scholarly journals The role of ATP citrate-lyase in the metabolic regulation of plasma lipids

1998 ◽  
Vol 334 (1) ◽  
pp. 113-119 ◽  
Author(s):  
Nigel J. PEARCE ◽  
John W. YATES ◽  
Theo A. BERKHOUT ◽  
Brian JACKSON ◽  
David TEW ◽  
...  
Keyword(s):  
Plasma Lipids ◽  
De Novo ◽  
Plasma Cholesterol ◽  
Low Density Lipoprotein ◽  
Lipid Synthesis ◽  
Density Lipoprotein ◽  
Acid Synthesis ◽  
Atp Citrate Lyase ◽  
Cholesterol Levels ◽  
Citrate Lyase

ATP citrate (pro-S)-lyase (EC 4.1.3.8), a cytosolic enzyme that generates acetyl-CoA for cholesterol and fatty acid synthesis de novo, is a potential target for hypolipidaemic intervention. Here we describe the biological effects of the inhibition of ATP citrate-lyase on lipid metabolism in Hep G2 cells, and plasma lipids in rats and dogs, by using SB-204990, the cell-penetrant γ-lactone prodrug of the potent ATP citrate-lyase inhibitor SB-201076 (Ki = 1 µM). Consistent with an important role of ATP citrate-lyase in the supply of acetyl-CoA units for lipid synthesis de novo, SB-204990 inhibited cholesterol synthesis and fatty acid synthesis in Hep G2 cells (dose-related inhibition of up to 91% and 82% respectively) and rats (76% and 39% respectively). SB-204990, when administered orally to rats, was absorbed into the systemic circulation; pharmacologically relevant concentrations of SB-201076 were recovered in the liver. When administered in the diet (0.05–0.25%, w/w) for 1 week, SB-204990 caused a dose-related decrease in plasma cholesterol (by up to 46%) and triglyceride levels (by up to 80%) in rats. This hypolipidaemic effect could be explained, at least in part, by a decrease (up to 48%) in hepatic very-low-density lipoprotein (VLDL) production as measured by the accumulation of VLDL in plasma after injection of Triton WR-1339. SB-204990 (25 mg/kg per day) also decreased plasma cholesterol levels (by up to 23%) and triglyceride levels (by up to 38%) in the dog, preferentially decreasing low-density lipoprotein compared with high-density lipoprotein cholesterol levels. Overall these results are consistent with the concept that ATP citrate-lyase is an important enzyme in controlling substrate supply for lipid synthesis de novo and a potential enzyme target for hypolipidaemic intervention.

Plasma Lipid and Lipoprotein Abnormalities in Patients with Malabsorption

1973 ◽  
Vol 45 (5) ◽  
pp. 583-592 ◽  
Author(s):  
Gilbert R. Thompson ◽  
J. Paul Miller
Keyword(s):  
Plasma Lipids ◽  
Plasma Cholesterol ◽  
Low Density Lipoprotein ◽  
Plasma Lipid ◽  
Density Lipoprotein ◽  
Serum Triglyceride ◽  
Plasma Lipoproteins ◽  
Low Density ◽  
Cholesterol Levels ◽  
Lipids And Lipoproteins

1. Plasma lipids and lipoproteins have been studied in control subjects and patients with various types of steatorrhoea. 2. Low plasma cholesterol levels were found in malabsorbers and were associated with decreased amounts of low-density lipoprotein (LDL) in males and high-density lipoprotein (HDL) in females. 3. Serum triglyceride levels were normal in males, but exceeded control values in some of the females, due to an increase in very-low-density lipoprotein. 4. LDL composition was abnormal in both male and female malabsorbers, with a decreased proportion of cholesterol ester and an increased proportion of triglyceride. There was also an increased proportion of triglyceride in HDL. 5. These findings show that malabsorption markedly influences not only the concentration but also the composition of plasma lipoproteins.

scholarly journals Dietary Cholesterol Is Highly Associated with Severity of Hyperlipidemia and Atherosclerotic Lesions in Heterozygous LDLR-Deficient Hamsters

2019 ◽  
Vol 20 (14) ◽  
pp. 3515 ◽  
Author(s):  
Jinjie Wang ◽  
Kunxiang He ◽  
Chun Yang ◽  
Xiao Lin ◽  
Xin Zhang ◽  
...  
Keyword(s):  
Coronary Arteries ◽  
Plasma Lipids ◽  
Plasma Cholesterol ◽  
Low Density Lipoprotein ◽  
Dietary Cholesterol ◽  
Gene Mutations ◽  
Density Lipoprotein ◽  
Inherited Disease ◽  
Atherosclerotic Lesions ◽  
Cholesterol Levels

