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Lipid Homeostasis (lipid + homeostasi)
Selected AbstractsIslet adaptation to insulin resistance: mechanisms and implications for interventionDIABETES OBESITY & METABOLISM, Issue 1 2005B. Ahrén Abstract:, Insulin sensitivity and insulin secretion are reciprocally related such that insulin resistance is adapted by increased insulin secretion to maintain normal glucose and lipid homeostasis. The relation between insulin sensitivity and secretion is curvilinear and mathematically best described as a hyperbolic relation. Several potential mediators have been suggested to be signals for the beta cells to respond to insulin resistance such as glucose, free fatty acids, autonomic nerves, fat-derived hormones and the gut hormone glucagon-like peptide-1 (GLP-1). Failure of these signals or of the pancreatic beta cells to adequately adapt insulin secretion in relation to insulin sensitivity results in inappropriate insulin levels, impaired glucose intolerance (IGT) and type 2 diabetes. Therefore, treatment of IGT and type 2 diabetes should aim at restoring the normal relation between insulin sensitivity and secretion. Such treatment includes stimulation of insulin secretion (sulphonylureas, repaglinide and nateglinide) and insulin sensitivity (metformin and thiazolidinediones), as well as treatment aimed at supporting the signals mediating the islet adaptation (cholinergic agonists and GLP-1). Both, for correct understanding of diabetes pathophysiology and for development of novel treatment modalities, therefore, the non-linear inverse relation between insulin sensitivity and secretion needs to be acknowledged. [source] Effects of ,-aminoisobutyric acid on leptin production and lipid homeostasis: mechanisms and possible relevance for the prevention of obesityFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 3 2010Karima Begriche Abstract ,-Aminoisobutyric acid (BAIBA) is a catabolite of thymine and antiretroviral thymine analogues AZT and d4T. We recently discovered that this ,-amino acid is able to enhance fatty acid oxidation and reduce body weight in mice through an increased production of leptin by the white adipose tissue (WAT). Furthermore, BAIBA could have favourable effects on nonalcoholic steatohepatitis in a leptin-independent manner. In the present review, we shall recall the circumstances that led us to discover the effects of BAIBA on body fat mass and lipid homeostasis. In addition, we put forward several hypothetical mechanisms whereby BAIBA could enhance leptin secretion by WAT and present some anti-inflammatory effects in the liver. We also discuss in this review (i) the deleterious impacts caused by the absence of, or low leptin expression on lipid homeostasis and body weight in humans and animals and (ii) recent data from other investigators suggesting that increasing leptin levels and/or responsiveness may be indeed an attractive pharmacological strategy in order to prevent (and/or treat) obesity, at least in some individuals. [source] Impaired efflux of cholesterol from aged cells and its molecular mechanism: A basis for age-related enhancement of atherosclerosisGERIATRICS & GERONTOLOGY INTERNATIONAL, Issue 3 2007Shizuya Yamashita Aging is one of the risk factors for atherosclerotic cardiovascular diseases, however, its molecular mechanism is currently unknown. Many types of cells in the atherosclerotic lesions are considered to have various biological abnormalities such as impaired lipid homeostasis and slow cell proliferation, which may be related to senescence at cellular levels. One of the common characteristics of senescent cells in vitro is the alteration of actin cytoskeletons, which were reported to be involved in the intracellular transport of lipids. Cholesterol efflux from the cells is the initial step of reverse cholesterol transport, a major protective system against atherosclerosis. Recently, we demonstrated that Cdc42, a member of the Rho -GTPase family, might be crucial for cellular lipid transport and cholesterol efflux based upon studies of Tangier cells that are deficient in ABCA1 gene. In the current review, we also indicate that the expression of Cdc42 is decreased in the cells from aged subjects in close association with the retarded intracellular lipid transport. Furthermore, the Cdc42 expression is reduced by culturing fibroblasts in vitro for a long duration. Werner syndrome (WS) is characterized by the early onset of senescent phenotypes including premature atherosclerotic cardiovascular diseases, although the underlying molecular mechanism for the enhanced atherosclerosis has not been fully understood yet. We examined the intracellular lipid transport and cholesterol efflux and the expression levels of cholesterol efflux-related molecules in skin fibroblasts obtained from patients with WS. Cholesterol efflux was markedly reduced in the WS fibroblasts in association with an increased cellular cholesterol content. Fluorescent recovery after photobleaching technique revealed that intracellular lipid transport around Golgi apparatus was markedly reduced when using a C6-NBD-ceramide as a tracer. Cdc42 protein and its