Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.34 (lipoprotein lipase)
 7,025 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Progressive weight loss is a common feature of many types of cancer and is responsible not only for a poor quality of life and poor response to chemotherapy, but also a shorter survival time than is found in patients with comparable tumors without weight loss. Although anorexia is common, a decreased food intake alone is unable to account for the changes in body composition seen in cancer patients, and increasing nutrient intake is unable to reverse the wasting syndrome. Although energy expenditure is increased in some patients, cachexia can occur even with a normal energy expenditure. Various factors have been investigated as mediators of tissue wasting in cachexia. These include cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interferon-gamma (IFN-gamma) and leukemia inhibitory factor (LIF), as well as tumor-derived factors such as lipid mobilizing factor (LMF) and protein mobilizing factor (PMF), which can directly mobilize fatty acids and amino acids from adipose tissue and skeletal muscle respectively. Induction of lipolysis by the cytokines is thought to result from an inhibition of lipoprotein lipase (LPL), although clinical studies provide no evidence for an inhibition of LPL in the adipose tissue of cancer patients. Instead there is an increased expression of hormone sensitive lipase, the enzyme activated by LMF. Protein degradation in cachexia is associated with an increased activity of the ATP-ubiquitin-proteasome pathway. The biological activity of both the LMF and PMF was shown to be attenuated by eicosapentaenoic acid (EPA). Clinical studies show that this polyunsaturated fatty acid is able to stabilize the rate of weight loss and adipose tissue and muscle mass in cachectic patients with unresectable pancreatic cancer. Knowledge of the mechanism of cancer cachexia should lead to the development of new therapeutic agents.
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PMID:Wasting in cancer. 991 7

The ascites hepatoma Yoshida AH130 causes in the host a rapid and progressive body weight loss, associated with reduced food intake, and protein and lipid hypercatabolism. Because insulin regulates glucose as well as lipid and protein metabolism, we suggest that the observed alterations are at least in part secondary to hypoinsulinemia and/or to the increase of counterregulatory hormones in AH130-bearing rats. To verify this hypothesis, controls with free access to food (n = 4), controls with free access to food plus insulin (107 micromol. kg body wt-1. d-1) (n = 4), controls pair-fed to the tumor-bearing rats (n = 4), pair-fed controls treated with insulin (n= 4), tumor hosts (n = 9), and tumor hosts treated with insulin (n = 6) were used. The Yoshida ascites hepatoma cells ( approximately 10(8) cells/rat) were inoculated intraperitoneally. Daily food intake and body weight were measured; insulin was injected starting the day of tumor implantation for 6 d. The metabolism of both cholesterol and lipids was investigated in tumor cells, and ascitic fluid and blood serum were investigated at the end of treatment. Insulin prevented the reduction of food intake (19 +/- 0.6 vs. 13 +/- 0.4 g/d, P < 0.01; AH130 hosts treated and not treated with insulin, respectively), the loss of body weight (202 +/- 12 vs. 135 +/- 9 g, P < 0.01), lowered the circulating triglycerides (48.3 +/- 4.9 vs. 84.5 +/- 7.1 mmol/L, P < 0.01), and free fatty acids (561 +/- 47 vs. 989 +/- 54 mmol/L (P < 0.01), while corrected the decrease of adipose lipoprotein lipase activity (1,240 +/- vs. 300 +/- pmol FA, P < 0.01) observed in AH130 hosts. Moreover, insulin prevented the decrease in HDL cholesterol (13.2 +/- 0.8 vs. 9.3. +/- 0.7 mmol/L, P < 0.01) and significantly increased hepatic cholesterol synthesis as evaluated by 14C-acetate incorporation into cholesterol, in both liver (3,337 +/- 245 vs. 830 +/- 115 Bq/g, P < 0.01) and AH130 cells (11,676 +/- 1,693 vs. 4,196 +/- 527 Bq/10(6) cells, P < 0.01). Thus insulin treatment ameliorated many metabolic derangements, with a lengthening of rats survival time (7 +/- 1 vs. 11 +/- 1 d, P < 0.05) without significantly stimulating tumor growth. These data, together with our previous observations on the effectiveness of insulin on protein turnover perturbations, suggest that many metabolic alterations occurring during cancer cachexia can be avoided by the administration of this hormone.
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PMID:Alterations of lipid and cholesterol metabolism in cachectic tumor-bearing rats are prevented by insulin. 1008 77

Our recent study has demonstrated that ponalrestat, an aldose reductase inhibitor, activates lipoprotein lipase (LPL) activity in the adipose tissue and alleviates the cachectic symptoms induced by B16 melanoma in mice. In this study, the effect of ponalrestat on cachexia symptoms in nude mice bearing human melanomas G361 and SEKI was investigated because it has been suggested that the suppression of LPL has an important role in cachexia induction by these two melanomas in nude mice. Mice bearing G361 subcutaneously did not gain weight and became cachectic, associated with the tumor growth. Tumor growth was not affected by ponalrestat, nevertheless treatment with ponalrestat resulted in an amelioration of the reduction in the weight of body mass, epididymal fat, gastrocnemius muscle, carcass and whole body lipid induced by the presence of G361. A severe weight loss observed in nude mice bearing SEKI was also partially attenuated by ponalrestat treatment. Overall, this study showed that ponalrestat is effective in the attenuation of the cachectic symptoms induced by human melanomas G361 and SEKI in nude mice, suggesting that ponalrestat has a potential usefulness for the treatment of cancer cachexia.
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PMID:Ponalrestat, an aldose reductase inhibitor, inhibits cachexia syndrome in nude mice bearing human melanomas G361 and SEKI. 1062 59

