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)

Reported herein is a case of focal hepatic steatosis surrounding a metastatic insulinoma in the liver of a 69-year-old woman. The patient complained of losing consciousness after meals, and hypoglycemia and hyperinsulinemia were confirmed. On CT and abdominal angiography a mass, 1 cm in diameter, was seen in the tail of the pancreas. In the early phase of dynamic CT a mass, 5 mm in diameter, was seen in the liver. In the late phase this mass appeared to be 3 cm in diameter. An arterial calcium stimulation/venous sampling test showed insulin levels after calcium injections in the hepatic artery to be extremely high. Thus, the liver tumor was diagnosed as a metastatic insulinoma, and distal pancreatectomy and partial resection of the liver were performed. The pancreatic tumor cells were immunohistochemically positive for insulin. The liver tumor was pale yellow. A white area surrounded the tumor. Histologically, the liver tumor was an insulinoma and the white area was focal fatty change of the liver. High insulin levels are said to inhibit oxidation of free fatty acids into triglycerides, causing free fatty acids to accumulate in hepatocytes. Focal hepatic steatosis caused by the local effects of insulin can present as a focal rim surrounding a metastatic insulinoma.
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PMID:Focal hepatic steatosis surrounding a metastatic insulinoma. 1806 43

In this review, standards of diagnosis and treatment of colorectal liver metastases are described on the basis of a workshop discussion. Algorithms of care for patients with synchronous / metachronous colorectal liver metastases or locoregional recurrent tumour are presented. Surgical resection is the procedure of choice in the curative treatment of liver metastases. The decision about the resection of liver metastases should consider the following parameters: 1. General operability of the patient (comorbidity); 2. Achievability of an R 0 situation: i. if necessary, in combination with ablative methods, ii. if necessary, neoadjuvant chemotherapy, iii. the ability to eradicate extrahepatic tumour manifestations; 3. Sufficient volume of the liver remaining after resection ("future liver remnant = FLR): i. if necessary, in combination with portal vein embolisation or two-stage hepatectomy; 4. The feasibility to preserve two contiguous hepatic segments with adequate vascular inflow and outflow as well as biliary drainage; 5. Tumour biological aspects ("prognostic variables"); 6. Experience of the surgeon and centre! Extrahepatic disease does not contraindicate hepatectomy for colorectal liver metastases provided a complete resection of both intra- and extrahepatic disease is feasible. Even in bilobar colorectal metastases and 5 or more tumours in the liver, a complete tumour resection has been described. The type of resection (hepatic wedge resection or anatomic resection) does not influence the recurrence rate. Preoperative volumetry is indicated when major hepatic resection is planned. The FLR should be 25 % in patients with normal liver, 40 % in patients who have received intensive chemotherapy or in cases of fatty liver, liver fibrosis or diabetes, and 50-60 % in patients with cirrhosis. In patients with initially unresectable colorectal liver metastases, preoperative chemotherapy enables complete resection in 15-30 % of the cases, whereas the value of neoadjuvant chemotherapy in patients with resectable liver metastases has not been sufficiently supported. In situ ablative procedures (radiofrequency ablation = RFA and laser-induced interstitial thermotherapy = LITT) are local therapy options in selected patients who are not candidates for resection (central recurrent liver metastases, bilobar multiple metastases and high-risk resection or restricted patient operability). Patients with tumours larger than 3 cm have a high local recurrence rate after percutaneous RFA and are not optimal candidates for this procedure. The physician's experience influences the results significantly, both after hepatectomy and after in situ ablation. Therefore, patients with colorectal liver metastases should be treated in centres with experience in liver surgery.
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PMID:[Diagnosis and treatment of colorectal liver metastases - workflow]. 1856 94

