tretinoin and Liver-Diseases

Vitamin A (VA), all-trans-retinol (ROL), and its analogs are collectively called retinoids. Acting through the retinoic acid receptors RARα, RARβ, and RARγ, all-trans-retinoic acid, an active metabolite of VA, is a potent regulator of numerous biological pathways, including embryonic and somatic cellular differentiation, immune functions, and energy metabolism. The liver is the primary organ for retinoid storage and metabolism in humans. For reasons that remain incompletely understood, a body of evidence shows that reductions in liver retinoids, aberrant retinoid metabolism, and reductions in RAR signaling are implicated in numerous diseases of the liver, including hepatocellular carcinoma, non-alcohol-associated fatty liver diseases, and alcohol-associated liver diseases. Conversely, restoration of retinoid signaling, pharmacological treatments with natural and synthetic retinoids, and newer agonists for specific RARs show promising benefits for treatment of a number of these liver diseases. Here we provide a comprehensive review of the literature demonstrating a role for retinoids in limiting the pathogenesis of these diseases and in the treatment of liver diseases.

Topics: Humans; Liver Diseases; Receptors, Retinoic Acid; Retinoids; Tretinoin; Vitamin A

The poor prognosis for patients with hepatocellular carcinoma (HCC) is associated with its high rate of recurrence in the cirrhotic liver. Therefore, more effective strategies need to be urgently developed for the chemoprevention of this malignancy. The malfunction of retinoid X receptor α, a retinoid receptor, due to phosphorylation by Ras/mitogen-activated protein kinase is closely associated with liver carcinogenesis and may be a promising target for HCC chemoprevention. Acyclic retinoid (ACR), a synthetic retinoid, can prevent HCC development by inhibiting retinoid X receptor α phosphorylation and improve the prognosis for this malignancy. Supplementation with branched-chain amino acids (BCAA), which are used to improve protein malnutrition in patients with liver cirrhosis, can also reduce the risk of HCC in obese cirrhotic patients. In experimental studies, both ACR and BCAA exert suppressive effects on HCC development and the growth of HCC cells. In particular, combined treatment with ACR and BCAA cooperatively inhibits the growth of HCC cells. Furthermore, ACR and BCAA inhibit liver tumorigenesis associated with obesity and diabetes, both of which are critical risk factors for HCC development. These findings suggest that pharmaceutical and nutraceutical approaches using ACR and BCAA may be promising strategies for preventing HCC and improving the prognosis of this malignancy.

Topics: Amino Acids, Branched-Chain; Carcinoma, Hepatocellular; Chronic Disease; Clinical Trials as Topic; Dietary Supplements; Humans; Liver Diseases; Liver Neoplasms; Phosphorylation; Retinoid X Receptor alpha; Retinoid X Receptors; Retinoids; Tretinoin

Quiescent hepatic stellate cells (HSCs) in healthy liver store 80% of total liver retinols and release them depending on the extracellular retinol status. However, HSCs activated by liver injury lose their retinols and produce a considerable amount of extracellular matrix, subsequently leading to liver fibrosis. Emerging evidence suggests that retinols and their metabolites such as retinoic acids (RAs) contribute to liver regeneration, fibrosis and tumor. However, it is not clear yet why HSCs lose retinol, which enzymes are involved in the retinol metabolism of HSCs and what function of retinol metabolites on HSCs upon liver injury. Recently, our group and collaborators have demonstrated that during activation, HSCs not only lose retinols but also metabolize them into RAs by alcohol dehydrogenases and retinaldehyde dehydrogenases. As transcriptional factors, metabolized RAs induce retinoic acid early inducible-1 and suppressor of cytokine signaling 1 in HSCs, which plays an important role in the interaction between HSCs and natural killer cells. In addition, RAs released from HSCs may induce hepatic cannabinoid receptor 1 expression in alcoholic liver steatosis or regulate immune responses upon liver inflammation. The present review summarizes the role of endogenous metabolized RAs on HSCs themselves and on other liver cells including hepatocytes and immune cells. Moreover, the effects of exogenous retinol and RA treatments on HSCs and liver disease are discussed.

