CD36 deficiency and insulin resistance.
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Animals↗
Biomedical subjects
T Gotoda
Publications and source records attributed to T Gotoda.
Severe hypercholesterolemia, hypertriglyceridemia, and atherosclerosis in mice lacking both leptin and the low density lipoprotein receptor.
Leptin-deficient mice (ob/ob) are an excellent murine model for obesity, insulin resistance, and diabetes, all of which are components of a multiple risk factor syndrome that, along with hypercholesterolemia, precipitates a potential high risk for atherosclerosis. In the current study, we show an unexpectedly severe hyperlipidemia in ob/ob mice on a background of low density lipoprotein receptor (LDLR) deficiency (-/-). Doubly mutant mice (LDLR-/-;ob/ob) exhibited striking elevations in both total plasma cholesterol (TC) and triglyceride (TG) levels (1715 +/- 87 and 1016 +/- 172 mg/dl, respectively), at age 3-4 months, resulting in extensive atherosclerotic lesions throughout the aorta by 6 months. Lipoprotein analyses revealed the elevated TC and TG levels to be due to a large increase in an apoB-containing broad-beta remnant lipoprotein fraction. While fasting, diet restriction, and low level leptin treatment significantly lowered TG levels, they caused only slight changes in TC levels. Hepatic cholesterol and triglyceride contents as well as mRNA levels of cholesterologenic and lipogenic enzymes suggest that leptin deficiency increased hepatic triglyceride production but did not change cholesterol production in ob/ob mice regardless of their LDLR genotype. These data provide evidence that the hypertriglyceridemia and hypercholesterolemia in the doubly mutant mice are caused by distinct mechanisms and point to the possibility that leptin might have some impact on plasma cholesterol metabolism, possibly through an LDLR-independent pathway. This model will be an excellent tool for future studies on the relationship between impaired fuel metabolism, increased plasma remnant lipoproteins, diabetes, and atherosclerosis.
Animals↗
Asialoglycoprotein receptor deficiency in mice lacking the major receptor subunit. Its obligate requirement for the stable expression of oligomeric receptor.
The asialoglycoprotein receptor is an abundant hetero-oligomeric endocytic receptor that is predominantly expressed on the sinusoidal surface of the hepatocytes. A number of physiological and pathophysiological functions have been ascribed to this hepatic lectin (HL), the removal of desialylated serum glycoproteins and apoptotic cells, clearance of lipoproteins, and the sites of entry for hepatotropic viruses. The assembly of two homologous subunits, HL-1 and HL-2, is required to form functional, high affinity receptors on the cell surface. However, the importance of the individual subunits for receptor transport to the cell surface is controversial. We have previously generated HL-2-deficient mice and showed that the expression of HL-1 was significantly reduced, and the functional activity as the asialoglycoprotein receptor was virtually eliminated. However, we failed to detect phenotypic abnormalities. To explore the significance of the major HL-1 subunit for receptor expression and function in vivo, we have disrupted the HL-1 gene in mice. Homozygous HL-1-deficient animals are superficially normal. HL-2 expression in the liver is virtually abrogated, indicating that HL-1 is strictly required for the stable expression of HL-2. Although these mice are almost unable to clear asialo-orosomucoid, a high affinity ligand for asialoglycoprotein receptor, they do not accumulate desialylated glycoproteins or lipoproteins in the plasma.
Animals↗
Increased expression of cyclooxygenase-2 in human pancreatic neoplasms and potential for chemoprevention by cyclooxygenase inhibitors.
BACKGROUND: Cyclooxygenase-2 (COX-2) is thought to be linked to carcinogenesis; however, very little is known about its expression in pancreatic neoplasms. The authors studied the expression of COX-2 in human pancreatic neoplasms and investigated the effect of COX inhibitors on the growth of human pancreatic carcinoma cells. METHODS: Expression of COX-2 protein was immunohistochemically examined in 42 human pancreatic duct cell carcinomas (PDCs) and in 29 intraductal papillary mucinous tumors (IPMTs [adenomas, 19; carcinomas, 10]) of the pancreas that were resected surgically at the National Cancer Center Hospital in Tokyo. The growth of four human pancreatic carcinoma cell lines also was evaluated in the presence of COX inhibitors. RESULTS: Marked COX-2 expression was observed in 57% (24 of 42) of PDCs, in 58% (11 of 19) of adenomas, and in 70% (7 of 10) of adenocarcinomas of IPMTs. However, there was no correlation between COX-2 expression and clinicopathologic indices of the patients. All four pancreatic cancer cell lines expressed COX-2 protein weakly or strongly, and the inhibitory effect of aspirin on cell growth was correlated with the expression of COX-2. CONCLUSIONS: COX-2 was expressed in adenomas of IPMTs as well as in carcinomas and might have played a role in the development of pancreatic tumors. In this study, COX inhibitors, as nonsteroidal anti-inflammatory drugs, were shown to be possible preventive agents against pancreatic neoplasms.