Our recent study has demonstrated that ponalrestat, an aldose reductase inhibitor, activates lipoprotein lipase activity and alleviates B16 melanoma-induced cachexia in mice. In this study, the effect of ponalrestat on murine adenocarcinoma colon26-induced cachexia was investigated in mice. Mice bearing colon26 subcutaneously lost weight and became cachectic, associated with the tumor growth. Although tumor growth was slightly stimulated when tumor bearing mice were treated with ponalrestat: nevertheless, the drug attenuated the reduction in the weight of body mass, epididymal fat, gastrocnemius muscle and carcass induced by colon26, as well as significantly prolonged the survival of the colon26 bearing mice. Ponalrestat inhibited the production of interleukin-1 (IL-1) from human monocytes stimulated by Lipopolysaccharide (LPS) in vitro, and also suppressed LPS-induced increase of IL-1 in the blood in mice. Overall, this study showed that ponalrestat suppresses IL-1 production both in vitro and in vivo, and inhibits the cachectic symptoms induced by colon26 adenocarcinoma in mice, suggesting that ponalrestat has a therapeutic potential for the treatment of cancer cachexia.
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PMID:Ponalrestat, an aldose reductase inhibitor, inhibits cachexia syndrome induced by colon26 adenocarcinoma in mice. 1062 61

Several lines of evidence have postulated that reduction in the activity of lipoprotein lipase (LPL) is involved in cachexia induction in cancer patients. Recently we have demonstrated that murine melanoma B16 has the ability to reduce the LPL activity and thereby induce cachexia symptoms in mice following intraperitoneal inoculation. In order to further investigate the relationship between LPL activity and cachectic syndrome, cachexia models other than melanoma B16 are required. However, there are few animal cachexia models in which LPL activity is involved in the induction of cachectic symptoms. In this study, cachectic symptoms and plasma LPL activity were investigated in mice bearing EL-4 mouse lymphoma. In EL-4 bearing mice the body weight including tumor weight in the abdominal cavity was rather higher than that of normal mice without tumor, whereas weights of carcass wet and gastrocnemius muscle were significantly decreased in EL-4 bearing mice. Elevated blood levels of triglyceride and non-esterified fatty acid were observed in mice bearing EL-4, associated with the impaired plasma LPL activity. Overall, this study indicated that EL-4 lymphoma in mice results in a severe cachexia which is possibly related to impaired LPL activity and also provided a useful cachexia model for understanding the role of LPL in the development of cancer cachexia.
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PMID:Cachexia induction by EL-4 lymphoma in mice and possible involvement of impaired lipoprotein lipase activity. 1106 30

Targretin (LGD1069; a high-affinity ligand for the retinoid X receptors) is an efficacious chemotherapeutic and chemopreventive agent in the N-nitroso-N-methylurea-induced rat mammary carcinoma model. To evaluate the molecular action of LGD1069 in mammary carcinoma we have examined gene expression patterns in controls and nonresponding tumors compared with tumors undergoing regression (responding) by LGD1069. When compared with controls or nonresponding tumors, the expression of adipocyte-related genes such as adipocyte P2 (aP2), adipsin, peroxisome proliferator-activated receptor gamma (PPARgamma), and lipoprotein lipase was elevated in LGD1069-responding tumors. Further analysis showed that gene expression changes occurred rapidly, in as little as 6 h, after the first dose of LGD1069. Immunohistochemical analysis showed that aP2 protein was also highly expressed in responding tumors when compared with control or nonresponding tumors. More importantly, aP2 protein was localized in the tumor cells in addition to the adipocytes present in the tumors. Similar changes in gene expression and inhibition in growth were seen in tumor cells (cloned from N-nitroso-N-methylurea-induced carcinoma) exposed to LGD1069 in vitro. These data suggest that tumor regression by LGD1069 involves differentiation induction along the adipocyte lineage.
Cancer Res 2000 Nov 01
PMID:Induction of adipocyte-specific gene expression is correlated with mammary tumor regression by the retinoid X receptor-ligand LGD1069 (targretin). 1108 24