Topics: Animals; Carcinoma, Hepatocellular; Extracellular Matrix; Fatty Liver; Hepatic Stellate Cells; Hepatitis; Humans; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Liver Regeneration; Tretinoin; Vitamin A

Prompted by recent demonstrations that all-trans-retinoic acid (all-trans-RA) had efficacy in acute promyelocytic leukemia, a phase I trial of all-trans-RA was conducted to establish the maximum-tolerated dose (MTD) before phase II testing.. Forty patients with a histologic or cytologic diagnosis of malignancy other than leukemia were treated with single daily oral doses of all-trans-RA ranging from 45 mg/m2 to 200 mg/m2. Doses of all-trans-RA were escalated in the next cohort of patients until the MTD was determined if the preceding dose level was not associated with significant toxicity.. Lung cancer was the most common type of tumor included in the study (26 cases) followed by head and neck squamous cell carcinomas (three cases), and squamous cell carcinoma of the skin (two cases); other miscellaneous solid tumors were also represented. Toxicities included cheilitis, skin reactions, headache, and nausea and vomiting, as well as transient elevations of liver enzymes and triglyceride levels. Skin toxicities, consisting of erythema with desquamation and paronychia, were considered to be the dose-limiting toxicity, and were observed in two of six patients who received 175 mg/m2/d, and in two of five patients who received 200 mg/m2/d. Of the 30 patients with assessable lesions, response was evaluated in 26 patients and no major objective tumor response was observed. Two patients were able to receive the drug for longer than 1 year without significant toxicities. There was considerable variation in individual patients' peak plasma all-trans-RA levels, and a decrease in the area under the curve of all-trans-RA plasma concentration was observed in all four patients evaluated.. For phase II study of adult patients, we recommend 150 mg/m2 of all-trans-RA administered orally once a day. However, for better optimization of drug administration schedules, further studies are needed.

Topics: Adult; Aged; Alkaline Phosphatase; Cheilitis; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Female; Headache; Hearing Disorders; Humans; Liver; Liver Diseases; Male; Middle Aged; Nausea; Neoplasms; Skin Diseases; Tretinoin; Vomiting

Hepatic progenitor cells (HPCs) are potential seed cells for hepatocyte transplantation treatment of liver diseases. ATRA can induce the differentiation and mature function of hepatic progenitor cells, but the mechanism is still poorly understood. Here, by using microRNA array to analyze the expression profiles of microRNA (miR), we found that miR-200 family molecules in HPCs were upregulated after ATRA treatment, especially miR-200a-3p, 200c-3p, and 141-3p. ATRA induction could downregulate the expression of hepatic stem markers Oct4 and AFP, and improve the expression of hepatic markers ALB, CK18, and TAT, and the activity of ALB-GLuc, as well as indocyanine green uptake and glycogen storage function of HPCs. These above effects of ATRA on HPC differentiation were almost inhibited by blocking of miR-200a-3p, but not miR-200c-3p and 141-3p using antagomir. Cell autophagy is associated with ATRA regulation in HPCs, compared with control group, the expression of LC3 and Beclin1 increased in ATRA-treated HPCs, and orange and red fluorescent spot, which represents autophagy flow, also enhanced after ATRA treatment. However, ATRA-induced cell autophagy level was inhibited in antagomir-200a-3p+ATRA-treated cells. Therefore, the present study indicates that antagomir-200a-3p is related to ATRA-induced hepatic differentiation of HPCs through regulating cell autophagy, supporting the possible use of ATRA as a key inducer in HPC-based therapy of liver diseases.

