hepatic stellate cell has surprised and engaged physiologists, pathologists, and hepatologists for over 130 years, yet clear evidence of its role in hepatic injury and fibrosis only emerged following the refinement of methods for its isolation and characterization. The paradigm in liver injury of activation of quiescent vitamin A-rich stellate cells into proliferative, contractile, and fibrogenic myofibroblasts has launched an era of astonishing progress in understanding the mechanistic basis of hepatic fibrosis progression and regression. But this simple paradigm has now yielded to a remarkably broad appreciation of the cell's functions not only in liver injury, but also in hepatic development, regeneration, xenobiotic responses, intermediary metabolism, and immunoregulation. Among the most exciting prospects is that stellate cells are essential for hepatic progenitor cell amplification and differentiation. Equally intriguing is the remarkable plasticity of stellate cells, not only in their variable intermediate filament phenotype, but also in their functions. Stellate cells can be viewed as the nexus in a complex sinusoidal milieu that requires tightly regulated autocrine and paracrine cross-talk, rapid responses to evolving extracellular matrix content, and exquisite responsiveness to the metabolic needs imposed by liver growth and repair. Moreover, roles vital to systemic homeostasis include their storage and mobilization of retinoids, their emerging capacity for antigen presentation and induction of tolerance, as well as their emerging relationship to bone marrow-derived cells. As interest in this cell type intensifies, more surprises and mysteries are sure to unfold that will ultimately benefit our understanding of liver physiology and the diagnosis and treatment of liver disease.

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Section: Effects Of Retinoids On Stellate Cellscontrasting

confidence: 53%

Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver

Friedman

2008

Physiological Reviews

2,356

2,549

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“…A link between oxidative stress and retinoid metabolism in the intestine is also provided by studies which demonstrate that mild whole‐body heat stress increases retinoic acid levels along with increased activity of retinaldehyde oxidase in enterocytes 52 and also has a protective effect against oxidative stress‐induced intestinal damage following surgical stress 53 . The present data along with our earlier published data 11,18 suggest that alterations in retinoid metabolism appear at the same time point when pathophysiological changes in the intestine are observed. The lack of significant change in retinoid level or retinoid‐metabolizing enzyme activity between controls, 1 and 2 months of CCl 4 ‐ or TAA‐treated animals, suggest that these effects are not mediated by direct effects of the hepatotoxins on the intestine.…”

Section: Discussionsupporting

confidence: 78%

“…In addition, all‐trans retinoic acid is known to suppress alpha 2(I) collagen gene expression and it also inhibits matrix metalloproteinase (MMP) 9 and MMP 1 by its action on tissue inhibitor of metalloproteinase (TIMP) 9,10 . Our earlier work has demonstrated alterations in the level of retinoids in the liver during the early stages of cirrhosis, as well as after development of gross disease and this was accompanied by reciprocal transfer of retinoid metabolites between liver and circulation 11 …”

Section: Introductionmentioning

confidence: 99%

Retinoid metabolism in the small intestine during development of liver cirrhosis

Natarajan

Amirtharaj

Anup

et al. 2009

J of Gastro and Hepatol

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“…The reason for the discrepancy between these models is not clear. Since elevation of hepatic RA was observed only in the early stages of liver fibrosis (1 and 2 mo post-CCl 4 treatment), but not the late stages (after 4 mo of CCl 4 treatment) (23), and production of RA was also diminished in fully activated HSCs, it is plausible that HSCs in the bile duct ligation model at 19 days postsurgery (26) have already become completely activated and lost all of its retinol, resulting in low levels of RA. Indeed, diminished RA signaling was found in HSCs obtained after 19-day but not 7-to 10-day bile duct ligation (H. Tsukamoto personal communication), suggesting that HSCs from 19-day bile duct ligation are fully activated since RA signaling is decreased only in fully activated HSCs (Fig.…”

Section: Discussionmentioning

confidence: 95%

Retinoic acid signaling sensitizes hepatic stellate cells to NK cell killing via upregulation of NK cell activating ligand RAE1

Radaeva

Wang

Radaev

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

113

128

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Hepatic stellate cells (HSCs) store 75% of the body's supply of vitamin A (retinol) and play a key role in liver fibrogenesis. During liver injury, HSCs become activated and susceptible to natural killer (NK) cell killing due to increased expression of the NK cell activating ligand retinoic acid early inducible gene 1 (RAE-1). To study the mechanism by which RAE-1 is upregulated in HSCs during activation, an in vitro model of cultured mouse HSCs was employed. RAE-1 was detected at low levels in quiescent HSCs but upregulated in 4- and 7-day cultured HSCs (early activated HSCs), whereas 21-day cultured HSCs (fully activated HSCs) lost RAE-1 expression. High levels of RAE-1 in 4- and 7-day cultured HSCs correlated with their susceptibility to NK cell killing, which was diminished by treatment with RAE-1 neutralizing antibody. Furthermore, retinoic acid (RA) and retinal dehydrogenase (Raldh) levels were upregulated in early activated HSCs compared with quiescent or fully activated HSCs. Blocking RA synthesis by the Raldh inhibitor or blocking RA signaling by the retinoic acid receptor antagonist abolished upregulation of RAE-1 whereas treatment with RA induced RAE-1 expression in HSCs. In conclusion, during activation, HSCs lose retinol, which is either secreted out or oxidized into RA; the latter stimulates RAE-1 expression and sensitizes early activated HSCs to NK cell killing. In contrast, fully activated HSCs become resistant to NK cell killing because of lack of RAE1 expression, leading to chronic liver fibrosis and disease.

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Retinoid metabolism during development of liver cirrhosis

Cited by 24 publications

References 32 publications

Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver

Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver

Retinoid metabolism in the small intestine during development of liver cirrhosis

Retinoic acid signaling sensitizes hepatic stellate cells to NK cell killing via upregulation of NK cell activating ligand RAE1

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