LiSa-2 is a stable cell line derived from a poorly differentiated, pleomorphic liposarcoma. In serum-containing medium, LiSa-2 cells are fibroblastoid and rapidly dividing. In a serum-free, chemically defined culture medium containing physiological concentrations of insulin, triiodothyronine and cortisol, LiSa-2 cells divide slower and, extensively storing fat, acquire adipocyte morphology. In contrast to fibroblastoid LiSa-2 cells, these adipocyte-like LiSa-2 cells highly express transcripts for peroxisome proliferator-activated receptor-gamma, lipoprotein lipase, fatty acid synthetase, hormone-sensitive lipase, adipocyte most abundant gene transcript-1, glycerol-3-phosphate-dehydrogenase and the insulin-sensitive glucose transporter-4, all of which are specific for differentiated adipocytes. However, leptin mRNA expression was demonstrated only after preventing DNA methylation by incorporation of 5-aza-deoxycytidine into cellular DNA. Functionally, adipocyte-like LiSa-2 cells show increased insulin-dependent glucose uptake and lipid synthesis and are sensitive to lipolytic agents. This cell line may serve as an in vitro model for studying the regulation of human liposarcoma differentiation and for screening drugs for induction of differentiation-associated growth arrest in liposarcomas.
Int J Cancer 2000 Dec 15
PMID:LiSa-2, a novel human liposarcoma cell line with a high capacity for terminal adipose differentiation. 1109 10

Chylomicrons are the lipoproteins that transport dietary lipids in the blood. Although neoplastic diseases are often accompanied by alterations in lipid metabolism, chylomicrons are scarcely explored in cancer, despite their importance for the body's energy supply. Moreover, no data are available regarding chylomicron metabolism in chronic lymphocytic leukemia (CLL). Chylomicron metabolism in the bloodstream consists of lipolysis by lipoprotein lipase and uptake of remnants by the liver and is difficult to assess in the human body. Among the methods to evaluate this pathway, the determination of the plasma kinetics of triglyceride-rich emulsions that mimic chylomicrons is a practical and straightforward approach. A double-labeled chylomicron-resembling emulsion was injected into 10 patients with CLL and into 11 normolipidemic healthy subjects. The plasma kinetic curves of the emulsion 3H-triglyceride and 14Ccholesteryl ester were determined in plasma samples collected over 30 min. The fractional clearance rate (FCR) of triglycerides in CLL was not changed compared with controls. The FCR of cholesteryl esters was also no different from controls. These results indicate that chylomicron lipolysis and remnant removal are not affected in CLL.
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PMID:Plasma kinetics of an artificial emulsion resembling chylomicrons in patients with chronic lymphocytic leukemia. 1119 6

Tumor necrosis factor (TNF, cachectin), a cytokine secreted by macrophages and T-cells, mediates inflammatory and immune responses, and is associated with wasting in persons with malignancies or AIDS. In inflammation, TNF attracts and activates neutrophils, stimulating phagocytic function of neutrophils and macrophages. TNF also increases hepatic cell resistance to damaging parasitic effects; enhances endothelial permeability, causing edema; aids in wound healing by stimulating tissue and vascular growth; enhances lymphocytic activity through cytokine activation; acts with interleukin (IL) to produce fever, anorexia, lethargy and sleep; and possesses antitumor activity, particularly against the presumed origin of Kaposi's sarcoma, capillary endothelial cells. The host has an acute phase response (APR) following TNF- and IL-induced immunologic activation. TNF and IL decrease production and activity of lipoprotein lipase (LPL), resulting in reduced uptake and improper storage of fat; and they stimulate anabolism of fatty acids, causing hypertriglyceridemia. This "futile cycling" causes shuttling of fatty acids between adipose tissue and the liver, and use of muscle protein as the main fuel source. This, along with further muscular breakdown due to the increased caloric demands of fever, may affect cachexia. TNF benefits the HIV-infected through selective killing of HIV-infected cells, although effects may be dose and time dependent. The negative effects of TNF may be impeded by anti-cytokine therapy. Possible therapies include dietary N-3 fatty acid (fish oil), an inhibitor of TNF and IL production in vitro; pentoxifylline (Trental), another TNF production inhibitor; anti-TNF monoclonal antibodies; and soluble TNF receptors.
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PMID:Tumor necrosis factor: its role in HIV/AIDS. 1136 96

Previous studies have shown that five human cancer cell lines, LS180, MKN-1, MMG-1, C32 and LX-1, induced remarkable weight loss in tumor-bearing nude mice. With the aim of identifying novel molecules involved in lipid catabolism, conditioned media of these cancer cell lines were analyzed in terms of lipoprotein lipase (LPL)-inhibiting or lipolytic activities. All conditioned media from the five cell lines significantly suppressed LPL activity in 3T3-L1 cells, while media from LX-1 and C32 promoted lipolytic activity in a dose-dependent manner. RT-PCR and ELISA demonstrated that the major factors responsible for LPL inhibition and lipolysis were not IL-1beta, IL-6, IL-11, TNF-alpha, TGF-beta1 or LIF in all the cancer cell lines except for MMG-1 cells. Preliminary biochemical analysis showed that the LPL-inhibiting factor produced by LX-1 cells was approximately 65 kD and vulnerable to heat, whereas the lipolytic factor was less than 1 kD and heat stable. These results suggested that unknown factors are partially involved in the pathogenesis of cancer cachexia in tumor-bearing nude mice and further purification will be needed.
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PMID:Lipolytic and lipoprotein lipase (LPL)-inhibiting activities produced by a human lung cancer cell line responsible for cachexia induction. 1184 98


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