Topics: Animals; Antagomirs; Autophagy; Biomarkers; Cell Differentiation; Gene Expression Regulation, Developmental; Hepatocytes; Liver; Liver Diseases; Mice; MicroRNAs; Stem Cells; Transcriptional Activation; Tretinoin

After proteolysis, the majority of released amino acids from dietary protein are transported to the liver for gluconeogenesis or to peripheral tissues where they are used for protein synthesis and eventually catabolized, producing ammonia as a byproduct. High ammonia levels in the brain are a major contributor to the decreased neural function that occurs in several pathological conditions such as hepatic encephalopathy when liver urea cycle function is compromised. Therefore, it is important to gain a deeper understanding of human ammonia metabolism. The objective of this study was to predict changes in blood ammonia levels resulting from alterations in dietary protein intake, from liver disease, or from partial loss of urea cycle function.. A simple mathematical model was created using MATLAB SimBiology and data from published studies. Simulations were performed and results analyzed to determine steady state changes in ammonia levels resulting from varying dietary protein intake and varying liver enzyme activity levels to simulate liver disease. As a toxicity reference, viability was measured in SH-SY5Y neuroblastoma cells following differentiation and ammonium chloride treatment.. Results from control simulations yielded steady state blood ammonia levels within normal physiological limits. Increasing dietary protein intake by 72% resulted in a 59% increase in blood ammonia levels. Simulations of liver cirrhosis increased blood ammonia levels by 41 to 130% depending upon the level of dietary protein intake. Simulations of heterozygous individuals carrying a loss of function allele of the urea cycle carbamoyl phosphate synthetase I (CPS1) gene resulted in more than a tripling of blood ammonia levels (from roughly 18 to 60 μM depending on dietary protein intake). The viability of differentiated SH-SY5Y cells was decreased by 14% by the addition of a slightly higher amount of ammonium chloride (90 μM).. Data from the model suggest decreasing protein consumption may be one simple strategy to decrease blood ammonia levels and minimize the risk of developing hepatic encephalopathy for many liver disease patients. In addition, the model suggests subjects who are known carriers of disease-causing CPS1 alleles may benefit from monitoring blood ammonia levels and limiting the level of protein intake if ammonia levels are high.

Topics: Ammonia; Ammonium Chloride; Carbamoyl-Phosphate Synthase (Ammonia); Cell Differentiation; Cell Line, Tumor; Cell Survival; Computer Simulation; Diet, High-Protein; Humans; Kinetics; Liver; Liver Diseases; Male; Models, Biological; Nitrogen; Tretinoin; Urea

Cholestatic liver injury is mediated by bile acid-induced inflammatory responses. We hypothesized that superior therapeutic effects might be achieved by combining treatments that reduce the bile acid pool size with one that blocks inflammation.. All-trans retinoic acid alone reduced bile acid pool size and liver necrosis in BDL rats. However, the combination with CVC further reduced liver to body weight ratio, bile acid pool size, plasma liver enzyme, bilirubin, liver necrosis and fibrosis when compared to the atRA treatment. The assessment of hepatic hydroxyproline content further confirmed the reduced liver injury concurrent with reduction of pro-inflammatory cytokines emphasizing the synergistic effects of these two agents. Profiling of hepatic inflammatory cells revealed that combination therapy reduced neutrophils and T cells but not macrophages. The superior therapeutic effects of combination treatment were also confirmed in Mdr2. Multitargeted therapy is an important paradigm for treating cholestatic liver injury. The combination of CVC with atRA or other FXR activators may warrant a clinical trial in patients with cholestatic liver disease.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B; ATP-Binding Cassette Sub-Family B Member 4; Bile Acids and Salts; Cholestasis; Disease Models, Animal; Drug Therapy, Combination; Imidazoles; Ligation; Liver; Liver Diseases; Male; Mice; Mice, Knockout; Rats; Rats, Sprague-Dawley; Receptors, Cytokine; Sulfoxides; Tretinoin

Topics: Animals; Imidazoles; Liver Diseases; Receptors, Cytokine; Rodentia; Sulfoxides; Tretinoin

