Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We analysed the Proprotein Convertase Subtilisin Kexin type 9 (PCSK9) exons and intronic junctions of 71 patients with familial hypercholesterolemia (FH) in whom LDL receptor (LDLR) or apolipoprotein B100 mutations were excluded. The previously reported S127R and R237W mutations were found in South African families, whereas new missense mutations D129G and A168E were found in families from New Zealand. Only, the S127R and D129G mutations modify a highly conserved residue and segregate with the FH phenotype. We overexpressed those mutants in hepatoma cells and found that both S127R and D129G have reduced autocatalytic activity compared with wild-type PCSK9, whereas the A168E mutant is processed normally. The S127R and D129G mutants were not secreted from cells, unlike the A168E mutant and wild-type PCSK9. By immunoblot, we showed that the expression of the LDLR was reduced by 40% in cells overexpressing wild-type or A168E PCSK9 and further reduced by 30% when the S127R or D129G mutants were used. Paralleling the LDLR levels, LDL cellular binding decreased by 25% upon wild-type PCSK9 or A168E overexpression, and by 45% with both S127R and D129G mutants. Our study therefore indicates that PCSK9 mediated inhibition of the LDLR does not require PCSK9 autocatalytic cleavage or secretion, suggesting that PCSK9 may also function intracellularly.
Atherosclerosis 2008 Feb
PMID:Identification and characterization of two non-secreted PCSK9 mutants associated with familial hypercholesterolemia in cohorts from New Zealand and South Africa. 1776 44

Inflammation can produce abnormalities that could increase the risk for atherosclerosis including alterations in lipid and lipoprotein metabolism. Apolipoprotein M is a recently described HDL-associated apoprotein expressed mainly in the liver and kidney with protective effects against atherosclerosis. In this study, we describe the regulation of apolipoprotein M during the acute phase response. Stimuli that produce systemic inflammation, LPS, zymosan, or turpentine, decrease apolipoprotein M mRNA levels in the liver and kidney. Treatment of Hep3B hepatoma cells with TNF or IL-1 also decreased apolipoprotein M mRNA levels. The decrease in apolipoprotein M mRNA leads to a decrease in apolipoprotein M secretion into the media in Hep3B cells and a decrease in mouse serum following LPS administration. Moreover, in humans with acute bacterial infections or chronic HIV infection, serum apolipoprotein M levels are decreased. Apolipoprotein M is a negative acute response protein that decreases during infection and inflammation. These results are consistent with the finding that infections and inflammatory disorders accompanied by systemic inflammation are associated with an increased risk of atherosclerosis.
Atherosclerosis 2008 Jul
PMID:Infection and inflammation decrease apolipoprotein M expression. 1805 59

Although not associated with the metabolic syndrome, HCV is linked with impaired insulin signalling, insulin resistance, hypocholesterolemia and steatosis which represent a distinct HCV-associated dysmetabolic syndrome. Insulin resistance affects the development of diabetes, fibrosis, impaired response to antivirals and perhaps hepatocellular carcinoma risk. HCV infection is associated with hypocholesterolemia and steatosis reversible after sustained virologic response. A "viral", and a "metabolic" steatosis exist as function of viral genotypes. Little is known about the possible role of HCV in further components of the metabolic syndrome such as atherosclerosis, obesity, arterial hypertension, hyperuricemia and thrombotic risk factors.
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PMID:Dysmetabolic changes associated with HCV: a distinct syndrome? 1827 9

Several reasons result in the finding that patients with cirrhosis need surgery more often than other patients groups. Patients with cirrhosis frequently have comorbidities resulting in gastrointestinal, lung or cervical cancer, among others. Independent of cirrhosis, surgical resection may be the best alternative for a number of those malignancies. Comorbidities may also result in an increased incidence of vascular complications (such as lower extremity atherosclerosis and coronary stenosis) some of them being potential indications for surgery. Patients with alcoholic cirrhosis are more frequently subjected to trauma and bone fractures. Ascites leads to umbilical hernia which can be strangulated or ruptured. Emergency surgery may be needed in this context. Finally, a significant proportion of patients with cirrhosis develop hepatocellular carcinoma (HCC) during the course of the disease. Surgical resection remains a first line option for HCC. While reliable guidelines have been proposed for surgical resection of HCC and liver transplantation, no precise guidelines are available for other aspects of surgical management during cirrhosis. Specific surgical procedures such as hepatectomy and transplantation are concentrated in highly specialised centres, where detailed evaluation is relatively easy to obtain. In contrast, more general surgical procedures, either abdominal or non abdominal, are performed in various centres, making it more difficult to obtain detailed evaluation and draw recommendations. General surveys are still needed to precisely assess the risk of non-specific surgery in patients with cirrhosis, to identify risk factors and to propose reliable guidelines.
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PMID:The risk of surgery in patients with cirrhosis. 1839 51

