tretinoin and Non-alcoholic-Fatty-Liver-Disease

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

Obesity and its related metabolic disorders are serious health problems worldwide, and lead to various health-related complications, including cancer. Among human cancers, hepatocellular carcinoma (HCC) is one of the most common malignancies affected by obesity. Therefore, obesity and its related disorders might be a key target for the prevention of HCC. Recently, new research indicates that the molecular abnormalities associated with obesity, including insulin resistance/hyperinsulinemia, chronic inflammation, adipokine imbalance, and oxidative stress, are possible molecular mechanisms underlying the pathogenesis of obesity-related hepatocarcinogenesis. Green tea catechins and branched-chain amino acids, both of which are classified as nutraceutical agents, have been reported to prevent obesity-related HCC development by improving metabolic abnormalities. The administration of acyclic retinoid, a pharmaceutical agent, reduced the incidence of HCC in obese and diabetic mice, and was also associated with improvements in insulin resistance and chronic inflammation. In this article, we review the detailed molecular mechanisms that link obesity to the development of HCC in obese individuals. We also summarize recent evidence from experimental and clinical studies using either nutraceutical or pharmaceutical agents, and suggest that nutraceutical and pharmaceutical approaches targeting metabolic abnormalities might be a promising strategy to prevent the development of obesity-related HCC.

Topics: Amino Acids, Branched-Chain; Animals; Carcinoma, Hepatocellular; Catechin; Chemoprevention; Diabetes Mellitus, Experimental; Dietary Supplements; Humans; Liver Neoplasms; Mice; Non-alcoholic Fatty Liver Disease; Obesity; Tea; Tretinoin

Retinoic acid (RA), a bioactive metabolite of vitamin A, has shown therapeutic effects in liver disease, and its effect in improving non-alcoholic fatty liver disease (NAFLD) is associated with the inhibition of adipogenesis in the white adipose tissue (WAT) and fatty acid oxidation induction in the liver. However, the major target organ of RA is unknown. We performed chronic administration of RA in high-fat diet (HFD)-induced NAFLD mice. Further, hepatic and adipose cells were used to study the direct effect of RA on lipid metabolism. In addition, qRT-PCR was performed to examine differential gene expression in mouse adipose tissue. RA administration ameliorated NAFLD in HFD-induced obese mice and increased mouse energy expenditure. Although RA had therapeutic effects on liver histology and lipid accumulation, it did not directly affect lipid metabolism in HepG2 cells. In contrast, RA reduced the weight of several adipose tissues and improved lipid accumulation in OP9 cells. In addition, RA upregulated genes responsible for fatty acid oxidation and thermogenesis in three different WATs. Our work suggests that the liver may not be the main target organ of RA during NAFLD treatment. WAT browning induced by RA may be the primary contributor towards the amelioration of NAFLD in HFD-induced obese mice.

Topics: Adipose Tissue; Animals; Diet, High-Fat; Lipid Metabolism; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Thermogenesis; Tretinoin

The aim of this study is to evaluate the role of All-Trans Retinoic Acid, the biologically active metabolite of retinoids, on liver steatosis in a rabbit model of high fat induced lever steatosis. 30 male rabbits were evaluated in 5 groups: group 1 treated with normal diet, group 2-5 included rabbit's groups 2 to 5 were fed on high cholesterol diet, group 2 received no drugs, group 3 received atorvastatin, group 4 received atRA, and group 5 received both the drugs. the liver was obtained for histopathological evaluation. oral administration of atRA, atorvastatin or their combination significantly decreased serum levels of total cholesterol, LDL, AST and ALT. atorvastatin slightly but atRA remarkably decreased liver steatosis where the difference was significant. atRA group showed the highest TAC and the lowest PCO concentrations. atRA can be effective in reducing liver steatosis and its antioxidant effect plays a crucial role in the process.HighlightsNon-alcoholic fatty liver disease (NAFLD) is the most common disorder of the liver in general population and is strongly associated with metabolic risk factors including hyperlipidaemia, obesity and diabetes.atRA is very effective in reducing liver steatosis and its antioxidant effect plays a crucial role in the process.we suggest focussing on other aspects of liver steatosis such as carbohydrate metabolism and insulin resistance in order to find better ways of controlling and treating liver steatosis.