Apoptosis is a major feature in alcoholic hepatitis. During apoptosis, the M30 neoepitope becomes exposed after keratin-18 cleavage. The tissue polypeptide-specific antigen (TPS) is a keratin-18 fragment that is routinely used as a tumor marker. Serum TPS levels are increased in patients with alcoholic hepatitis. The aim of this study was to investigate the possible relationship of TPS levels with hepatocyte apoptosis in alcoholic hepatitis. Thirty-one patients with alcoholic hepatitis and 22 with fatty liver were included. Hepatocyte apoptosis was evaluated by M30 immunostaining. Serum TPS levels were measured by a commercial immunoassay. The apoptotic score was higher in patients with alcoholic hepatitis than in patients with fatty liver. There was a significant correlation between the apoptotic score and TPS levels. The correlation of the apoptotic score with TPS levels was stronger than with standard liver tests. Serum TPS may be a marker of apoptosis in alcoholic hepatitis.
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PMID:Serum levels of keratin-18 fragments [tissue polypeptide-specific antigen (TPS)] are correlated with hepatocyte apoptosis in alcoholic hepatitis. 1861 53

Group VI phospholipase A2 (PLA2) is a family of acyl hydrolases that targets the sn-2 fatty acid on the glycerophospholipid (GPL) backbone. These enzymes are grouped together based on structural homologies and catalytic activities that are independent of calcium and hence are also called the iPLA(2)s. Although the best characterized of these enzymes, iPLA2beta and iPLA2gamma, have long been proposed as homeostatic enzymes involved in basal GPL metabolism, recent studies indicate roles for these enzymes in biomedically relevant processes as well. For example, iPLA2 modulates calcium homeostasis by promoting replenishment of intracellular calcium stores. This function is likely of importance in the pathogenesis of Duchenne muscular dystrophy and potentially allergy as well. iPLA2 has a variety of roles in bacterial pathogenesis and the host response against bacterial and fungal infections. These characteristics suggest that the enzyme as a potential target to control infectious diseases. iPLA2 is linked to both proliferation and chemotherapy-induced apoptosis of tumor cells. As such, the enzyme is a potential target for cancer chemotherapy. Recent studies indicate essential roles for iPLA2 in glucose homeostasis, maintenance of energy balance, adipocyte development, and hepatic lipogenesis. Thus, the enzyme is an attractive target for drugs to control type II diabetes, fatty liver disease, and other manifestations of the metabolic syndrome. Several recent studies have associated iPLA2 inactivation with neurodegenerative diseases, suggesting the possibility that products of the iPLA2 reaction as potential treatments for these disorders. Together, these observations suggest iPLA2 as a novel and important target for drug development. However given the ubiquitous expression of the enzyme and its roles in basal GPL metabolism, drug strategies targeting iPLA2 must exhibit exquisite selectivity to avoid undesired side effects. Furthermore, the cell-specific nature of many iPLA2 functions may present another challenge in the design and implementation of drugs targeted to the enzyme.
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PMID:Group VI phospholipases A2: homeostatic phospholipases with significant potential as targets for novel therapeutics. 1869 Oct 15

Hepatic apolipoprotein B (apoB) lipoprotein production is metabolically regulated via the phosphoinositide 3-kinase cascade; however, the role of the key negative regulator of this pathway, the tumor suppressor phosphatase with tensin homology (PTEN), is unknown. Here, we demonstrate that hepatic protein levels of apoB100 and microsomal triglyceride transfer protein (MTP) are significantly down-regulated (73% and 36%, respectively) in the liver of PTEN liver-specific knockout (KO) mice, and this is accompanied by increased triglyceride (TG) accumulation and lipogenic gene expression, and reduced hepatic apoB secretion in freshly isolated hepatocytes. MTP protein mass and lipid transfer activity were also significantly reduced in liver of PTEN KO mice. Overexpression of the dominant negative mutant PTEN C/S124 (adenovirus expressing PTEN C/S mutant [AdPTENC/S]) possessing constitutive phospoinositide 3-kinase activity in HepG2 cells led to significant reductions in both secreted apoB100 and cellular MTP mass (76% and 34%, respectively), and increased messenger RNA (mRNA) levels of sterol regulatory element binding protein 1c (SREBP-1c), fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC). Reduced apoB100 secretion induced by AdPTENC/S was associated with increased degradation of newly-synthesized cellular apoB100, in a lactacystin-sensitive manner, suggesting enhanced proteasomal degradation. AdPTENC/S also reduced apoB-lipoprotein production in McA-RH7777 and primary hamster hepatocytes. Our findings suggest a link between PTEN expression and hepatic production of apoB-containing lipoproteins. We postulate that perturbations in PTEN not only may influence hepatic insulin signaling and hepatic lipogenesis, but also may alter hepatic apoB-lipoprotein production and the MTP stability. On loss of PTEN activity, increased lipid substrate availability in the face of reduced hepatic lipoprotein production capacity can rapidly lead to hepatosteatosis and fatty liver.
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PMID:Phosphatase and tensin homolog (PTEN) regulates hepatic lipogenesis, microsomal triglyceride transfer protein, and the secretion of apolipoprotein B-containing lipoproteins. 1902 12