To study the role of autophagy and the relationship between retinoic acid receptor α (RARα) and autophagy in liver ischemia and reperfusion (IR) injury.. All-trans retinoic acid (ATRA) was administered to mice for two weeks before operation. Reverse transcription-polymerase chain reaction and Western blot were used to detect the expression levels of related factors. To demonstrate the role of RARα, LE540, a RARα inhibitor, was used to treat hepatocytes injured by H2O2 in vitro.. ATRA pretreatment noticeably diminished levels of serum alanine aminotransferase and aspartate aminotransferase as well as the degree of histopathological changes. Apoptosis was also inhibited, whereas autophagy was promoted. In vitro, RARα was inhibited by LE540, which resulted in decreased autophagy and increased apoptosis. Similarly, the expression of Foxo3a and p-Akt was downregulated, but Foxo1 expression was upregulated.. This research provides evidence that ATRA can protect the liver from IR injury by promoting autophagy, which is dependent on Foxo3/p-Akt/Foxo1 signaling.

Topics: Animals; Apoptosis; Autophagy; Cytoprotection; Dibenzazepines; Disease Models, Animal; Forkhead Box Protein O1; Forkhead Box Protein O3; Forkhead Transcription Factors; Hepatocytes; Hydrogen Peroxide; Liver; Liver Diseases; Male; Mice, Inbred C57BL; Oxidative Stress; Phosphorylation; Proto-Oncogene Proteins c-akt; Receptors, Retinoic Acid; Reperfusion Injury; Retinoic Acid Receptor alpha; Signal Transduction; Time Factors; Tretinoin

All-trans retinoic acid (atRA) is an active metabolite of vitamin A with antioxidant effects. There have been few reports on the effects of atRA on liver ischemia/reperfusion (I/R) injury. Here we have used a rat liver ischemia/ reperfusion model to analyze the protective effect of atRA. Rats were administered with different does (5-15 mg/kg/d) of atRA intraperitoneally (i.p.) for 14 d before I/R. Partial (70%) hepatic ischemia was induced by clamping the hepatic artery, portal vein, and bile duct to the left and median lobes of the liver using a vascular clamp for 60 min, followed by 24 h of reperfusion. The serum aminotransferase (ALT and AST) and hepatic pathology were used to evaluate I/R injury. The results demonstrate that atRA pretreatment attenuates liver I/R injury by inhibiting the release of malondialdehyde (MDA) and by enhancing the activity of superoxide dismutase (SOD). To gain insight into the mechanism of the SOD up-regulation by atRA, the activity of p38 mitogenactivated protein kinase (p38MAKP) and Akt was measured. The results showed that the phosphorylation of p38MAPK and Akt paralleled the expression of manganese superoxide dismutase (MnSOD). That these activities are related was demonstrated by the addition of a p38 inhibitor which markedly decreased MnSOD levels. Taken together, our data reveal that atRA can protect liver from I/R injury by increaseing MnSOD, which is associated with an increased activity of p38MAPK and Akt.

Topics: Animals; Antioxidants; Disease Models, Animal; Liver; Liver Diseases; Male; Malondialdehyde; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Superoxide Dismutase; Tretinoin; Up-Regulation