Topics: Animals; Antioxidants; Atorvastatin; Diet, High-Fat; Humans; Hyperlipidemias; Liver; Male; Non-alcoholic Fatty Liver Disease; Rabbits; Tretinoin

White rice and its unrefined form, brown rice, contain numerous compounds that are beneficial to human health. However, the starch content of rice can contribute to obesity, a main risk factor for nonalcoholic fatty liver disease (NAFLD).. We investigated the effect of rice consumption on NAFLD and its underlying molecular mechanism.. We randomly divided 7-week-old male obese Zucker (fa/fa) rats, an animal model of NAFLD, into 3 groups (n = 10 each) fed 1 of 3 diets for 10 weeks: a control diet (Cont; AIN-93G diet; 53% cornstarch), a white rice diet (WR; AIN-93G diet with cornstarch replaced with white rice powder), or a brown rice diet (BR; AIN-93G diet with cornstarch replaced with brown rice powder). Liver fat accumulation and gene expression related to lipid and vitamin A metabolisms, including retinoic acid (RA) signaling, were analyzed.. Hepatic lipid values were significantly decreased in the BR group compared with the Cont group, by 0.4-fold (P < 0.05). The expression of genes related to hepatic fatty acid oxidation, such as carnitine palmitoyltransferase 2, was approximately 2.1-fold higher in the BR group than the Cont group (P < 0.05). The expression of peroxisomal acyl-coenzyme A oxidase 1 and acyl-CoA dehydrogenase medium chain was also significantly increased, by 1.6-fold, in the BR group compared with the Cont group (P < 0.05). The expression of VLDL-secretion-related genes, such as microsomal triglyceride transfer protein, was also significantly higher in the BR group (2.4-fold; P < 0.05). Furthermore, aldehyde dehydrogenase 1 family member A1, an RA synthase gene, was 2-fold higher in the BR group than the Cont group (P < 0.05).. Brown rice prevented development of NAFLD in obese Zucker (fa/fa) rats. The beneficial effects of pregelatinized rice on NAFLD could be manifested as increased fatty acid oxidation and VLDL secretion, which are regulated by RA signaling.

Topics: Animals; Lipid Metabolism; Lipids; Liver; Male; Non-alcoholic Fatty Liver Disease; Obesity; Oryza; Rats; Rats, Zucker; Tretinoin

Pharmacological dosing of all-

Topics: Adipogenesis; Adipose Tissue; Adiposity; Alcohol Oxidoreductases; Animals; Diet, High-Fat; Female; Fibroblasts; Glucose Intolerance; Heterozygote; Insulin Resistance; Lipid Metabolism; Liver; Male; Mice; Non-alcoholic Fatty Liver Disease; Oxidation-Reduction; Receptors, Retinoic Acid; Sex Factors; Tretinoin; Vitamin A

Topics: Animals; Blood Proteins; Brain; Cartilage; Growth Plate; Humans; Liver Cirrhosis; Membrane Proteins; Microtubules; Neurons; Non-alcoholic Fatty Liver Disease; Peroxisomes; Tretinoin

The farnesoid X receptor (FXR) and C/EBP homologous protein (CHOP) have critical functions in hepatic lipid metabolism. Here, we aimed to explore a potential relationship between FXR and CHOP. We fed wild-type (WT) and FXR KO mice a MCD diet (model of steatohepatitis) and found that Chop mRNA expression is upregulated in WT but not FXR KO mice. The absence of FXR aggravates hepatic inflammation after MCD feeding. In HepG2 cells, we found that Chop expression is regulated in a FXR/Retinoid X receptor (RXR)-dependent manner. We identified a FXR/RXR-binding site in the human CHOP promoter, demonstrating a highly conserved regulatory pathway. Our study shows that FXR/RXR regulates Chop expression in a mouse model of steatohepatitis, providing novel insights into pathogenesis of this disorder.