Apolipoprotein (apo) B is essential for the assembly and secretion of triglyceride-rich lipoproteins made by the liver. As the sole protein component in LDL, apoB is an important determinant of atherosclerosis susceptibility and a potential pharmaceutical target. Single-chain antibodies (sFvs) are the smallest fragment of an IgG molecule capable of maintaining the antigen binding specificity of the parental antibody. In the present study, we describe the cloning and construction of two intracellular antibodies (intrabodies) to human apoB. We targeted these intrabodies to the endoplasmic reticulum for the purpose of retaining nascent apoB within the ER, thereby preventing its secretion. Expression of the 1D1 intrabody in the apoB-secreting human hepatoma cell line HepG2 resulted in marked reduction of apoB secretion. This study demonstrates the utility of an intrabody to specifically block the secretion of a protein determinant of plasma LDL as a therapeutic strategy for the treatment of hyperlipidemia.
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PMID:Cloning of apoB intrabodies: specific knockdown of apoB in HepG2 cells. 1855 87

Fibrates are widely prescribed in hyperlpidemic patients to prevent atherosclerosis. Their therapeutic use, however, can be associated with adverse effects like gastrointestinal disorders, myalgia, myositis and hepatotoxicity. In rodents large doses can even cause hepatocellular carcinoma. Additionally, interactions with the biotransformation of other compounds at the cytochrome P450 (CYP) system have been observed. Thus, the discovery of new substances or derivatives with less side effects is of great interest. In the present study the influence of a four-week daily oral administration of 2 mg/kg body weight ciprofibrate (CAS 52214-84-3) or of 100 mg/kg body weight clofibric acid (CAS 882-09-7) was compared to that of the respective doses of their newly synthesized glycine conjugates in adult male lean and obese Zucker rats. Although obese rats displayed distinctly higher serum lipid concentrations, after fibrate treatment values were significantly lowered in lean animals only. Livers of obese rats were significantly enlarged, histologically showing a fine-droplet like fatty degeneration and an increase in glycogen content, but no signs of inflammation. After fibrate administration histologically a hypertrophy, an eosinophilia, a reduced glycogen content and also hepatocyteapoptosis were observed. Livers of obese rats displayed higher CYP1A1 andCYP2E1 expression, but lower immunostaining for CYP2B1 and CYP3A2. No differences between the two groups of rats were seen with respect to CYP4A1 expression. Due to fibrate treatment especially CYP2E1 and CYP4A1, but also CYP1A1, 2B1 and 3A2 were induced. Resulting CYP mediated monooxygenase activities were also elevated in most cases. In general, effects of clofibric acid and clofibric acid glycinate (CAS 4896-55-3) were less distinct than those of ciprofibrate and its glycinate (CAS 640772-36-7). With no parameterinvestigated major differences were seen between the parent fibrates and their glycine conjugates. Thus, the present investigations revealed no noticeable advantages of the glycinates over ciprofibrate or clofibric acid.
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PMID:Ciprofibrate, clofibric acid and respective glycinate derivatives. Effects of a four-week treatment on male lean and obese Zucker rats. 1858 57

The ATP-binding cassette transporter A1 (ABCA1) is a membrane transporter that directly contributes to high-density lipoprotein (HDL) biogenesis by mediating the cellular efflux of cholesterol and phospholipids to lipid-poor apolipoprotein A-I. Therefore, identification of a novel upregulator of ABCA1 would be beneficial for atherosclerosis prevention and/or therapy because of its pivotal role in cholesterol homeostasis and HDL metabolism. In this study, a high-throughput assay method for ABCA1 upregulators was developed and used for screening a synthetic and natural compound library. The cell-based high-throughput screen is conducted in a 96-well format using the human hepatoma HepG2 cells stably transfected with ABCA1 promoter-luciferase construct and calibrated with reference ABCA1 upregulators (oxysterols, 9-cis-retinoic acid, thiazolidinediones, cyclic adenosine monophosphate, verapamil, fenofibrate, and oncostatin M). Among 2600 compounds, 4 microbial compounds (pyrromycin, aclarubicin, daidzein, and pratensein) were picked up as hits by the high-throughput screening assay, and those compounds were further identified as upregulators of ABCA1 expression by real-time quantitative reverse transcription-polymerase chain reaction and Western blot analysis.
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PMID:Identification of upregulators of human ATP-binding cassette transporter A1 via high-throughput screening of a synthetic and natural compound library. 1859 22