guanosine 5,-triphosphate-bound active form were markedly reduced in the WS fibroblasts. The adenovirus-mediated complementation of wild-type Cdc42 corrected the impaired cholesterol efflux, intracellular lipid transport and cellular cholesterol levels in the WS fibroblasts. These data indicate that the reduced expression of Cdc42 might be responsible for the abnormal lipid transport, which in turn might be related to the accelerated cardiovascular manifestations in WS patients. The current review focuses on the impaired efflux of cholesterol from aged cells and its molecular mechanism as a basis for age-related enhancement of atherosclerosis. [source] Transcription factor 7,like 2 polymorphism modulates glucose and lipid homeostasis, adipokine profile, and hepatocyte apoptosis in NASH,HEPATOLOGY, Issue 2 2009Giovanni Musso Genetic factors underlying the association of NAFLD with diabetes and atherosclerosis are unknown. Recent human studies suggest transcription factor 7,like 2 (TCF7L2) polymorphism predisposes to diabetes through modulation of ,-cell function and modulates lipid levels in familial dyslipidemia. Emerging experimental evidence connects TCF7L2 to adipocyte metabolism and lipid homeostasis, as well. We tested if TCF7L2 polymorphism is a risk factor for nonalcoholic fatty liver disease (NAFLD) and if it modulates liver injury, glucose homeostasis, lipoprotein, and adipokine profiles in NASH. TCF7L2 genotype and dietary habits of 78 nondiabetic normolipidemic NAFLD subjects and 156 age-, body mass index,, sex-matched healthy controls were assessed. In 39 biopsy-proven nonalcoholic steatohepatitis (NASH) and matched controls TCF7L2 polymorphism was correlated to liver histology and oral glucose tolerance test,derived parameters of glucose homeostasis. Patients with NASH and controls consumed a high-fat meal and TCF7L2 genotype was correlated to postprandial circulating lipoproteins, adipokines, and cytokeratin-18 fragments. The TCF7L2 CT/TT genotype was more frequent in NAFLD and predicted the presence and severity of liver disease, of ,-cell dysfunction, of reduced incretin effect and hepatic insulin resistance in NASH; it also modulated postprandial hepatocyte apoptosis, lipoproteins, and adipokine profiles in both groups. Conclusion: TCF7L2 polymorphism predisposes to NAFLD and significantly impacts liver injury, glucose homeostasis, and postprandial lipoprotein and adipokine responses to fat ingestion. This polymorphism also modulates a fat-induced increase in circulating markers of hepatocyte apoptosis in NASH. Targeting postprandial lipemia, at least in at-risk TCF7L2 genotypes, may improve liver disease and glucose dysmetabolism in these patients. (HEPATOLOGY 2008.) [source] Serum Lipid Levels and Cognitive Change in Late LifeJOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 3 2010Chandra A. Reynolds PhD OBJECTIVES: To assess the effect of lipids and lipoproteins on longitudinal cognitive performance and cognitive health in late life and to consider moderating factors such as age and sex that may clarify conflicting prior evidence. DESIGN: Prospective cohort study. SETTING: A 16-year longitudinal study of health and cognitive aging. PARTICIPANTS: Eight hundred nineteen adults from the Swedish Adoption Twin Study of Aging aged 50 and older at first cognitive testing, including 21 twin pairs discordant for dementia. MEASUREMENTS: Up to five occasions of cognitive measurements encompassing verbal, spatial, memory, and perceptual speed domains across a 16-year span; baseline serum lipids and lipoproteins including high-density lipoprotein cholesterol (HDL-C), apolipoprotein (apo)A1, apoB, total serum cholesterol, and triglycerides. RESULTS: The effect of lipids on cognitive change was most evident before age 65. In women, higher HDL-C and lower apoB and triglycerides predicted better maintenance of cognitive abilities, particularly verbal ability and perceptual speed, than age. Lipid values were less predictive of cognitive trajectories in men and, where observed, were in the contrary direction (i.e., higher total cholesterol and apoB values predicted better perceptual speed performance though faster rates of decline). In twin pairs discordant for dementia, higher total cholesterol and apoB levels were observed in the twin who subsequently developed dementia. CONCLUSION: High lipid levels may constitute a more important risk factor for cognitive health before age 65 than after. Findings for women are consistent with clinical recommendations, whereas for men, the findings correspond with earlier age-associated shifts in lipid profiles and the importance of lipid homeostasis to cognitive health. [source] Distinct spatio-temporal expression of ABCA and ABCG transporters in the developing and adult mouse brainJOURNAL OF NEUROCHEMISTRY, Issue 1 2005Masanori Tachikawa Abstract Using in situ hybridization for the mouse brain, we analyzed developmental changes in gene expression for the ATP-binding cassette (ABC) transporter subfamilies ABCA1,4 and 7, and ABCG1, 2, 4, 5 and 8. In the embryonic brains, ABCA1 and A7 were highly expressed in the ventricular (or germinal) zone, whereas ABCA2, A3 and G4 