Adenocarcinoma, Mucinous↗
The LDL receptor is the major pathway for beta-VLDL uptake by mouse peritoneal macrophages.
In order to determine the contribution of the low density lipoprotein receptor (LDL-R) to the removal of apoB-containing native lipoproteins by macrophages, we compared the uptake of beta-VLDL in peritoneal macrophages (MPM) from wild type mice and mice lacking the LDL-R. The d<1.006 g/ml lipoproteins obtained from apoE deficient mice fed a high fat diet were poorly degraded by macrophages and caused only a slight formation of CE in macrophages from both types of mice. On the other hand, d<1.006 g/ml lipoproteins obtained from LDL-R deficient mice fed a high fat diet, beta-VLDL with apoE, were avidly taken up by and markedly stimulated CE formation in wild type macrophages, but not in macrophages lacking the LDL-R. The degradation of 125I-labeled-apoE-containing beta-VLDL by wild type MPM was poorly inhibited by unlabeled human LDL, and beta-VLDL without apoE had no effects. In conclusion, we propose that the in vitro uptake of native apoE-enriched lipoproteins by murine macrophages is primarily mediated by the LDL receptor and not by other apoE-recognizing receptor systems such as: the LDL receptor related protein, the VLDL receptor or the triglyceride-rich lipoprotein receptor.
Animals↗
Evaluation of the necessity for gastrectomy with lymph node dissection for patients with submucosal invasive gastric cancer.
BACKGROUND: When cancer cells are found in the submucosal layer of an endoscopically resected specimen, patients are recommended to undergo gastrectomy with lymph node dissection. If it were possible to identify those patients in whom the risk of lymph node metastasis was negligible, it might be possible to avoid surgery. METHODS: Among those who underwent gastrectomy for gastric cancer from 1980 to 1999, 1091 patients with a cancer invading the submucosa were studied. Clinicopathological factors (sex, age, tumour location, macroscopic type, size, ulceration, histological type, lymphatic-vascular involvement and degree of submucosal penetration) were investigated for their possible association with lymph node metastasis. RESULTS: Lymph node metastases were found in 222 patients (20.3 per cent). Univariate analysis showed that larger tumour size (more than 30 mm), undifferentiated histological type, lymphatic-vascular involvement and massive submucosal penetration had a significant association with lymph node metastasis. Tumour size, histological type and lymphatic-vascular involvement were independent risk factors for lymph node metastasis. By combining these three factors with submucosal penetration of less than 500 microm, 117 patients could be selected as having a minimal risk of lymph node metastasis (95 per cent confidence interval 0-3.1 per cent). CONCLUSION: Lymphadenectomy may not be necessary for patients with gastric cancer invading the submucosa who fulfil the above conditions
Female↗
Thiazolidinedione- and tumor necrosis factor alpha-induced downregulation of peroxisome proliferator-activated receptor gamma mRNA in differentiated 3T3-L1 adipocytes.
Thiazolidinediones (TZDs) are antidiabetic insulin-sensitizing agents that bind to peroxisome proliferator-activated receptor gamma (PPARgamma) and have potent adipogenic effects on 3T3-L1 preadipocytes. In fully differentiated 3T3-L1 adipocytes, TZDs markedly decreased PPARgamma mRNA levels without reducing the expression of genes that are positively regulated by PPARgamma, such as adipocyte lipid-binding protein 2 (aP2) or lipoprotein lipase-(LPL). PPARgamma mRNA levels were also downregulated by tumor necrosis factor alpha (TNFalpha), an antiadipogenic cytokine. We propose that the downregulation of PPARgamma is not the common denominator of the metabolic effects of TZDs and TNFalpha on mature adipocytes.
3T3 Cells↗
Metastatic tumors to the stomach: analysis of 54 patients diagnosed at endoscopy and 347 autopsy cases.