Mutations that cause a reduction in protein kinase A (PKA) activity have been shown to extend lifespan in yeast. Loss of function of mammalian RIIbeta, a regulatory subunit of PKA expressed in brain and adipose tissue, results in mice that are lean and insulin sensitive. It was therefore hypothesized that RIIB null (RIIbeta(-/-)) mice would express anti-aging phenotypes. We conducted lifespan studies using 40 mutant and 40 wild type (WT) littermates of equal gender numbers and found that both the median and maximum lifespans were significantly increased in mutant males compared to WT littermates. The median lifespan was increased from 884 days to 1005 days (p = 0.006 as determined by the log rank test) and the 80% lifespan (defined here as 80% deaths) was increased from 941 days to 1073 days (p = 0.004 as determined by the Wang-Allison test). There was no difference in either median or 80% lifespan in female genotypes. WT mice of both genders became increasingly obese with age, while mutant mice maintained their lean phenotype into old age. Adiposity was found to correlate with lifespan for males only. 50% of male mice between 30 and 35 g, corresponding to about 5% body fat, for either genotype lived over 1000 days. No male mouse outside of this weight range achieved this lifespan. During their last month of life, WT mice began losing weight (a total of 8% and 15% of body weight was lost for males and females, respectively), but RIIbeta(-/-) male mice maintained their lean body mass to end of life. This attenuation of decline was not seen in female mutant mice. Old male mutant mice were insulin sensitive throughout their life. Both genders showed modestly lower blood glucose levels in old mutants compared to WT. Male mutants were also resistant to age-induced fatty liver. Pathological assessment of tissues from end of life male mutant mice showed a decrease in tumor incidence, decreased severity of renal lesions, and a trend towards a decrease in age-related cardiac pathology. These findings help establish the highly conserved nature of PKA and suggest that disruption of PKA affects physiological mechanisms known to be associated with healthy aging.
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PMID:Disruption of protein kinase A in mice enhances healthy aging. 1953 87

Hepatic steatosis is a risk factor for the progression of non-alcoholic fatty liver disease. The role of pro-inflammatory interleukin (IL)-6 in hepatic steatosis etiology is controversial. We investigated in vivo and in primary hepatocyte cultures whether IL-6 has a modulator role in liver and mitochondria lipid composition and cell death in a choline-deficient (CD) diet rat model of hepatic steatosis. Dietary choline deficiency increased triglycerides and cholesterol, and reduced phosphatidylcholine (PC), phosphatidylethanolamine (PE) and the membrane integrity marker PC:PE ratio in liver. Choline-deficient diet enhanced systemic IL-6, and IL-6 receptor expression and cell death vulnerability in hepatocytes. Derangement of the mitochondrial electron transport chain and of its phospholipid environment was found in CD rat liver mitochondria, which exhibited elevated concentrations of triglycerides, cardiolipin and PC and elevated PC:PE ratio. The cell treatment with IL-6, but not PC, eliminated much of the CD-promoted lipid imbalance in mitochondria but not tumor-necrosis factor (TNF)-alpha-induced cell death. However, PC supplementation prevented the TNF-alpha-induced DNA fragmentation, cytochrome-c release and caspase-3 activity in control and CD hepatocytes. In conclusion, IL-6 ameliorated the mitochondria lipid disturbance in hepatocytes isolated from steatotic animals. Furthermore, PC is identified as a new survival agent that reverses several TNFalpha-inducible responses that are likely to promote steatosis and necrosis.
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PMID:Interleukin-6 is associated with liver lipid homeostasis but not with cell death in experimental hepatic steatosis. 1971 Jan 4

