Differential regulation of cholesterol homeostasis in transgenic mice expressing human cholesterol ester transfer proteinThis paper is one of a selection of papers published in this Special Issue, entitled The Cellular and Molecular Basis of Cardiovascular Dysfunction, Dhalla 70th Birthday Tribute.

2007 ◽  
Vol 85 (3-4) ◽  
pp. 430-438 ◽  
Author(s):  
Alka Agarwal-Mawal ◽  
Cathy M. Murray ◽  
Suresh Belkhode ◽  
Sukhinder Kaur Cheema
Keyword(s):  
Fatty Acid ◽  
Transgenic Mice ◽  
Cholesterol Ester ◽  
Cholesterol Metabolism ◽  
Cholesterol Homeostasis ◽  
Dietary Fats ◽  
Hmg Coa Reductase ◽  
Transfer Protein ◽  
Coa Reductase ◽  
Mufa Diet

We investigated whether expression of cholesterol ester transfer protein (CETP) in mice alters the regulation of cholesterol metabolism. Transgenic mice expressing human CETP (CETP-TG) and nontransgenic littermates (non-TG) were fed either a monounsaturated fatty acid (MUFA) or a saturated fatty acid (SFA)-rich diet in the presence or absence of cholesterol. Mice fed with MUFA diet had higher CETP activity compared with SFA-fed mice. Addition of cholesterol to the MUFA diet decreased CETP activity, whereas addition of cholesterol to the SFA diet had no effect. Cholesterol 7α-hydroxylase (Cyp7a) activity was higher in CETP-TG mice compared with non-TG mice when fed a MUFA diet, whereas SFA fed CETP-TG mice showed lower Cyp7a activity as compared with non-TG. Microsomal triglyceride transfer protein (MTTP) activity was higher in CETP-TG mice compared with non-TG mice when fed a MUFA diet. HMG-CoA reductase activity was lower in CETP-TG mice compared with non-TG mice when fed a MUFA or a SFA diet. These data demonstrate that the regulation of Cyp7a, HMG-CoA reductase, and MTTP is altered in CETP-TG mice as compared with non-TG mice and these alterations are further modulated by the quality of dietary fats. These findings highlight the importance of CETP in regulating cholesterol homeostasis.

scholarly journals Stimulation of hepatic cholesterol biosynthesis by fatty acids. Effects of oleate on cytoplasmic acetoacetyl-CoA thiolase, acetoacetyl-CoA synthetase and hydroxymethylglutaryl-CoA synthase

1989 ◽  
Vol 258 (2) ◽  
pp. 563-568 ◽  
Author(s):  
W H Salam ◽  
H G Wilcox ◽  
L M Cagen ◽  
M Heimberg
Keyword(s):  
Fatty Acids ◽  
Oleic Acid ◽  
Fatty Acid ◽  
Cholesterol Metabolism ◽  
Cholesterol Biosynthesis ◽  
Isolated Perfused Rat Liver ◽  
Hepatic Cholesterol ◽  
Hmg Coa Reductase ◽  
Coa Reductase ◽  
Stimulation Of

The effects of oleic acid on the activities of cytosolic HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) synthase, AcAc-CoA (acetoacetyl-CoA) thiolase and AcAc-CoA synthetase, as well as microsomal HMG-CoA reductase, all enzymes in the pathway of cholesterol biosynthesis, were studied in the isolated perfused rat liver. Oleic acid bound to bovine serum albumin, or albumin alone, was infused for 4 h at a rate sufficient to sustain an average concentration of 0.61 +/- 0.05 mM fatty acid during the perfusion. Hepatic cytosol and microsomal fractions were isolated at the termination of the perfusion. Oleic acid simultaneously increased the activities of the cytosolic cholesterol-biosynthetic enzymes 1.4-2.7-fold in livers from normal fed rats and from animals fasted for 24 h. These effects were accompanied by increased net secretion by the liver of cholesterol and triacylglycerol in the very-low-density lipoprotein (VLDL). We confirmed the observations reported previously from this laboratory of the stimulation by oleic acid of microsomal HMG-CoA reductase. In cytosols from perfused livers, the increase in AcAc-CoA thiolase activity was characterized by an increase in Vmax. without any change in the apparent Km of the enzyme for AcAc-CoA. In contrast, oleic acid decreased the Km of HMG-CoA synthase for Ac-CoA, without alteration of the Vmax. of the enzyme. The Vmax. of AcAc-CoA synthetase was increased by oleic acid, and there was a trend towards a small increase in the Km of the enzyme for acetoacetate. These data allow us to conclude that the enzymes that supply the HMG-CoA required for hepatic cholesterogenesis are stimulated, as is HMG-CoA reductase, by a physiological substrate, fatty acid, that increases rates of hepatic cholesterol synthesis and cholesterol secretion. Furthermore, we suggest that these effects of fatty acid on hepatic cholesterol metabolism result from stimulation of secretion of triacylglycerol in the VLDL by fatty acids, and the absolute requirement of cholesterol as an important structural surface component of the VLDL necessary for transport of triacylglycerol from the liver.