BACKGROUND AND STUDY AIMS: There have been several published reports on metastatic lesions in the stomach, but the numbers of cases have been limited due to the low frequency of the condition. The present study examined the clinicopathological features of metastatic tumors in the stomach from distant sites in a large series of cases. PATIENTS AND METHODS: A total of 389 patients with gastric metastases from solid malignant tumors were examined between 1968 and 1998 at our institution. Of these, 347 were identified from a series of 6380 autopsy cases; 54 patients were diagnosed endoscopically while alive, 12 of whom had confirmation of the condition at autopsy. RESULTS: In the endoscopically diagnosed cases, the metastases presented as solitary (65%) or multiple lesions (35 %), and were more frequently located in the middle or upper third of the stomach. Although the endoscopic appearance often resembled that of submucosal tumor (51%) or primary gastric cancer (39%), the final diagnosis was easily obtained in over 90% of cases from endoscopic biopsies. In two cases of lung cancer and breast cancer, gastric metastases were found before the primary tumors. In the autopsy cases with solid malignancies, metastatic lesions to the stomach were found in 5.4%, and the lung, breast, and esophagus were common primary sites. Malignant melanoma was the most frequent tumor to metastasize to the stomach (29.6%). CONCLUSIONS: Since metastatic lesions to the stomach are rare, the above characteristics of the lesions should be borne in mind, and biopsies should be taken for precise diagnosis during endoscopic examinations.
Adult↗
Endoscopic mucosal resection.
We are now finding more malignancies in their early stages than previously. Attempts to ablate these lesions are difficult and do not provide the histological information required to decide on further treatment. Surgery is difficult to justify, as only a minority of lesions are associated with lymph node metastases and lesions may not become clinically relevant within the lifetime of an elderly patient. Endoscopic mucosal resection allows cancers to be resected at minimal cost, morbidity and mortality. It is also the most reliable investigation when assessing lesions which are suspicious for containing early cancer. After endoscopic removal, histological assessment of depth of penetration and a search for invasion into lymphatics or venules allows the risk of microscopic lymph node metastases to be predicted. The risk of developing metastatic disease can then be balanced against the risks of surgery in view of the patient's age and health.
Biopsy↗
Sodium thiosulfate solution spray for relief of irritation caused by Lugol's stain in chromoendoscopy.
BACKGROUND: Mucosal iodine staining is known to improve the endoscopic visualization of esophageal squamous dysplasia and cancer. However, it often causes mucosal irritation leading to retrosternal discomfort. The clinical usefulness of sodium thiosulfate solution (STS) for easing symptoms induced by mucosal staining with Lugol's solution was evaluated in this study. METHODS: One hundred twenty healthy men over 50 years of age were enrolled in the study. They each underwent esophagogastroscopy including the spraying of Lugol's iodine solution (10 mL) on the mid and distal esophagus and were subsequently randomized into three groups: (I) no treatment (n = 40), (II) spraying of 20 mL of aluminum-magnesium hydroxide gel (Maalox) by means of endoscopic catheter (n = 40), and (III) spraying of 20 mL of 5% sodium thiosulfate solution by means of endoscopic catheter (n = 40). An hour after the endoscopic examination the subjects were asked to complete a questionnaire that addressed adverse symptoms induced by Lugol's iodine staining. RESULTS: Sodium thiosulfate solution spray substantially reduced adverse symptoms that lasted more than 30 minutes after chromoendoscopy, compared with the no-treatment group. There was no significant difference in the proportion of subjects with symptoms between the Maalox and no-treatment groups. Cost of sodium thiosulfate solution spray per use was $0.15 (15 yen). CONCLUSIONS: Sodium thiosulfate solution is recommended for routine use after Lugol's staining.
Coloring Agents↗
Identification of liver X receptor-retinoid X receptor as an activator of the sterol regulatory element-binding protein 1c gene promoter.
