Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015695 (fatty liver)
 13,941 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tamoxifen is a nonsteroidal anti-estrogenic drug used for adjuvant treatment of breast cancer and recently as a chemopreventative agent for breast cancer and, on an investigational basis, for other cancers. To date there are case reports of hypertriglyceridemia and fatty liver disease in tamoxifen users. Fatty liver is associated with visceral obesity and other components of the metabolic syndrome. Here we evaluated steatosis and adipose tissue distribution by CT scan in a cross-sectional study of 32 women on tamoxifen and 39 control women. Tamoxifen users had more visceral adipose tissue (VAT) and more liver fat than controls. This is the first study to demonstrate that fatty liver and intra-abdominal fat accumulation are common in breast cancer patients receiving tamoxifen. Prospective studies of tamoxifen should monitor metabolic changes in obese women with or without breast cancer.
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PMID:Relationships between tamoxifen use, liver fat and body fat distribution in women with breast cancer. 1141 Aug 35

Tamoxifen is a potent antagonist of estrogen, and hepatic steatosis is a frequent complication in adjuvant tamoxifen for breast cancer. Recently, aromatase-deficient (ArKO, Ar-/-) mice lacking intrinsic estrogen was developed and the molecular mechanism involved in progression of massive hepatic steatosis in estrogen-deficiency was elucidated; impairment in hepatic fatty acid beta-oxidation of peroxisomes, microsomes and mitochondria. This impairment is latent, but is potentially serious, because hepatic energy supply depends greatly on fatty acid beta-oxidation. Therefore in the present study, we tried to conquer impaired hepatic fatty acid beta-oxidation by administrating bezafibrate, a potent peroxisome proliferator, to Ar-/- mice through activating fatty acid beta-oxidation via the peroxisome proliferator activated receptor-alpha mediated signaling pathway. Northern blot analysis of Ar-/- mice liver revealed a significant restoration of mRNA expression of very long fatty acyl-CoA synthetase in peroxisome, peroxisomal fatty acyl-CoA oxidase, and medium-chain acyl-CoA dehydrogenase in mitochondria, essential enzymes in fatty acid beta-oxidation by administration of bezafibrate. Severe hepatic steatosis observed in Ar-/- mice regressed dramatically. Consistent findings were obtained in the in vitro assays of fatty acid beta-oxidation activity. These findings demonstrate that bezafibrate is capable of restoring impaired fatty acid beta-oxidation in vivo via the peroxisome proliferator-activated receptor-alpha mediated signaling pathway and is potent enough to regress severe hepatic steatosis in mice deficient in intrinsic estrogen.
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PMID:Aromatase-deficient (ArKO) mice are retrieved from severe hepatic steatosis by peroxisome proliferator administration. 1192 13

Tamoxifen has been used for a long time as a hormonal treatment in breast cancer. Recent studies in pre and postmenopausal women have shown that tamoxifen exhibits favorable effects on the lipid profile. In this study we investigated the effects of tamoxifen on lipid profile and hepatic steatosis. Fifty two (31 postmenopausal and 21 premenopausal) women with breast cancer treated with tamoxifen at a dose of 20 mg daily were included in the study. Serum lipid parameters (total cholesterol, high and low density lipoprotein cholesterol and triglyceride) were measured baseline and at the 6th month of tamoxifen treatment. Upper abdominal ultrasonography was performed before and at the 6th month of therapy for assessment of liver steatosis. We obtained decreased levels of serum total cholesterol after 6 months of tamoxifen treatment (p < 0.05). However, we did not detect any changes in triglyceride and high-density lipoprotein cholesterol levels (p > 0.05). Increased liver steatosis was observed in 22 patients (42.3%) after tamoxifen treatment. We could not detect increase in lipid levels in these patients. There was no significant difference between the lipid levels in the patients with increased liver steatosis and stable or no liver steatosis. Whether hepatic steatosis is dependent on lipid changes in tamoxifen use should be further investigated.
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PMID:Tamoxifen therapy and hepatic steatosis. 1204 63

The purpose of the present study was to investigate the effects of tamoxifen on the size and oxidative susceptibility of low-density lipoprotein (LDL) particles in breast cancer patients with tamoxifen-induced fatty liver. We investigated the following breast cancer patients: 13 receiving no tamoxifen (group A), 13 receiving tamoxifen 40 mg daily but without fatty liver (group B), and 13 receiving tamoxifen 40 mg daily with fatty liver (group C). Plasma lipids and diameter of LDL particles were measured. Susceptibility of LDL to oxidation was analyzed by incubation with CuSO(4) while monitoring conjugated diene formation and assaying thiobarbituric acid reactive substances (TBARS). Plasma total and LDL cholesterol concentrations in groups B and C were significantly lower than those in group A. In group C, concentrations of plasma triglyceride (TG) and TBARS were significantly greater, but LDL particle diameter and lag time for LDL oxidation were significantly smaller than those in groups A and B. Plasma TG concentrations correlated negatively with computed tomography ratio of liver to spleen (r = -0.76; P < 0.001). LDL particle diameter correlated negatively with plasma TG (r = -0.62; P < 0.001) and TBARS (r = -0.44; P < 0.01), but positively with LDL lag time (r = 0.47; P < 0.01). Tamoxifen-induced fatty liver in breast cancer patients may be atherogenic, via increased TG and consequent small, easily oxidized LDL particles.
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PMID:Size and oxidative susceptibility of low-density lipoprotein particles in breast cancer patients with tamoxifen-induced fatty liver. 1216 95

