tretinoin and Liver-Diseases--Alcoholic

Topics: Alcoholic Intoxication; Animals; Carcinogenesis; Cell Line, Tumor; Chlormethiazole; Cytochrome P-450 CYP2E1; Cytochrome P-450 CYP2E1 Inhibitors; Ethanol; Humans; Liver Cirrhosis; Liver Diseases, Alcoholic; Liver Neoplasms; Non-alcoholic Fatty Liver Disease; Tretinoin; Vitamin A

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Hidekazu Tsukamoto and Yoshiyuki Takei. The presentations were (1) Tribute to Professor Rajendar K. Chawla, by Craig J. McClain; (2) Dysregulated TNF signaling in alcoholic liver disease, by Craig J. McClain, S. Joshi-Barve, D. Hill, J Schmidt, I. Deaciuc, and S. Barve; (3) The role of mitochondria in ethanol-mediated sensitization of the liver, by Anna Colell, Carmen Garcia-Ruiz, Neil Kaplowitz, and Jose C. Fernandez-Checa; (4) A peroxisome proliferator (bezafibrate) can prevent superoxide anion release into hepatic sinusoid after acute ethanol administration, by Hirokazu Yokoyama, Yukishige Okamura, Yuji Nakamura, and Hiromasa Ishii; (5) S-adenosylmethionine affects tumor necrosis factor-alpha gene expression in macrophages, by Rajendar K. Chawla, S. Barve, S. Joshi-Barve, W. Watson, W. Nelson, and C. McClain; (6) Iron, retinoic acid and hepatic macrophage TNFalpha gene expression in ALD, by Hidekazu Tsukamoto, Min Lin, Mitsuru Ohata, and Kenta Motomura; and (7) Role of Kupffer cells and gut-derived endotoxin in alcoholic liver injury, by N. Enomoto, K. Ikejima, T. Kitamura, H. Oide, Y. Takei, M. Hirose, B. U. Bradford, C. A. Rivera, H. Kono, S. Peter, S. Yamashina, A. Konno, M. Ishikawa, H. Shimizu, N. Sato, and R. Thurman.

Topics: Animals; Bezafibrate; Endotoxins; Gene Expression; Hepatocytes; Humans; Hypolipidemic Agents; Iron; Kupffer Cells; Liver; Liver Diseases, Alcoholic; Mitochondria, Liver; Peroxisome Proliferators; S-Adenosylmethionine; Superoxides; Tretinoin; Tumor Necrosis Factor-alpha

The effects of all-trans-retinoic acid (ATRA) in low doses supplementation on concentrations of polar retinoid metabolites (PRM) and retinoids in the ethanol-fed rat liver, and on hepatocyte injury were investigated. The rat model of alcoholic liver disease (ALD) was induced by intragastric infusion of ethanol, and then the rats were administrated with ATRA in two different doses (150 microg/kg body weight and 1.5 mg/kg body weight) for 4 weeks. Concentrations of retinoids in rat liver and plasma were determined by using HPLC. Liver tissues pathologic changes were observed under the light microscopy and electron microscopy. The serum transaminases concentrations were measured. The results showed that the HPLC analysis of retinoids revealed that retinoids (vitamin A, RA, retinyl palmitate) concentrations in ethanol-fed rat liver and RA concentration in ethanol-fed rat plasma were markedly diminished (P<0.01) after ethanol feeding for 12 weeks. Furthermore, obvious peaks of PRM were formed in livers of ethanol-fed rats. ATRA 150 microg/kg supplementation in ethanol-fed rats for 4 weeks raised RA concentration in both liver and plasma, and also raised vitamin A concentration in liver to control levels, partially restored retinyl palmitate concentration (P<0.05) in liver. ATRA 1.5 mg/kg supplementation raised not only RA concentrations in liver and plasma but also retinyl palmitate concentrations in liver. However, the vitamin A concentration in liver of ATRA-supplemented rats (1.5 mg/kg) was higher than that of controls (P<0.05). The histologic observation of liver tissues indicated that ATRA treatment notably alleviated hepatocellular swelling, steatosis, the swelling of mitochondria and proliferation of smooth endoplasmic reticulum (SER). ATRA treatment greatly decreased levels of serum transaminases as compared with the only ethanol-fed group (P<0.05). It was concluded that low-dose ATRA treatment could restore retinoids concentrations and abolish the PRM formation in liver of ALD rats, and then ameliorate the injury of liver cells.

Topics: Animals; Ethanol; Liver; Liver Diseases, Alcoholic; Male; Rats; Retinoids; Tretinoin

Retinoic acid (RA) inhibits hepatic macrophage (HM) cytokine expression, and retinoids are depleted in alcoholic liver disease (ALD). However, neither the causal link between the two nor the mechanism underlying RA-mediated HM inhibition is known. The aim of the present study was to determine the mechanism of RA-induced inhibition of HM tumor necrosis factor (TNF)-alpha expression and the relevance of this regulation to ALD. Treatment with all-trans RA (500 nM) caused a 50% inhibition in lipopolysaccharide (LPS)-stimulated TNF-alpha expression by cultured normal rat HM. The mRNA levels for inducible nitric oxide synthase, interleukin (IL)-6, IL-1alpha, and IL-1beta were also reduced, whereas those for transforming growth factor-beta1, MMP-9, and membrane cofactor protein-1 were unaffected. The inhibitory effect on TNF-alpha expression was reproduced by LG268, a retinoid X receptor (RXR)-specific ligand, but not by TTNPB, an RA receptor (RAR)-specific ligand. RA did not alter LPS-stimulated NF-kB and activation protein-1 binding but significantly decreased TNF-alpha mRNA stability in HM. HM isolated from the ALD model showed significant decreases in all-trans RA (-48%) and 9-cis RA (-61%) contents, RA response element (RARE) binding, and mRNA levels for RARbeta, RXRalpha, and cytosolic retinol binding protein-1, whereas TNF-alpha mRNA expression was induced. TNF-alpha mRNA stability was increased in these cells, and an ex vivo treatment with all-trans RA normalized both RARbeta and TNF-alpha mRNA levels. These results demonstrate the RA-induced destabilization of TNF-alpha mRNA by cultured HM and the association of RA depletion with increased TNF-alpha mRNA stability in HM from experimental ALD. These findings suggest that RA depletion primes HM for proinflammatory cytokine expression in ALD, at least in part, via posttranscriptional regulation.

Topics: Animals; Anticholesteremic Agents; Benzoates; Cells, Cultured; Gene Expression; Lipopolysaccharides; Liver; Liver Diseases, Alcoholic; Macrophages; Male; Organic Chemicals; Rats; Rats, Wistar; Receptors, Retinoic Acid; Retinoid X Receptors; Retinoids; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transcription Factors; Tretinoin; Tumor Necrosis Factor-alpha