In an attempt to identify transcription factors which activate sterol-regulatory element-binding protein 1c (SREBP-1c) transcription, we screened an expression cDNA library from adipose tissue of SREBP-1 knockout mice using a reporter gene containing the 2.6-kb mouse SREBP-1 gene promoter. We cloned and identified the oxysterol receptors liver X receptor (LXRalpha) and LXRbeta as strong activators of the mouse SREBP-1c promoter. In the transfection studies, expression of either LXRalpha or -beta activated the SREBP-1c promoter-luciferase gene in a dose-dependent manner. Deletion and mutation studies, as well as gel mobility shift assays, located an LXR response element complex consisting of two new LXR-binding motifs which showed high similarity to an LXR response element recently found in the ABC1 gene promoter, a reverse cholesterol transporter. Addition of an LXR ligand, 22(R)-hydroxycholesterol, increased the promoter activity. Coexpression of retinoid X receptor (RXR), a heterodimeric partner, and its ligand 9-cis-retinoic acid also synergistically activated the SREBP-1c promoter. In HepG2 cells, SREBP-1c mRNA and precursor protein levels were induced by treatment with 22(R)-hydroxycholesterol and 9-cis-retinoic acid, confirming that endogenous LXR-RXR activation can induce endogenous SREBP-1c expression. The activation of SREBP-1c by LXR is associated with a slight increase in nuclear SREBP-1c, resulting in activation of the gene for fatty acid synthase, one of its downstream genes, as measured by the luciferase assay. These data demonstrate that LXR-RXR can modify the expression of genes for lipogenic enzymes by regulating SREBP-1c expression, providing a novel link between fatty acid and cholesterol metabolism.
Alitretinoin↗
Endoscopic mucosal resection for treatment of early gastric cancer.
BACKGROUND: In Japan, endoscopic mucosal resection (EMR) is accepted as a treatment option for cases of early gastric cancer (EGC) where the probability of lymph node metastasis is low. The results of EMR for EGC at the National Cancer Center Hospital, Tokyo, over a 11 year period are presented. METHODS: EMR was applied to patients with early cancers up to 30 mm in diameter that were of a well or moderately histologically differentiated type, and were superficially elevated and/or depressed (types I, IIa, and IIc) but without ulceration or definite signs of submucosal invasion. The resected specimens were carefully examined by serial sections at 2 mm intervals, and if histopathology revealed submucosal invasion and/or vessel involvement or if the resection margin was not clear, surgery was recommended. RESULTS: Four hundred and seventy nine cancers in 445 patients were treated by EMR from 1987 to 1998 but submucosal invasion was found on subsequent pathological examination in 74 tumours. Sixty nine percent of intramucosal cancers (278/405) were resected with a clear margin. Of 127 cancers without "complete resection", 14 underwent an additional operation and nine were treated endoscopically; the remainder had intensive follow up. Local recurrence in the stomach occurred in 17 lesions followed conservatively, in one lesion treated endoscopically, and in five lesions with complete resection. All tumours were diagnosed by follow up endoscopy and subsequently treated by surgery. There were no gastric cancer related deaths during a median follow up period of 38 months (3-120 months). Bleeding and perforation (5%) were two major complications of EMR but there were no treatment related deaths. CONCLUSION: In our experience, EMR allows us to perform less invasive treatment without sacrificing the possibility of cure.
Adult↗
Troglitazone inhibits atherosclerosis in apolipoprotein E-knockout mice: pleiotropic effects on CD36 expression and HDL.
Atherosclerotic coronary heart disease is a common complication of the insulin resistance syndrome that can occur with or without diabetes mellitus. Thiazolidinediones (TZDs), which are insulin-sensitizing antidiabetic agents, can modulate the development of atherosclerosis not only by changing the systemic metabolic conditions associated with insulin resistance but also by exerting direct effects on vascular wall cells that express peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a nuclear receptor for TZDs. Here we show that troglitazone, a TZD, significantly inhibited fatty streak lesion formation in apolipoprotein E-knockout mice fed a high-fat diet (en face aortic surface lesion areas were 6.9+/-2.5% vs 12.7+/-4.7%, P<0.05; cross-sectional lesion areas were 191 974+/-102 911 micrometer(2) vs 351 738+/-175 597 micrometer(2), P<0.05; n=10). Troglitazone attenuated hyperinsulinemic hyperglycemia and increased high density lipoprotein cholesterol levels. In the aorta, troglitazone markedly increased the mRNA levels of CD36, a scavenger receptor for oxidized low density lipoprotein, presumably by upregulating its expression, at least in part, in the macrophage foam cells. These results indicate that troglitazone potently inhibits fatty streak lesion formation by modulating both metabolic extracellular environments and arterial wall cell functions.
Animals↗
The Pro12 -->Ala substitution in PPAR-gamma is associated with resistance to development of diabetes in the general population: possible involvement in impairment of insulin secretion in individuals with type 2 diabetes.