were enriched in the mantle (or differentiating) zone. At the postnatal stages, ABCA1 was detected in both the gray and white matter and in the choroid plexus. On the other hand, ABCA2, A3 and A7 were distributed in the gray matter. In addition, marked up-regulation of ABCA2 occurred in the white matter at 14 days-of-age when various myelin protein genes are known to be up-regulated. In marked contrast, ABCA4 was selective to the choroid plexus throughout development. ABCG1 was expressed in both the gray and white matters, whereas ABCG4 was confined to the gray matter. ABCG2 was diffusely and weakly detected throughout the brain at all stages examined. Immunohistochemistry of ABCG2 showed its preferential expression on the luminal membrane of brain capillaries. Expression signals for ABCG5 and G8 were barely detected at any stages. The distinct spatio-temporal expressions of individual ABCA and G transporters may reflect their distinct cellular expressions in the developing and adult brains, presumably, to regulate and maintain lipid homeostasis in the brain. [source] The role of hepatic peroxisome proliferator-activated receptors (PPARs) in health and diseaseLIVER INTERNATIONAL, Issue 3 2000Lynn Everett Abstract: The liver has long been known to respond to exposure to certain chemicals with hyperplasia and proliferation of the peroxisomal compartment. This response is now known to be mediated by specific receptors. The peroxisome proliferator-activated receptors (PPARs) were cloned 10 years ago, and in that interval, have been found to serve as receptors for a number of endogenous lipid compounds, in addition to the peroxisome proliferators that originally led to their study. Three receptors, designated the ,, ,, and , receptors, have been found in mammals. PPAR, is the most abundant form found in the liver, with smaller amounts of the , and , forms also expressed there. Kupffer cells, like other macrophages, appear to express the , and , isoforms. Hepatic stellate cells are reported to express the , isoform. PPAR, knock-out mice fail to undergo peroxisome proliferation when challenged with the proliferators. Moreover, they have severe derangements of lipid metabolism, particularly during fasting, indicating that normal function of the alpha receptors is needed for lipid homeostasis. This in turn suggests that inadequate PPAR-mediated responses may contribute to abnormal fatty acid metabolism in alcoholic and non-alcoholic steatohepatitis. Recent information suggests that PPAR, receptors may be important in control of the activation state of the stellate cells, and their repression or inactivation may predispose to hepatic fibrosis. The first approved drug that specifically activates PPAR,, troglitazone, has rarely been found to cause serious liver injury. Although this is likely to represent an idiosyncratic reaction, the medical community will need to be alert to the possibility that activation or blockade of these receptors may cause hepatic dysfunction. [source] A20 protects mice from lethal liver ischemia/reperfusion injury by increasing peroxisome proliferator-activated receptor-, expressionLIVER TRANSPLANTATION, Issue 11 2009Haley E. Ramsey The nuclear factor-,B inhibitory protein A20 demonstrates hepatoprotective abilities through combined antiapoptotic, anti-inflammatory, and pro-proliferative functions. Accordingly, overexpression of A20 in the liver protects mice from toxic hepatitis and lethal radical hepatectomy, whereas A20 knockout mice die prematurely from unfettered liver inflammation. The effect of A20 on oxidative liver damage, as seen in ischemia/reperfusion injury (IRI), is unknown. In this work, we evaluated the effects of A20 upon IRI using a mouse model of total hepatic ischemia. Hepatic overexpression of A20 was achieved by recombinant adenovirus (rAd.)-mediated gene transfer. Although only 10%-25% of control mice injected with saline or the control rAd., galactosidase survived IRI, the survival rate reached 67% in mice treated with rAd.A20. This significant survival advantage in rAd.A20-treated mice was associated with improved liver function, pathology, and repair potential. A20-treated mice had significantly lower bilirubin and aminotransferase levels, decreased hemorrhagic necrosis and steatosis, and increased hepatocyte proliferation. A20 protected against liver IRI by increasing hepatic expression of peroxisome proliferator-activated receptor alpha (PPAR,), a regulator of lipid homeostasis and of oxidative damage. A20-mediated protection of hepatocytes from hypoxia/reoxygenation and H2O2 -mediated necrosis was reverted by pretreatment with the PPAR, inhibitor MK886. In conclusion, we demonstrate that PPAR, is a novel target for A20 in hepatocytes, underscoring its novel protective effect against oxidative necrosis. By combining hepatocyte protection from necrosis and promotion of proliferation, A20-based therapies are well-poised to protect livers from IRI, especially in the context of small-for-size and steatotic liver grafts. Liver Transpl 15:1613,1621, 2009. © 2009 AASLD. [source] Peroxisome proliferator-activated receptor gamma in human prostate carcinomaPATHOLOGY