All-trans retinoic acid (ATRA) is a natural derivative of vitamin A, which is well known to suppress inflammatory cytokine production. To date, there have been few reports about the systemic use of ATRA for inflammation because of acute resistance and the highly lipophilic nature of ATRA.. ATRA-lipoplexes were prepared by mixing CMV-Luc plasmid DNA with ATRA-incorporated 1,2-dioleoyl-3-trimethylammoniopropane (DOTAP)/cholesterol liposome. After intravenous injection, tissue accumulation, transfection efficacy, NFkappaB activation, cytokine production, and hepatic toxicity of ATRA-lipoplexes were evaluated and compared with lipoplexes lacking ATRA.. The particle size and zeta potential of ATRA-lipoplexes were similar to those of lipoplexes. After intravenous injection of ATRA-lipoplexes, tissue accumulation in liver and gene expression in liver and lung were similar to those of lipoplexes, supporting the hypothesis that ATRA incorporation did not affect the delivery and gene transfection efficacy. In addition, ATRA incorporated in ATRA-lipoplexes was delivered to liver in a manner similar to that for ATRA incorporated in liposomes. In addition, intravenous injection of ATRA-lipoplexes inhibited the activation of NFkappaB in liver, and subsequently suppressed the serum levels of tumor necrosis factor-alpha (TNF-alpha) and alanine aminotransferase (ALT) compared with lipoplexes. Liver histology data also demonstrated a low degree of liver injury produced by ATRA-lipoplexes compared with lipoplexes.. ATRA-incorporated lipoplexes effectively suppress NFkappaB activation, cytokine response and liver injury induced by lipoplexes without affecting gene delivery and transfection efficacy in vivo.

Topics: Alanine Transaminase; Animals; DNA; Female; Gene Expression Profiling; Injections, Intravenous; Interleukin-6; Liposomes; Liver Diseases; Mice; Mice, Inbred ICR; NF-kappa B; Organ Specificity; Particle Size; Phosphorus Radioisotopes; Tretinoin; Tritium; Tumor Necrosis Factor-alpha

A 22-year-old female presented with acute promyelocytic leukemia (APL). Treatment with all-trans retinoic acid (ATRA) resulted in a severe exacerbation of the coagulopathy 5 days after its introduction. This was complicated by bone marrow necrosis, parenchymal liver damage and acute tubular necrosis. Temporary cessation of the drug and subsequent dose reduction was effective in controlling the coagulopathy.

Topics: Adult; Antineoplastic Agents; Blood Coagulation Disorders; Bone Marrow; Chemical and Drug Induced Liver Injury; Female; Humans; Kidney Diseases; Leukemia, Promyelocytic, Acute; Liver Diseases; Necrosis; Tretinoin

All-trans retinoic acid (ATRA) has been reported to exert major effects on the immune system, including monocytes/macrophages. The present study was designed to determine whether ATRA would modulate macrophage-associated liver injury induced by Propionibacterium acnes and lipopolysaccharide (LPS) in rats. All-trans retinoic acid administration alleviated the liver injury and reduced the incidence of death following hepatic failure. Serum alanine aminotransferase (ALT) levels 5 h after, and survival rates within 12 h after the administration of LPS were significantly lower in the ATRA-treated group (134+/-119 IU/L and 72.7%) compared with the control group (713+/-411 IU/L and 18.2%; P< 0.05). Histological findings supported these results. These effects may be due to suppression of tumour necrosis factor-alpha (TNF-alpha) and superoxide anions produced by activated macrophages. Serum levels of TNF-alpha 1 h after LPS administration were significantly lower in the ATRA-treated group (60.5+/-7.0 ng/mL) as compared with the control group (105.2+/-39.3 ng/mL; P< 0.05). Formazan deposition that was generated by the perfusion of the liver with nitroblue tetrazolium, also suggested suppression of the release of superoxide anions from hepatic macrophages. These results suggest that ATRA acts as an immunomodulator in liver injury by suppressing the activation of liver macrophages.

Topics: Animals; Anions; Chemical and Drug Induced Liver Injury; Gram-Positive Bacterial Infections; Lipopolysaccharides; Liver; Liver Diseases; Macrophages; Male; Propionibacterium acnes; Rats; Rats, Wistar; Superoxides; Survival Analysis; Tretinoin; Tumor Necrosis Factor-alpha

A study was conducted to examine the inhibitory effect of acyclic retinoid (polyprenoic acid) on the secretion of alpha-fetoprotein (AFP) in rats with chronic liver damage induced by CCl4. Oral administration of the compound brought about a significant reduction of serum AFP levels at the time when liver cirrhosis was formed. Acyclic retinoid also decreased the activities of serum aminotransferases and ornithine carbamyl transferase, while it increased serum albumin levels, demonstrating the reduction of hepatic parenchymal damage. Significant negative correlation was observed between serum AFP and albumin levels. This cytoprotective effect of the retinoid on the parenchymal cell may well be related to the inhibition of the synthesis and/or secretion of AFP. No significant side effect was observed, despite a long-term administration of the compound. The present finding will provide a potential scope for the future use of acyclic retinoid for the treatment of chronic liver damage.