Tamoxifen is a potent antagonist of estrogen, and hepatic steatosis is a frequent complication in adjuvant tamoxifen for breast cancer. Impaired hepatic FA beta-oxidation in peroxisomes, microsomes, and mitochondria results in progression of massive hepatic steatosis in estrogen deficiency. This impairment, although latent, is potentially serious: About 3% of the general population in the United States is now suffering from nonalcoholic steatohepatitis associated with obesity and hyperlipidemia. Therefore, in the present study we tried to restore impaired hepatic FA beta-oxidation by administering a novel statin, pitavastatin, to aromatase-deficient (Ar-/-) mice defective in intrinsic estrogen synthesis. Northern blot analysis of Ar-/- mice liver revealed a significant restoration of mRNA expression of essential enzymes involved in FA beta-oxidation such as very long fatty acyl-CoA synthetase in peroxisome, peroxisomal fatty acyl-CoA oxidase, and medium-chain acyl-CoA dehydrogenase. Severe hepatic steatosis observed in Ar-/- mice substantially regressed. Consistent findings were obtained in the in vitro assays of FA beta-oxidation activity. These findings demonstrate that pitavastatin is capable of restoring impaired FA beta-oxidation in vivo via the peroxisome proliferator-activated receptor-alpha-mediated signaling pathway and is potent enough to ameliorate severe hepatic steatosis in mice deficient in intrinsic estrogen.
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PMID:Pitavastatin ameliorates severe hepatic steatosis in aromatase-deficient (Ar-/-) mice. 1288 Jan 7

Nonalcoholic steatohepatitis (NASH) is a common feature of the metabolic syndrome and toxic reactions to pharmacological drugs. Tamoxifen, (TMX) a widely used anti-breast cancer drug, can induce NASH and changes in plasma cholesterol levels through mechanisms that are unclear. We studied primary actions of TMX using a short-term treatment (5 days) that induces microvesicular hepatic steatosis and marked hypercholesterolemia in male rats. Using a combined approach of gene expression profiling and NMR-based metabolite analysis, we found that TMX-treated livers have increased saturated fatty acid content despite changes in gene expression, indicating decreased de novo lipogenesis and increased fatty acid oxidation. Our results show that TMX predominantly down-regulates FAS expression and activity as indicated by the accumulation of malonyl-CoA, a known inhibitor of mitochondrial beta-oxidation. In the face of a continued supply of exogenous free fatty acids, the blockade of fatty acid oxidation produced by elevated malonyl-CoA is likely to be the major factor leading to steatosis. Use of a combination of metabolomic and transcriptomic analysis has allowed us to identify mechanisms underlying important metabolic side effects of a widely prescribed drug. Given the broader importance of hepatic steatosis, the novel molecular mechanism revealed in this study should be examined in other forms of steatosis and nonalcoholic steatohepatitis.
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PMID:Transcript and metabolite analysis of the effects of tamoxifen in rat liver reveals inhibition of fatty acid synthesis in the presence of hepatic steatosis. 1598 34

We experienced changes in ultrasonographic features of hepatic parenchyma in 156 patients treated with Tamoxifen (TAM) as an adjuvant hormonal therapy for breast cancer. After the treatment with TAM subsequent to the surgery for breast cancer, 36% of patients showed changes in ultrasonographic features of the liver more than Grade 2, despite no obvious hepatic involvement at the start of the medication. Forty-five percent of affected patients showed Grade 2 or 3 changes in hepatic parenchymal images within the first 6 months of TAM medication, while the average interval of change was 11.3 months. Abdominal ultrasound inspection should be undertaken within 6 months of surgery to aid the early detection of liver metastasis and fatty liver changes, which may play an important role in determining postoperative follow-up care for breast cancer patients.
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PMID:Changes in hepatic parenchymal ultrasound images in tamoxifen medication patients. 1628 28