Non-alcoholic fatty liver disease is present in 15-25% of the general population. The fundamental derangement in non-alcoholic fatty liver disease is insulin resistance, a key component of the metabolic syndrome, which includes type 2 diabetes mellitus, dyslipidemia, hypertension, and obesity. The natural history of non-alcoholic fatty liver disease is not always benign, and causality for chronic liver disease and cirrhosis is well known in clinical practice and sometimes it is accompanied by hepatocellular carcinoma. Non-alcoholic fatty liver disease is likely to be associated with increased cardiovascular disease risk, and it raises the possibility that non-alcoholic fatty liver disease may be not only a marker but also an early mediator of atherosclerosis. Therapy is currently directed at treating components of the metabolic syndrome which may be beneficial also for the liver.
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PMID:[Non-alcoholic fatty liver disease and cardiovascular risk]. 1861 57

Plasminogen activator inhibitor type 1 (PAI-1), produced partly from liver is a risk factor for macrovascular and microvascular complications of diabetes. Ghrelin, a recently described orexigenic peptide hormone, attenuates PAI-1 induced by TNF-alpha in the human hepatoma cell line (HepG2). Exposure to TNF-alpha (1 ng/ml) for 24h caused a significant increase in PAI-1 mRNA expression and protein secretion, as evaluated by RT-PCR and ELISA, but pretreatment with ghrelin (1-100 ng/ml) inhibited both basal and TNF-alpha-induced PAI-1 release in a dose and time-dependent manner in HepG2. PDTC, selective NF-kappaB inhibitor, had no additive inhibitory effects with ghrelin. The results indicate that ghrelin inhibits both basal and TNF-alpha-induced PAI-1 production via NF-kappaB pathway in HepG2 cells, and suggest that the peptide plays a therapeutic role in atherosclerosis, especially in obese patients with insulin resistance, in whom ghrelin levels were reduced.
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PMID:Ghrelin attenuates plasminogen activator inhibitor-1 production induced by tumor necrosis factor-alpha in HepG2 cells via NF-kappaB pathway. 1870 Jan 66

Liver X receptor (LXR) agonists have the potential to treat atherosclerosis based on their ability to enhance reverse cholesterol transport. However, their side effects, such as induction of liver lipogenesis and triglyceridemia, may limit their pharmaceutical development. In contrast to the nonsteroidal LXR agonist N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide (T0901317), 3alpha, 6alpha, 24-trihydroxy-24, 24-di(trifluoromethyl)-5beta-cholane (ATI-829), a novel potent synthetic steroidal LXR agonist, was a poor inducer of sterol regulatory element-binding protein 1c expression in hepatoma HepG2 cells, whereas both compounds increased ABCA1 expression in macrophage THP-1 cells. In male low-density lipoprotein receptor-deficient mice, ATI-829 selectively activated LXR target gene expression in mouse intestines and macrophages but not in the liver. A significant increase in liver triglyceride and plasma triglyceriderich small very low-density lipoprotein (VLDL) was observed in T0901317 but not ATI-829-treated mice. Compared with vehicle-treated mice, atherosclerosis development was significantly inhibited in the innominate artery after treatment with either compound. However, in the aortic root, inhibition of atherosclerosis was only observed in the right (right coronary artery-associated sinus) but not the left coronary-related sinus (left coronary artery-associated sinus; LC) of mice treated with either compound. Lesions in the innominate artery were less complex after treatment with either compound and contained mostly macrophage foam cells. In contrast, LC lesions were more complex and had a large collagen-positive fibrous cap and less macrophage foam cell area after treatment with either compound. The T0901317-induced hypertriglyceridemia was accompanied by an increase in small triglyceride-rich VLDL that may influence LXR agonist-mediated antiatherosclerotic effects at certain vascular sites. ATI-829, by selectively activating LXR in certain tissues without inducing hypertriglyceridemia, is a good candidate for drug development.
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PMID:Antiatherosclerotic effects of a novel synthetic tissue-selective steroidal liver X receptor agonist in low-density lipoprotein receptor-deficient mice. 1872 76


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