Topics: Animals; Binding Sites; Chenodeoxycholic Acid; Diet, High-Fat; Disease Models, Animal; Gene Expression Regulation; Glucose; Hep G2 Cells; Humans; Lipid Metabolism; Liver; Mice; Mice, Inbred C57BL; Mice, Knockout; Non-alcoholic Fatty Liver Disease; Promoter Regions, Genetic; Protein Binding; Receptors, Cytoplasmic and Nuclear; Retinoid X Receptors; RNA, Messenger; Signal Transduction; Transcription Factor CHOP; Tretinoin

Retinoic acid (RA), an active metabolite of vitamin A (retinol), has been implicated in the regulation of lipid metabolism and hepatic steatosis in animal models. However, the relation between RA and liver histology in patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is unknown.. This study aimed at examining the association of RA with NAFLD and NASH in Chinese subjects.. Serum RA concentration was determined by ELISA in 41 control subjects, 45 patients with NAFLD, and 38 patients with NASH. The associations of RA with adiposity, serum glucose, lipid profiles, and markers of liver damage were studied. Moreover, both mRNA and protein levels of retinoic X receptor α (RXRα) in the liver were analyzed in subjects with different degrees of hepatic steatosis.. Serum RA concentrations in patients with NAFLD (1.42 ± 0.47 ng/mL) and NASH (1.14 ± 0.26 ng/mL) were significantly lower than those in control subjects (2.70 ± 0.52 ng/mL) (P < 0.01). Furthermore, serum RA concentrations were significantly different between subjects with normal glucose tolerance and those with type 2 diabetes in control [2.87 ± 0.52 (n = 28) vs. 2.32 ± 0.44 ng/mL (n = 13)], NAFLD [1.61 ± 0.37 (n = 29) vs. 1.28 ± 0.41 ng/mL (n = 16)], and NASH [1.35 ± 0.34 (n = 24) vs. 1.07 ± 0.29 ng/mL (n = 14)] groups. In human liver tissue, RXRα mRNA expression was inversely correlated with the exacerbation of hepatic steatosis. Both serum RA concentrations and RXRα mRNA levels were inversely correlated with intrahepatic triglyceride content (r = -0.700, P < 0.001, and r = -0.611, P = 0.002, respectively). Compared with grade 0 severity, the concentration of RXRα protein was lower in more severe grades in patients with NAFLD.. These results show that circulating RA concentrations were lower in subjects with NAFLD and were associated with hepatic lipid metabolism and insulin resistance. This trial was registered at clinicaltrials.gov as NCT01940263.

Topics: Adult; Aged; Asian People; Body Mass Index; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Humans; Insulin Resistance; Lipid Metabolism; Liver; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Randomized Controlled Trials as Topic; Retinoid X Receptors; RNA, Messenger; Tretinoin; Triglycerides

Topics: Female; Humans; Male; Non-alcoholic Fatty Liver Disease; Tretinoin

Mice deficient in small heterodimer partner (SHP) are protected from diet-induced hepatic steatosis resulting from increased fatty acid oxidation and decreased lipogenesis. The decreased lipogenesis appears to be a direct consequence of very low expression of peroxisome proliferator-activated receptor gamma 2 (PPAR-γ2), a potent lipogenic transcription factor, in the SHP(-/-) liver. The current study focused on the identification of a SHP-dependent regulatory cascade that controls PPAR-γ2 gene expression, thereby regulating hepatic fat accumulation. Illumina BeadChip array (Illumina, Inc., San Diego, CA) and real-time polymerase chain reaction were used to identify genes responsible for the linkage between SHP and PPAR-γ2 using hepatic RNAs isolated from SHP(-/-) and SHP-overexpressing mice. The initial efforts identify that hairy and enhancer of split 6 (Hes6), a novel transcriptional repressor, is an important mediator of the regulation of PPAR-γ2 transcription by SHP. The Hes6 promoter is specifically activated by the retinoic acid receptor (RAR) in response to its natural agonist ligand, all-trans retinoic acid (atRA), and is repressed by SHP. Hes6 subsequently represses hepatocyte nuclear factor 4 alpha (HNF-4α)-activated PPAR-γ2 gene expression by direct inhibition of HNF-4α transcriptional activity. Furthermore, we provide evidences that atRA treatment or adenovirus-mediated RAR-α overexpression significantly reduced hepatic fat accumulation in obese mouse models, as observed in earlier studies, and the beneficial effect is achieved by the proposed transcriptional cascade.. Our study describes a novel transcriptional regulatory cascade controlling hepatic lipid metabolism that identifies retinoic acid signaling as a new therapeutic approach to nonalcoholic fatty liver diseases.

Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Blood Glucose; Fatty Liver; Gene Expression Regulation; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; PPAR gamma; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid; Repressor Proteins; Retinoic Acid Receptor alpha; Transcription, Genetic; Tretinoin

Topics: Animals; Fatty Liver; Male; Non-alcoholic Fatty Liver Disease; PPAR gamma; Receptors, Cytoplasmic and Nuclear; Tretinoin

Transgenic mice expressing dominant-negative retinoic acid receptor (RAR) α specifically in the liver exhibit steatohepatitis, which leads to the development of liver tumors. Although the cause of steatohepatitis in these mice is unknown, diminished hepatic expression of insulin-like growth factor-1 suggests that insulin resistance may be involved. In the present study, we examined the effects of retinoids on insulin resistance in mice to gain further insight into the mechanisms responsible for this condition. Dietary administration of all-trans-retinoic acid (ATRA) significantly improved insulin sensitivity in C57BL/6J mice, which served as a model for high-fat, high-fructose diet-induced nonalcoholic fatty liver disease (NAFLD). The same effect was observed in genetically insulin-resistant KK-A(y) mice, occurring in concert with activation of leptin-signaling pathway proteins, including signal transducer and activator of transcription 3 (STAT3) and Janus kinase 2. However, such an effect was not observed in leptin-deficient ob/ob mice. ATRA treatment significantly up-regulated leptin receptor (LEPR) expression in the livers of NAFLD mice. In agreement with these observations, in vitro experiments showed that in the presence of leptin, ATRA directly induced LEPR gene expression through RARα, resulting in enhancement of STAT3 and insulin-induced insulin receptor substrate 1 phosphorylation. A selective RARα/β agonist, Am80, also enhanced hepatic LEPR expression and STAT3 phosphorylation and ameliorated insulin resistance in KK-A(y) mice.. We discovered an unrecognized mechanism of retinoid action for the activation of hepatic leptin signaling, which resulted in enhanced insulin sensitivity in two mouse models of insulin resistance. Our data suggest that retinoids might have potential for treating NAFLD associated with insulin resistance.

Topics: Animals; Cells, Cultured; Disease Models, Animal; Fatty Liver; Hepatocytes; Immunohistochemistry; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Non-alcoholic Fatty Liver Disease; Random Allocation; Receptors, Leptin; Reference Values; Sensitivity and Specificity; Signal Transduction; Tretinoin; Up-Regulation

Excess dietary fat can cause hepatic steatosis, which can progress into severe liver disorders including steatohepatitis and cirrhosis. Steroid receptor coactivator-3 (SRC-3), a member of the p160 coactivator family, is reported as a key regulator of adipogenesis and energy homeostasis. We sought to determine the influence of SRC-3 on hepatic steatosis and the mechanism beneath.. The influence of siRNA-mediated SRC-3 silencing on hepatic lipid accumulation was assessed in HepG2 cells. The molecular mechanism of SRC-3 regulation of hepatic lipid metabolism was also studied. Moreover, the effect of SRC-3 ablation on hepatic steatosis was examined in SRC-3 deficient mice.. In this study, we report that SRC-3 ablation reduces palmitic acid-induced lipid accumulation in HepG2 cells. Moreover, deletion of SRC-3 ameliorates hepatic steatosis and inflammation response in mice fed a high fat diet (HFD). These metabolic improvements can presumably be explained by the reduction in chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) expression and the subsequent elevation in peroxisome proliferator-activated receptor α (PPARα) level. At the molecular level, SRC-3 interacts with retinoic receptor α (RARα) to activate COUP-TFII expression under all-trans retinoic acid (ARTA) treatment.. These findings indicate a crucial role for SRC-3 in regulating hepatic lipid metabolism and provide the possible novel inner mechanisms.

Topics: Animals; COUP Transcription Factor II; Dietary Fats; Disease Models, Animal; Fatty Liver; Gene Knockdown Techniques; Hep G2 Cells; Humans; Immunohistochemistry; Lipid Metabolism; Liver Cirrhosis, Experimental; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Non-alcoholic Fatty Liver Disease; Nuclear Receptor Coactivator 3; PPAR alpha; Promoter Regions, Genetic; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; RNA Interference; RNA, Small Interfering; Tretinoin