Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020473 (hyperlipidemia)
 15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Accelerated formation of advanced glycation/lipoxidation and endproducts (AGEs/ALEs) has been implicated in the pathogenesis of various diabetic complications. Several natural and synthetic compounds have been proposed and tested as inhibitors of AGE/ALE formation. We have previously reported the therapeutic effects of several new AGE/ALE inhibitors on the prevention of nephropathy and dyslipidemia in streptozotocin (STZ)-induced diabetic rats. In this study, we investigated the effects of various concentrations of a compound, LR-90, on the progression of renal disease and its effects on AGE and receptor for AGE (RAGE) protein expression on the kidneys of diabetic STZ-rats. Diabetic male Sprague-Dawley rats were treated with or without LR-90 (0, 5, 20, 25, and 50 mg/l of drinking water). After 32 weeks, body weight, glycemic status, renal function, and plasma lipids were measured. Kidney histopathology and AGE/ALE accumulation and RAGE protein expression in tissues were also determined. In vitro studies were also performed to determine the possible mechanism of action of LR-90 in inhibiting AGE formation and AGE-protein cross-linking. LR-90 protected the diabetic kidneys by inhibiting the increase in urinary albumin-to-creatinine ratio and ameliorated hyperlipidemia in diabetic rats in a concentration-dependent fashion without any effects on hyperglycemia. LR-90 treatment also reduced kidney AGE/ALE accumulation and RAGE protein expression in a concentration-dependent manner. In vitro, LR-90 exhibited general antioxidant properties by inhibiting metal-catalyzed reactions and reactive oxygen species (OH radical) and reactive carbonyl species (methlyglyoxal, glyoxal) generations without any effect on pyridoxal 5' phosphate. The compound also prevents AGE-protein cross-linking reactions. These findings demonstrate the bioefficacy of LR-90 in treating nephropathy and hyperlipidemia in diabetic animals by inhibiting AGE accumulation, RAGE protein expression, and protein oxidation in the diabetic kidney. Additionally, our study suggests that LR-90 may be useful also to delay the onset and progression of diabetic atherosclerosis as the compound can inhibit the expression of RAGE and inflammation-related pathology, as well as prevent lipid peroxidation reactions.
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PMID:Novel inhibitors of glycation and AGE formation. 1770 84

Diabetic nephropathy is the leading cause of end-stage renal disease (ESRD) in Japan and other Westernized countries. Over 50% of the ESRD patients die from cardiovascular events. Cardiovascular disease (CVD) in ESRD patients with diabetes mellitus (DM) are implicated in the endothelial dysfunction caused by hyperglycemia, hyperlipidemia, and hypertension, and in the vascular calcification of intimal and medial arterial blood vessels caused by hyperphosphatemia. Therefore, dietary control of hyperglycemia and hyperphosphatemia should play an important role in the management of ESRD patients with DM. Furthermore, recent findings suggest that high concentrations of serum phosphate, even if within the normal range, may be a risk factor for CVD and mortality. An in vivo study using klotho knockout mice and fibroblast growth factor 23 (FGF-23) knockout mice has revealed that correction of hyperphosphatemia and hypervitaminosis D could ameliorate the premature aging-like phenotype. A low glycemic index and low phosphate diet may provide an advantage in the prevention of aging-related diseases in healthy individuals as well as in those with chronic kidney disease.
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PMID:Advantage of a low glycemic index and low phosphate diet on diabetic nephropathy and aging-related diseases. 1787 88

A substantial number of renal diseases progress to renal failure although the initaial injury is no more active. Enhanced understanding of the diverse pathogenic me-chanisms involved in progression of renal disease has pointed to the three main factors which initiate and/or sustain this progress. These factors are: altered activity of intrinsic glo-merular cells, enhanced activity of mononuclear cells infiltrating glomerulus, and tubulointerstitial injury. In addition several potentional risk factors, such as disturbed glomerular haemodinamics, proteinuria, systemic hypertension, intraglomerular coagulation, hyperlipidaemia, dietary protein and phosphate, may contribute to progression of renal disease and renal failure. These risk factors are disscused in detail in this review. There is now strong evidence that in clinical practice good control of risk factors slow the progression of renal failure.
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PMID:[Mechanisms of the progression of renal disease (risk factors)--part II]. 1797 95

Many patients with proteinuric chronic nephropathies progress relentlessly to end-stage renal failure (ESRF). Research in animal and human models has helped to identify the mechanisms involved in this progression and to indicate effective intervention. We review the main factors associated with the progression of chronic renal diseases including systemic and intra-glomerular hypertension, glomerular hypertrophy, proteinuria, hyperlipidemia, and intrarenal precipitation of calcium phosphate. We also describe a therapeutic strategy aimed at achieving maximal reno-protection.
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PMID:Mechanisms of progression of chronic renal disease. 1820 21