Streptozotocin-induced increase in cholesterol ester transfer protein (CETP) and its reversal by insulin in transgenic mice expressing human CETP

2003 ◽  
Vol 81 (10) ◽  
pp. 997-1004 ◽  
Author(s):  
Sukhinder Kaur Cheema ◽  
Fariborz Rashid-Kolvear
Keyword(s):  
Transgenic Mice ◽  
High Density Lipoprotein ◽  
High Density Lipoprotein Cholesterol ◽  
Cholesterol Ester ◽  
Density Lipoprotein ◽  
Cholesterol Ester Transfer Protein ◽  
High Density ◽  
Lipoprotein Cholesterol ◽  
Transfer Protein ◽  
Transfer Activity

High plasma triacylglycerol and low high-density lipoprotein levels are risk factors for cardiovascular disease in diabetes. Plasma high-density lipoprotein levels are regulated by cholesterol ester transfer protein (CETP). The regulation of CETP under diabetic conditions is not clear, and this is due to a lack of appropriate models. We used transgenic mice expressing human CETP to study the regulation of this protein under type-1 diabetic conditions and further investigated whether insulin reverses the effect of diabetes. Mice expressing human CETP under the control of its natural flanking region and age-matched littermates not expressing this protein were made diabetic by injecting streptozotocin, and the reversal of diabetes was assessed by injecting insulin. The plasma total cholesterol, low-density lipoprotein-cholesterol, and triacylglycerol concentrations were elevated, whereas high-density lipoprotein-cholesterol concentrations were reduced after the onset of diabetes. Insulin injection partially recovered this effect. The plasma cholesterol ester transfer activity, CETP mass, and hepatic CETP mRNA abundance were significantly higher in diabetic mice that were partially restored by insulin administration. There was a strong correlation between high-density lipoprotein-cholesterol concentrations and cholesterol ester transfer activity. These results suggest that an increase in CETP under diabetic conditions might be a major factor responsible for increased incidence of diabetes-induced atherosclerosis.Key words: transgenic mice, streptozotocin-induced diabetes, cholesterol ester transfer protein.

Dietary fatty acids and CD36-mediated cholesterol homeostasis: potential mechanisms

2020 ◽  
pp. 1-14 ◽  
Author(s):  
Elif Ulug ◽  
Reyhan Nergiz-Unal
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Cholesterol Metabolism ◽  
Fatty Acid Pattern ◽  
Dietary Fatty Acids ◽  
Cholesterol Homeostasis ◽  
Acid Uptake ◽  
Pufa Ratio ◽  
Mortality And Morbidity ◽  
Cd36 Receptor