The allele frequencies for a Pro12-->Ala substitution in peroxisome proliferator-activated receptor-gamma differ among ethnic groups, and its relationship with diabetes and associated diseases is controversial. The prevalence of this polymorphism and its effects on clinical characteristics have now been evaluated with a large number of Japanese individuals with type 2 diabetes (n = 2,201) and normal control subjects (n = 1,212) recruited by 10 institutions located in seven different cities in Japan. The allele frequency for the Ala12 variant was significantly lower in the type 2 diabetic group than in the control group (2.39 vs. 4.13%, P = 0.000054). However, compared with subjects without the Ala12 variant, the diabetic subjects with this variant exhibited a significantly higher serum concentration of total cholesterol (P = 0.001), manifested a reduced capacity for insulin secretion as evaluated by homeostasis model assessment (P = 0.007), and tended to possess a higher level of HbA1c. These data suggest that the Ala12 variant is associated with a reduced risk for the development of diabetes in the general population, but that it may be also a risk factor for insulin deficiency and disease severity in individuals with type 2 diabetes.
Adult↗
Usefulness of Maalox for detection of the precise bleeding points and confirmation of hemostasis on gastrointestinal hemorrhage.
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Aluminum Hydroxide↗
Early carcinoma of the gastric cardia in Japan: is it different from that in the West?
BACKGROUND: The incidence of adenocarcinoma of the gastric cardia has increased recently in the West. However, in Japan, most patients with gastric carcinoma have disease that is situated in the body and the distal stomach. The objectives of this study were to compare the clinicopathologic findings of patients with early gastric carcinoma (EGC) arising at the cardia and those with carcinoma in more distal parts of the stomach, then comparing the findings with those from patients with carcinoma of the gastric cardia in the West. METHODS: Three thousand one hundred forty-four patients with EGC who underwent surgical resection between 1962 and 1997 at the National Cancer Center Hospital in Tokyo were studied. Seventy patients with EGC at the cardia were compared with those who had lesions in the middle and lower parts of the stomach. The body mass index (BMI), smoking, and drinking were evaluated using all patients with cardia EGC and 344 patients in a matched cohort in the latter group. RESULTS: Seventy patients had an EGC located just at the cardia, whereas 2796 patients had lesions in the lower two-thirds of the stomach. The former lesions were different from those in the distal two-thirds of the stomach: More often, they were of an elevated type (34% vs. 14%, respectively, they were histologically well differentiated in 89% (vs. 59%), and there were more submucosal tumors (53% vs. 41%). The BMI, smoking, and drinking in the two groups were not different. The incidence of Barrett esophagus and gastroesophageal reflux disease (GERD) in patients with EGC were 2. 9% (2 of 70 patients) and 5.7% (4 of 70 patients), respectively. CONCLUSIONS: There were many significant differences in clinicopathologic characteristics between patients with carcinoma of the cardia and patients with carcinoma of the distal stomach in Japan. The incidence of early cardia carcinoma was very low in Japan, and obesity, smoking, drinking, Barrett esophagus, or GERD were not related to its occurrence, in contrast to reports in the West.
Adenocarcinoma↗
Sterol regulatory element-binding protein-1 is regulated by glucose at the transcriptional level.
In vivo studies suggest that sterol regulatory element-binding protein (SREBP)-1 plays a key role in the up-regulation of lipogenic genes in the livers of animals that have consumed excess amounts of carbohydrates. In light of this, we sought to use an established mouse hepatocyte cell line, H2-35, to further define the mechanism by which glucose regulates nuclear SREBP-1 levels. First, we show that these cells transcribe high levels of SREBP-1c that are increased 4-fold upon differentiation from a prehepatocyte to a hepatocyte phenotype, making them an ideal cell culture model for the study of SREBP-1c induction. Second, we demonstrate that the presence of precursor and mature forms of SREBP-1 protein are positively regulated by medium glucose concentrations ranging from 5. 5 to 25 mm and are also regulated by insulin, with the amount of insulin in the fetal bovine serum being sufficient for maximal stimulation of SREBP-1 expression. Third, we show that the increase in SREBP-1 protein is due to an increase in SREBP-1 mRNA. Reporter gene analysis of the SREBP-1c promoter demonstrated a glucose-dependent induction of transcription. In contrast, expression of a fixed amount of the precursor form of SREBP-1c protein showed that glucose does not influence its cleavage. Fourth, we demonstrate that the glucose induction of SREBP could not be reproduced by fructose, xylose, or galactose nor by glucose analogs 2-deoxy glucose and 3-O-methyl glucopyranose. These data provide strong evidence for the induction of SREBP-1c mRNA by glucose leading to increased mature protein in the nucleus, thus providing a potential mechanism for the up-regulation of lipogenic genes by glucose in vivo.
Animals↗