Hyperpolarized (13)C labeled molecular probes have been used to investigate metabolic pathways of interest as well as facilitate in vivo spectroscopic imaging by taking advantage of the dramatic signal enhancement provided by DNP. Due to the limited lifetime of the hyperpolarized nucleus, with signal decay dependent on T(1) relaxation, carboxylate carbons have been the primary targets for development of hyperpolarized metabolic probes. The use of these carbon nuclei makes it difficult to investigate upstream glycolytic processes, which have been related to both cancer metabolism as well as other metabolic abnormalities, such as fatty liver disease and diabetes. Glucose carbons have very short T(1)s (<1 s) and therefore cannot be used as an in vivo hyperpolarized metabolic probe of glycolysis. However, the pentose analogue fructose can also enter glycolysis through its phosphorylation by hexokinase and yield complementary information. The C(2) of fructose is a hemiketal that has a relatively longer relaxation time (approximately 16 s at 37 degrees C) and high solution state polarization (approximately 12%). Hyperpolarized [2-(13)C]-fructose was also injected into a transgenic model of prostate cancer (TRAMP) and demonstrated difference in uptake and metabolism in regions of tumor relative to surrounding tissue. Thus, this study demonstrates the first hyperpolarization of a carbohydrate carbon with a sufficient T(1) and solution state polarization for ex vivo spectroscopy and in vivo spectroscopic imaging studies.
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PMID:Hyperpolarized [2-13C]-fructose: a hemiketal DNP substrate for in vivo metabolic imaging. 1986 Apr 9

The transcription factor ATF2 was previously shown to be an ATM substrate. Upon phosphorylation by ATM, ATF2 exhibits a transcription-independent function in the DNA damage response through localization to DNA repair foci and control of cell cycle arrest. To assess the physiological significance of this phosphorylation, we generated ATF2 mutant mice in which the ATM phosphoacceptor sites (S472/S480) were mutated (ATF2(KI)). ATF2(KI) mice are more sensitive to ionizing radiation (IR) than wild-type (ATF2 (WT)) mice: following IR, ATF2(KI) mice exhibited higher levels of apoptosis in the intestinal crypt cells and impaired hepatic steatosis. Molecular analysis identified impaired activation of the cell cycle regulatory protein p21(Cip/Waf1) in cells and tissues of IR-treated ATF2(KI) mice, which was p53 independent. Analysis of tumor development in p53(KO) crossed with ATF2(KI) mice indicated a marked decrease in amount of time required for tumor development. Further, when subjected to two-stage skin carcinogenesis process, ATF2(KI) mice developed skin tumors faster and with higher incidence, which also progressed to the more malignant carcinomas, compared with the control mice. Using 3 mouse models, we establish the importance of ATF2 phosphorylation by ATM in the acute cellular response to DNA damage and maintenance of genomic stability.
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PMID:Radiation Sensitivity and Tumor Susceptibility in ATM Phospho-Mutant ATF2 Mice. 2074 50

A 41-year-old Japanese man had received successful interferon (IFN) therapy against chronic hepatitis C in 1994. Since then, serum hepatitis C virus (HCV) RNA had been negative, and aminotransferase levels had been continuously normal. He had abstained from alcohol. However, his serum aminotransferase levels showed slight elevation as his body weight increased gradually. He was diagnosed as having fatty liver and diabetes mellitus. In January 2006, 11 and a half years after the resolution of HCV infection, he was found to have a hepatic nodule 4.0 cm in diameter at liver S4/8 region by plain abdominal CT at an annual follow-up examination. He was diagnosed as having hepatocellular carcinoma (HCC) by angiography. The tumor was curatively resected and its histological diagnosis was moderately differentiated HCC. Noncancerous lesion of the liver revealed fibrosis of stage F2 and mild inflammation of grade A1 with mild steatosis. This case suggests that all patients with chronic HCV infection should be followed as long as possible for the potential development of HCC even after clearance of the virus.
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PMID:Hepatocellular Carcinoma 11 and a Half Years after the Resolution of Chronic Hepatitis C Virus Infection Successfully Treated with Interferon. 2110 71


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