Glucose-6-phosphatase-alpha (G6PC) is a key enzyme in glucose homeostasis that catalyzes the hydrolysis of glucose-6-phosphate to glucose and phosphate in the terminal step of gluconeogenesis and glycogenolysis. Mutations in the G6PC gene, located on chromosome 17q21, result in glycogen storage disease type Ia (GSD-Ia), an autosomal recessive metabolic disorder. GSD-Ia patients manifest a disturbed glucose homeostasis, characterized by fasting hypoglycemia, hepatomegaly, nephromegaly, hyperlipidemia, hyperuricemia, lactic acidemia, and growth retardation. G6PC is a highly hydrophobic glycoprotein, anchored in the membrane of the endoplasmic reticulum with the active center facing into the lumen. To date, 54 missense, 10 nonsense, 17 insertion/deletion, and three splicing mutations in the G6PC gene have been identified in more than 550 patients. Of these, 50 missense, two nonsense, and two insertion/deletion mutations have been functionally characterized for their effects on enzymatic activity and stability. While GSD-Ia is not more prevalent in any ethnic group, mutations unique to Caucasian, Oriental, and Jewish populations have been described. Despite this, GSD-Ia patients exhibit phenotypic heterogeneity and a stringent genotype-phenotype relationship does not exist.
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PMID:Mutations in the glucose-6-phosphatase-alpha (G6PC) gene that cause type Ia glycogen storage disease. 1844 99

Physicians have many options available for treating patients with type 2 diabetes mellitus (T2DM). Making decisions on types of pharmaceuticals to use and when to introduce them into the treatment regimen can be a complex process. In addition, nutrition and exercise must be considered in any comprehensive treatment plan. The author describes the case of an African American woman with uncontrolled T2DM, obesity, hyperlipidemia, low bone mass, menopausal symptoms, stage 3 chronic kidney disease, distal sensory neuropathy, and background retinopathy. An aggressive, comprehensive treatment plan developed for this patient included pharmaceuticals (triple oral therapy: metformin, pioglitazone hydrochloride, and sitagliptin phosphate), nutrition counseling (with a registered, licensed dietician), and exercise. Treatment led to substantial improvements in the patient's daytime glucose level, glycosylated hemoglobin level, and body weight at 3-month follow-up. Further interventions were needed to address the patient's hyperlipidemia and low bone mass. The author offers physician guidelines for making decisions on glycemic control for patients with T2DM and for managing hyperlipidemia. He also strongly recommends incorporating nutrition counseling by registered, licensed dietitians and exercise (preferably of a weight-bearing nature) into treatment plans for patients with T2DM, hyperlipidemia, and low bone mass.
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PMID:Aggressively managing type 2 diabetes mellitus, hyperlipidemia, and bone loss. 1851 39

Cardiovascular (CVS) morbidity and mortality in the end-stage renal disease (ESRD) patients on peritoneal dialysis therapy is 10-30 folds higher than in general population. The prevalence of well known traditional risk factors such as age, sex, race, arterial hypertension, hyperlipidaemia, diabetes, smoking, physical inactivity is higher in the uraemic patients. Besides these, there are specific, nontraditional risk factors for dialysis patients. Mild inflammation present in peritoneal dialysis (PD) patients which can be confirmed by specific inflammatory markers is the cause of CVS morbidity and mortality in these patients. Hypoalbuminaemia, hyperhomocysteinaemia and a higher level of leptin are important predictors of vascular complications as well as CVS events in the PD patients. Plasma norepinephrine, an indicator of sympathetic activity, is high in the ESRD patients and higher in the PD patients than in the patients on haemodialysis (HD). Therefore, norepinephrine may be a stronger risk factor in the PD patients. The same applies to asymmetric dimethylargine (ADMA), an endogenous inhibitor of nitric oxide synthase, which is an important risk factor of CVS morbidity and mortality 15 % higher in the PD than the HD patients. Hyperphosphataemia, secondary hyperparathyroidism and high calcium x phosphate product have been associated with the progression of the coronary artery calcification and valvular calcifications and predict all-cause CVS mortality in the PD patients. Residual renal function (RRF) declines with time on dialysis but is slower in the PD than the HD patients. RRF decline is associated with the rise of proinflammatory cytokines and the onset of hypervolaemia and hypertension which increase the risk of CVS diseases, mortality in general and CVS mortality. In conclusion, it is very important to establish all CVS risk factors in the PD patients to prevent CVS diseases and CVS mortality in this population.
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PMID:[Cardiovascular morbidity and mortality risk factors in peritoneal dialysis patients]. 1879 34