INTERNATIONAL, Issue 5 2009Yasuhiro Nakamura Peroxisome proliferator-activated receptor (PPAR) is a member of the nuclear hormone receptor superfamily of transcription factors. Peroxisome proliferator-activated receptor gamma (PPAR,) plays an important role in the regulation of lipid homeostasis, adipogenesis, insulin resistance, and development of various organs. Agonists of PPAR, have been also reported to inhibit proliferation of prostate carcinoma cells as in other human malignancies, and these synthetic ligands have been used in differentiation-mediated therapy of various human carcinomas associated with high levels of PPAR,. The significance of PPAR, expression, however, was unknown in human prostate carcinoma tissues. The purpose of the present study was therefore to examine the immunolocalization of PPAR, in human prostate cancer tissues (40 cases) and correlate the findings with clinicopathological features of the patients in order to evaluate its possible biological significance. Twenty-nine patients were positive for PPAR, immunoreactivity (73%) and a significant inverse correlation was detected between PPAR, immunoreactivity, pT stage (P = 0.036), and serum concentration of prostate-specific antigen (P = 0.0004). In conclusion, PPAR, immunoreactivity is considered to be a new clinicopathological parameter of human prostate cancer. [source] Insights into the membrane proteome of rat liver peroxisomes: Microsomal glutathione-S-transferase is shared by both subcellular compartmentsPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 3 2006Markus Islinger Dr. Abstract Peroxisomes are ubiquitous "multipurpose" organelles of eukaryotic cells. Their matrix enzymes catalyze mainly catabolic and anabolic reactions of lipid metabolism, thus contributing to the regulation of lipid homeostasis. Since most metabolites must be actively transported across the peroxisomal membrane and since individual proteins and protein complexes play functional roles in such transport processes, we analyzed the peroxisomal membrane proteome. Benzyldimethyl- n -hexadecylammoniumchloride (16-BAC)/SDS-2-D-PAGE and mass spectrometry were used to characterize the proteomes of highly purified "light" and "heavy" peroxisomes of rat liver obtained by density gradient centrifugation. In both populations, the major integral membrane proteins could be detected in high concentrations, verifying 16-BAC/SDS-2-D-PAGE as a suitable tool for the preparation of membrane proteomes destined for mass spectrometric analysis. Both reliable and reproducible detection of a distinct set of microsomal (ER) membrane proteins, including microsomal glutathione-S-transferase (mGST), in light and heavy peroxisomal fractions was also possible. Compared with the abundance of most microsomal membrane proteins, we found mGST to be specifically enriched in peroxisomal membrane fractions. Furthermore, C terminus epitope-tagged mGST versions were localized at least in part to peroxisomes in different mammalian cell lines. Taken together, these data suggest that the peroxisomal GST is not a mere ER-contaminant, but a bona fide protein comprising the membrane proteome of both intracellular compartments. In addition, we could detect several mitochondrial proteins in light peroxisome fractions. This finding may likely indicate a physical association of light peroxisomes with mitochondria, since the organelles could be partly separated by mechanical stress. Whether this association is of functional importance awaits further investigation. [source] RNA-Interference Approach to Study Functions of NADPH,:,Cytochrome P450 Oxidoreductase in Human HepatocytesCHEMISTRY & BIODIVERSITY, Issue 11 2009Diana Abstract Human NADPH,:,cytochrome P450 oxidoreductase (POR) is encoded by a single gene on chromosome 7q11.2. This flavoprotein donates electrons derived from NADPH to a variety of acceptor proteins, including squalene monooxygenase, heme oxygenase, cytochrome b5, and many microsomal cytochromes P450 (CYPs), which are involved in oxidative drug metabolism, steroidogenesis, and other functions. Numerous aspects related to cellular POR expression have not been systematically investigated. Interestingly, POR expression is lower compared to CYPs and may thus be limiting for monooxygenase activities, but conversely, POR knock-out in mice resulted in compensatory upregulation of CYPs. POR may also influence intracellular cholesterol and lipid homeostasis. To systematically investigate such effects, we developed specific POR gene silencing in cell lines and primary human hepatocytes by RNA interference using small interfering RNAs (siRNAs). In HepG2 cells, POR mRNA could be reduced by 95% over 4 days accompanied by reduced protein content and activity. In primary human hepatocytes, POR mRNA knock-down was less effective and more variable. Analysis of CYPs indicated induction of CYP3A4 but not CYP1A2 or CYP2D6. These results demonstrate that POR can be efficiently and almost completely silenced in HepG2 cells and, at least partially, in primary human hepatocytes. This will allow systematic studies of various consequences of POR variability in human cells. [source] | |||||||||||||||||||||||||