Tamoxifen can induce hepatic steatosis in women. In this study, we wanted to elucidate the mechanism behind the tamoxifen-induced accumulation of triacylglycerol in liver in female rats, and we hoped to prevent this development by combination treatment with the modified fatty acid tetradecylthioacetic acid (TTA). The increased hepatic triacylglycerol level after tamoxifen treatment was accompanied by decreased acetyl-coenzyme A carboxylase (ACC) and FAS activities, increased glycerol-3-phosphate acyltransferase (GPAT) activity, and a tendency to increased diacylglycerol acyltransferase (DGAT) activity. The activities and mRNA levels of enzymes involved in beta-oxidation, ketogenesis, and uptake of lipids from liver were unaffected by tamoxifen, whereas the uptake of lipoproteins was unchanged and the uptake of fatty acids was decreased. Combination treatment with tamoxifen and TTA (Tam+TTA) normalized the hepatic triacylglycerol level and increased the activities of ACC, FAS, GPAT, and DGAT compared with tamoxifen-treated rats. The activities and mRNA levels of enzymes involved in beta-oxidation, ketogenesis, and uptake of lipids were increased after Tam+TTA treatment. In conclusion, tamoxifen increased the hepatic triacylglycerol level, probably as a result of increased triacylglycerol biosynthesis combined with unchanged beta-oxidation. The tamoxifen-induced accumulation of triacylglycerol was prevented by cotreatment with TTA, through mechanisms of increased mitochondrial and peroxisomal beta-oxidation.
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PMID:Causes and prevention of tamoxifen-induced accumulation of triacylglycerol in rat liver. 1686 97

Recent progress of studies in NASH displays multi-disciplinary characters of the pathogeneses. Despite these advances, the strategic use of imaging modalities such as CT, US, and MRI, remains a relatively low priority in clinical situations, because these can only visualize the presence of fatty infiltration to the hepatic parenchyma, impossible to figure out the dynamic function of NASH liver. Morphological alteration such as CT value, MR signal intensity and echo-grade do not distinguish NASH from simple fatty liver. In this presentation, from a radiologic viewpoint, we show the feasibility of in vivo fatty acid imaging with (123)I-beta-methyl-p-iodophenyl-pentadecanoic acid (BMIPP). BMIPP is an (123)I labeled fatty acid analog for imaging damaged myocardium, using conventional nuclear imaging equipment. Under normal conditions, the energy source for myocardial utilization is dependent on the beta-oxidation of fatty acids. For energy production in ischemic myocardium, the drastic switch from reduced beta-oxidation of fatty acids to glucose metabolism is well known. BMIPP can detect the area of reduced fatty acids metabolism on myocardial imaging and the data can be converted into semiquantitative analysis. Therefore, we speculate that the use of BMIPP to in vivo hepatic imaging in NASH could highlight a lot of matters of NASH. Details of this presentation include: (1) Hepatic imaging with BMIPP; (2) Clearance of BMIPP from NASH liver; (3) semiquantitative analysis of hepatic BMIPP clearance and clinical features of NASH; (4) Profiles of NASH categorized by BMIPP imaging and (5) Preliminary data of BMIPP clearance in patients with Tamoxifen-induced NASH. The core of our stance in this presentation is searching for valuable advice on clinical use of BMIPP in patients with NASH from specialists in the field of HEPATOLOGY.
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PMID:In vivo imaging of hepatic fatty acid metabolism in patients with nonalcoholic steatohepatitis using semiquantative (123)I-BMIPP liver scan. 1689 Jan 72

Hepatitis C infection is associated with the development of hepatocellular carcinoma, and progress has been made in a number of areas. Transgenic mice lines expressing the hepatitis C core protein develop hepatic steatosis, adenomas, and hepatocellular carcinomas, with no significant hepatitis or fibrosis. This implies that hepatitis C can lead directly to malignant transformation. A new lesion, irregular regeneration, has been described in chronic hepatitis C infection and is associated with a 15-fold increase in the relative risk of developing hepatocellular carcinoma. A minority of patients with hepatitis C-related hepatocellular carcinoma have intense lymphocytic infiltration of the cancer, a feature associated with a better prognosis. Several studies have confirmed the association between large cell dysplasia and hepatocellular carcinoma. However, large cell dysplasia may not be a premalignant lesion and instead may be a marker for premalignant alterations elsewhere in the liver. Oral contraceptives previously have been linked to an increased risk of hepatocellular carcinoma. A large multicenter European case-control study has shown minimal increased risk of hepatocellular carcinoma with use of steroidal contraception. Tamoxifen had shown promise in the management of advanced hepatocellular carcinoma. However, a randomized placebo-controlled study of 477 patients with hepatocellular carcinoma found no benefit from tamoxifen. In a preliminary study, however, octreotide has shown improved survival and quality of life in patients with advanced hepatocellular carcinoma. Finally, interferon treatment continues to be linked to a reduced risk of hepatocellular carcinoma in patients with hepatitis C. These studies generally are not randomized, and a randomized prospective study is required to address this issue.
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PMID:Hepatocellular carcinoma. 1702 53


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