AMPK (AMP-activated protein kinase) has been suggested to be a central player regulating FA (fatty acid) metabolism through its ability to regulate ACC (acetyl-CoA carboxylase) activity. Nevertheless, its involvement in insulin resistance- and TD2 (Type 2 diabetes)-associated dyslipidaemia remains enigmatic. In the present study, we employed the Psammomys obesus gerbil, a well-established model of insulin resistance and TD2, in order to appreciate the contribution of the AMPK/ACC pathway to the abnormal hepatic lipid synthesis and increased lipid accumulation in the liver. Our investigation provided evidence that the development of insulin resistance/diabetic state in P. obesus is accompanied by (i) body weight gain and hyperlipidaemia; (ii) elevations of hepatic ACC-Ser79 phosphorylation and ACC protein levels; (iii) a rise in the gene expression of cytosolic ACC1 concomitant with invariable mitochondrial ACC2; (iv) an increase in hepatic AMPKalpha-Thr172 phosphorylation and protein expression without any modification in the calculated ratio of phospho-AMPKalpha to total AMPKalpha; (v) a stimulation in ACC activity despite increased AMPKalpha phosphorylation and protein expression; and (vi) a trend of increase in mRNA levels of key lipogenic enzymes [SCD-1 (stearoyl-CoA desaturase-1), mGPAT (mitochondrial isoform of glycerol-3-phosphate acyltransferase) and FAS (FA synthase)] and transcription factors [SREBP-1 (sterol-regulatory-element-binding protein-1) and ChREBP (carbohydrate responsive element-binding protein)]. Altogether, our findings suggest that up-regulation of the AMPK pathway seems to be a natural response in order to reduce lipid metabolism abnormalities, thus supporting the role of AMPK as a promising target for the treatment of TD2-associated dyslipidaemia.
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PMID:Increased hepatic lipogenesis in insulin resistance and Type 2 diabetes is associated with AMPK signalling pathway up-regulation in Psammomys obesus. 1884 11

The aim of this study was to evaluate the concentration of oleanolic acids (OA) in pomace, a winemaking byproduct, and its influence on the levels of plasma lipids in rats fed a high-fat diet and on hepatic gene expression using DNA microarray analysis in vivo. HPLC analyses of pomace ethanol extract (PEE) revealed a high amount of OA ranging from 4 to 11 g/100 g. Male Sprague-Dawley rats were fed a normal-fat diet (NF group), a high-fat diet with 21% lard (HF group), a high-fat diet with 0.05% OA (OA group, 50 mg/kg/day), or a high-fat diet with 0.45% PEE (PEE group, 450 mg/kg/day). Plasma triacylglycerol and phospholipid concentrations were significantly lower in the OA and PEE groups than in the HF group. The microarray analysis of hepatic mRNA revealed reduced expression levels of lipogenic genes including acetyl-CoA carboxylase and glycerol-3-phosphate acyltransferase, probably resulting from the suppression of transcription factor Srebf1 expression. Gene expression of gluconeogensis and inflammatory cytokines was also down-regulated in the OA and PEE groups, suggesting that administration of OA or PEE could ameliorate obesity-induced insulin resistance, as well as prevent hyperlipidemia.
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PMID:Effect of dietary wine pomace extract and oleanolic acid on plasma lipids in rats fed high-fat diet and its DNA microarray analysis. 1905 93

Sprague-Dawley rats received once daily tail-vein injections of 360 mM dibasic sodium phosphate solution at 8 mL/kg for fourteen or twenty-eight days. Clinical examination revealed persistent proteinuria from three days after the first dosing and thereafter severe proteinuria from eight days or later in the phosphate-treated groups. Proteinuria developed without remission even after fourteen-day withdrawal in the fourteen-day dosed group. Phosphate-treated animals developed lipemia, hypercholesterolemia, anemia, higher serum fibrinogen levels, and lower serum albumin/globulin ratios on day 29. Renal weight increased significantly compared with control animals, and the kidneys appeared pale and enlarged with a rough surface. Histopathologically, glomerular changes consisted of mineralization in whole glomeruli, glomerular capillary dilatation, partial adhesion of glomerular tufts to Bowman's capsule, and mesangiolysis. Ultrastructural lesions such as an increased number of microvilli, effacement of foot processes, and thickening of the glomerular basement membrane, and immunocytochemical changes in podocytes, mainly decreased podoplanin-positive cells and increased desmin expression, were also conspicuous in the phosphate-treated rats for twenty-eight days. Marked tubulointerstitial lesions were tubular regeneration and dilatation, protein casts, mineralization in the basement membrane, focal interstitial inflammation, and fibrosis in the cortex. These clinical and morphological changes were similar to features of human nephrotic syndrome.
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PMID:Nephrotic syndrome induced by dibasic sodium phosphate injections for twenty-eight days in rats. 1924 17


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