Abstract Currently, the prevention and treatment of CVD have been a global focus since CVD is the number one cause of mortality and morbidity. In the pathogenesis of CVD, it was generally thought that impaired cholesterol homeostasis might be a risk factor. Cholesterol homeostasis is affected by exogenous factors (i.e. diet) and endogenous factors (i.e. certain receptors, enzymes and transcription factors). In this context, the number of studies investigating the potential mechanisms of dietary fatty acids on cholesterol homeostasis have increased in recent years. As well, the cluster of differentiation 36 (CD36) receptor is a multifunctional membrane receptor involved in fatty acid uptake, lipid metabolism, atherothrombosis and inflammation. CD36 is proposed to be a crucial molecule for cholesterol homeostasis in various mechanisms including absorption/reabsorption, synthesis, and transport of cholesterol and bile acids. Moreover, it has been reported that the amount of fatty acids and fatty acid pattern of the diet influence the CD36 level and CD36-mediated cholesterol metabolism principally in the liver, intestine and macrophages. In these processes, CD36-mediated cholesterol and lipoprotein homeostasis might be impaired by dietary SFA and trans-fatty acids, whereas ameliorated by MUFA in the diet. The effects of PUFA on CD36-mediated cholesterol homeostasis are controversial depending on the amount of n-3 PUFA and n-6 PUFA, and the n-3:n-6 PUFA ratio. Thus, since the CD36 receptor is suggested to be a novel nutrient-sensitive biomarker, the role of CD36 and dietary fatty acids in cholesterol metabolism might be considered in medical nutrition therapy in the near future. Therefore, the novel nutritional target of CD36 and interventions that focus on dietary fatty acids and potential mechanisms underlying cholesterol homeostasis are discussed in this review.

Effect of geraniol on fatty-acid and mevalonate metabolism in the human hepatoma cell line Hep G2

2006 ◽  
Vol 84 (1) ◽  
pp. 102-111 ◽  
Author(s):  
Monica P Polo ◽  
Margarita G de Bravo
Keyword(s):  
Fatty Acid ◽  
Cell Line ◽  
Reductase Activity ◽  
Hepatoma Cell ◽  
Cellular Growth ◽  
Hepatoma Cell Line ◽  
Dependent Manner ◽  
Hep G2 ◽  
Hmg Coa Reductase ◽  
Coa Reductase

Monoterpenes have multiple pharmacological effects on the metabolism of mevalonate. Geraniol, a dietary monoterpene, has in vitro and in vivo anti-tumor activity against several cell lines. We have studied the effects of geraniol on growth, fatty-acid metabolism, and mevalonate metabolism in the human hepatocarcinoma cell line Hep G2. Up to 100 µmol geraniol/L inhibited the growth rate and 3-hydroxymethylglutaryl coenzyme A reductase (HMG-CoA) reductase activity of these cells. At the same concentrations, it increased the incorporation of cholesterol from the medium in a dose-dependent manner. Geraniol-treated cells incorporated less 14C-acetate into nonsaponifiable lipids, inhibiting its incorporation into cholesterol but not into squalene and lanosterol. This is indicative of an inhibition in cholesterol synthesis at a step between lanosterol and cholesterol, a fact confirmed when cells were incubated with 3H-mevalonate. The incorporation of 3H-mevalonate into protein was also inhibited, whereas its incorporation into fatty acid increased. An inhibition of Δ5 desaturase activity was demonstrated by the inhibition of the conversion of 14C-dihomo-γ-linolenic acid into arachidonic acid. Geraniol has multiple effects on mevalonate and lipid metabolism in Hep G2 cells, affecting cell proliferation. Although mevalonate depletion is not responsible for cellular growth, it affects cholesterogenesis, protein prenylation, and fatty-acid metabolism.Key words: geraniol, Hep G2, HMG-CoA reductase, mevalonate, fatty acids.

scholarly journals Anti-HMG-CoA Reductase, Antioxidant, and Anti-Inflammatory Activities ofAmaranthus viridisLeaf Extract as a Potential Treatment for Hypercholesterolemia

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Shamala Salvamani ◽  
Baskaran Gunasekaran ◽  
Mohd Yunus Shukor ◽  
Noor Azmi Shaharuddin ◽  
Mohd Khalizan Sabullah ◽  
...  
Keyword(s):  
Leaf Extract ◽  
Cholesterol Metabolism ◽  
Inhibitory Effect ◽  
Hmg Coa Reductase ◽  
Synthetic Drugs ◽  
Reductase Inhibitors ◽  
Plot Analysis ◽  
Hmg Coa Reductase Inhibitors ◽  
Anti Inflammatory ◽  
Coa Reductase