Topics: alpha-Fetoproteins; Animals; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Liver; Liver Diseases; Male; Ornithine Carbamoyltransferase; Rats; Rats, Inbred Strains; Serum Albumin; Tretinoin

We studied the effects of oral administration of the retinoid, 4-hydroxyphenyl retinamide (4-HPR), on group A streptococcal cell wall-induced polyarthritis in the rat, a model characterized initially by exudative inflammation of peripheral joints followed by chronic proliferative/erosive synovitis. Experimental arthritis was induced in female LEW/N rats by i.p. injection of streptococcal cell walls in saline (15 micrograms/g body weight). Depending upon the experiment, continuous daily oral administration of the retinoid was begun either 14 days prior to induction of the disease, at the time of cell wall administration and/or 11 days and 31 days after cell wall injection. Dosage was either 1 or 2 mmol 4-HPR/kg of chow. During the course of the disease, severity of clinical illness was assessed by determination of clinical severity index, by histological or radiologic examination, and by measurement of production in vitro of collagenase and prostaglandin E2 by excised synovial tissue. In rats fed the retinoid prior to cell wall injection, both the acute and the chronic responses were suppressed. In rats given the retinoid at the time of cell wall injection, the acute inflammatory response was only partially suppressed on the diet containing 2 mmol 4-HPR/kg chow, but the chronic disease was impressively inhibited in a dose dependent manner. Similarly, in animals with established disease, the drug was also effective; however, the more advanced the illness, the less effective the drug. Clinical observations were paralleled by the histological, radiographical and biochemical analyses. Treated animals showed far less synovial proliferation and joint destruction, and synovial tissues taken from these rats produced lesser amounts of collagenase and prostaglandin E2. No significant toxicity of the retinoid was noted. We conclude that oral administration of 4-HPR suppresses, in a dose and time dependent manner, both the acute and chronic stages of streptococcal cell wall-induced arthritis in rats without apparent significant toxicity. Our data suggest that studies of the effects of this retinoid on patients with chronic inflammatory synovitis are warranted.

Topics: Animals; Arthritis; Cell Wall; Dinoprostone; Disease Models, Animal; Female; Fenretinide; Granuloma; Liver Diseases; Microbial Collagenase; Prostaglandins E; Rats; Rats, Inbred Lew; Streptococcus pyogenes; Tretinoin

Topics: Abnormalities, Drug-Induced; Chemical and Drug Induced Liver Injury; Female; Heart Defects, Congenital; Humans; Hydrocephalus; Infant, Newborn; Infant, Premature, Diseases; Isotretinoin; Liver Diseases; Tretinoin

Etretinate was used to treat twenty patients who had severe, disabling psoriasis and an increased risk of liver damage. Potential hepatotoxicity was evaluated by obtaining liver biopsies prior to starting therapy and after a 6-month course on a dosage of 0.75 mg/kg/day. In comparing pretreatment biopsies to posttreatment biopsies, five of twenty patients demonstrated a morphologic change in their liver. Three showed progressive fatty metamorphosis, and two showed liver cell necrosis and progressive fibrosis. One of these was due to heavy alcohol intake. Based on our 6-month evaluation, etretinate does not produce a consistent toxic effect on the liver.

Topics: Adult; Aged; Chemical and Drug Induced Liver Injury; Etretinate; Female; Humans; Liver; Liver Diseases; Male; Middle Aged; Psoriasis; Tretinoin