Inflammation and oxidative stress are believed to contribute to the pathology of several chronic diseases including hypercholesterolemia (elevated levels of cholesterol in blood) and atherosclerosis. HMG-CoA reductase inhibitors of plant origin are needed as synthetic drugs, such as statins, which are known to cause adverse effects on the liver and muscles.Amaranthus viridis(A. viridis) has been used from ancient times for its supposedly medically beneficial properties. In the current study, different parts ofA. viridis(leaf, stem, and seed) were evaluated for potential anti-HMG-CoA reductase, antioxidant, and anti-inflammatory activities. The putative HMG-CoA reductase inhibitory activity ofA. viridisextracts at different concentrations was determined spectrophotometrically by NADPH oxidation, using HMG-CoA as substrate.A. viridisleaf extract revealed the highest HMG-CoA reductase inhibitory effect at about 71%, with noncompetitive inhibition in Lineweaver-Burk plot analysis. The leaf extract showed good inhibition of hydroperoxides, 2,2-diphenyl-1-picrylhydrazyl (DPPH), nitric oxide (NO), and ferric ion radicals in various concentrations.A. viridisleaf extract was proven to be an effective inhibitor of hyaluronidase, lipoxygenase, and xanthine oxidase enzymes. The experimental data suggest thatA. viridisleaf extract is a source of potent antioxidant and anti-inflammatory agent and may modulate cholesterol metabolism by inhibition of HMG-CoA reductase.

scholarly journals The Promoter of the Rat 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Gene Contains a Tissue-Specific Estrogen-Responsive Region

1999 ◽  
Vol 13 (8) ◽  
pp. 1225-1236 ◽  
Author(s):  
Luciano Di Croce ◽  
Guillermo P. Vicent ◽  
Adali Pecci ◽  
Giovannella Bruscalupi ◽  
Anna Trentalance ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Cell Lines ◽  
Coenzyme A ◽  
Cholesterol Metabolism ◽  
Hmg Coa Reductase ◽  
Tissue Specific ◽  
Reductase Gene ◽  
Responsive Element ◽  
Coa Reductase ◽  
Mcf 7

Abstract The isoprenoid metabolic pathway is mainly regulated at the level of conversion of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) to mevalonate, catalyzed by HMG CoA reductase. As estrogens are known to influence cholesterol metabolism, we have explored the potential regulation of the HMG CoA reductase gene promoter by estrogens. The promoter contains an estrogen-responsive element-like sequence at position −93 (termed Red-ERE), which differs from the ERE consensus by one mismatch in each half of the palindrome. A Red-ERE oligonucleotide specifically bound estrogen receptor in vitro and conferred receptor-dependent estrogen responsiveness to a heterologous promoter in all cell lines tested. However, expression of a reporter driven by the rat HMG CoA reductase promoter was induced by estrogen treatment after transient transfection into the breast cancer cell line MCF-7 cells but not in hepatic cell lines expressing estrogen receptor. Estrogen induction in MCF-7 cells was dependent on the Red-ERE and was strongly inhibited by the antiestrogen ICI 164,384. A functional cAMP-responsive element is located immediately upstream of the Red-ERE, but cAMP and estrogens inhibit each other in terms of transactivation of the promoter. Similarly, induction by estrogens was inhibited by micromolar concentrations of cholesterol, likely acting via changes in occupancy of the sterol-responsive element located 70 bp upstream of the Red-ERE. Thus, within its natural context, Red-ERE is able to mediate hormonal regulation of the HMG CoA reductase gene in tissues that respond to estrogens with enhanced cell proliferation, while it is not operative in liver cells. We postulate that this tissue-specific regulation of HMG CoA reductase by estrogens could partially explain the protective effect of estrogens against heart disease.

scholarly journals Ufd1 Is a Cofactor of gp78 and Plays a Key Role in Cholesterol Metabolism by Regulating the Stability of HMG-CoA Reductase

2007 ◽  
Vol 6 (2) ◽  
pp. 115-128 ◽  
Author(s):  
Jian Cao ◽  
Jiang Wang ◽  
Wei Qi ◽  
Hong-Hua Miao ◽  
Jing Wang ◽  
...  
Keyword(s):  
Cholesterol Metabolism ◽  
Hmg Coa Reductase ◽  
The Stability ◽  
Coa Reductase
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