Objective: Familial hypercholesterolemia (FH) is a dominant inherited disease caused mainly by low-density lipoprotein receptor (LDLR) gene mutations. To different extents, both heterozygous and homozygous FH patients develop premature coronary heart disease (CHD). However, most of the experimental animal models with LDLR deficiency could not fully recapitulate FH because they develop hyperlipidemia and atherosclerosis only in homozygous, but not in heterozygous, form. In the current study, we investigated the responsiveness of the LDLR+/− hamster to dietary cholesterol and whether plasma cholesterol levels were positively associated with the severity of atherosclerosis. Approach and Methods: wild type WT and LDLR+/− hamsters were fed a high fat diet with different cholesterol contents (HCHF) for 12 or 16 weeks. Plasma lipids, (apo)lipoproteins, and atherosclerosis in both the aorta and coronary arteries were analyzed. After a HCHF diet challenge, the levels of total cholesterol (TC) in WT and LDLR+/− hamsters were significantly elevated, but the latter showed a more pronounced lipoprotein profile, with higher cholesterol levels that were positively correlated with dietary cholesterol contents. The LDLR+/− hamsters also showed accelerated atherosclerotic lesions in the aorta and coronary arteries, whereas only mild aortic lesions were observed in WT hamsters. Conclusions: Our findings demonstrate that, unlike other rodent animals, the levels of plasma cholesterol in hamsters can be significantly modulated by the intervention of dietary cholesterol, which were closely associated with severity of atherosclerosis in LDLR+/− hamsters, suggesting that the LDLR+/− hamster is an ideal animal model for FH and has great potential in the study of FH and atherosclerosis-related CHD.

Bile Acids: The Good, the Bad, and the Ugly

Physiology ◽  
1999 ◽  
Vol 14 (1) ◽  
pp. 24-29 ◽  
Author(s):  
Alan F. Hofmann
Keyword(s):  
Bile Acids ◽  
Enterohepatic Circulation ◽  
Cholesterol Metabolism ◽  
Plasma Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipid Absorption ◽  
Bile Acid Metabolism ◽  
Cholesterol Levels ◽  
Density Lipoprotein Receptor

Bile acids, amphipathic end products of cholesterol metabolism, are “good” in the infant because they enhance lipid absorption and thereby promote growth. Bile acids also induce bile flow and biliary lipid secretion. The enterohepatic circulation of bile acids is “bad” in the adult because it downregulates hepatocyte low-density lipoprotein receptor activity and thereby elevates plasma cholesterol levels. Defects in bile acid metabolism such as impaired biosynthesis or transport are “ugly” because they cause morbidity and death. New approaches for treating these defects are being developed.

Abstract 115: Microrna-30c Reduces Hyperlipidemia and Atherosclerosis by Decreasing Lipid Synthesis and Lipoprotein Secretion

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
James Soh ◽  
Jahangir Iqbal ◽  
Joyce Queiroz ◽  
Carlos Fernandez-Hernando ◽  
M. Mahmood Hussain
Keyword(s):  
Metabolic Disorders ◽  
Plasma Lipids ◽  
De Novo ◽  
Plasma Cholesterol ◽  
Lipid Synthesis ◽  
Microsomal Triglyceride Transfer Protein ◽  
Atherosclerotic Plaques ◽  
Over Expression ◽  
Transfer Protein ◽  
Lipoprotein Secretion

Hyperlipidemia is a risk factor for various cardiovascular and metabolic disorders. Overproduction of lipoproteins, a process critically dependent on microsomal triglyceride transfer protein (MTP), can contribute to hyperlipidemia. We have shown that hepatic over expression of miR-30c reduces MTP mRNA, protein and activity. Further, MTP mRNA is degraded faster due to the binding of miR-30c to its 3[[Unable to Display Character: ΄]]-UTR. miR-30c lowers plasma cholesterol by reducing production of triglyceride-rich apoB-containing lipoproteins; a phenotype most likely secondary to lower MTP expression. It also reduces de novo lipogenesis by targeting other genes such as LPGAT1. Additionally, atherosclerotic plaques are smaller in Apoe -/- mice expressing miR-30c. Taken together, we have provided evidence that high miR-30c levels reduce plasma lipids and atherosclerosis and avoids steatosis by regulating different sets of genes.

Abstract 577: MicroRNA-30c Reduces Plasma Cholesterol in Different Hypercholesterolemic and Hyperglycemic Mouse Models

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Sara Irani ◽  
Jahangir Iqbal ◽  
M.Mahmood Hussain
Keyword(s):  
Mouse Models ◽  
Metabolic Disorders ◽  
Leptin Receptor ◽  
Plasma Lipids ◽  
Plasma Cholesterol ◽  
Lipid Synthesis ◽  
Density Lipoprotein ◽  
High Plasma ◽  
Western Diet ◽  
Lower Plasma

High plasma cholesterol levels are found in several metabolic disorders and their reductions are advocated to reduce risk of atherosclerosis. A way to lower plasma lipids is to curtail lipoprotein assembly and secretion; however, this is associated with steatosis. We have shown that microRNA-30c (miR-30c) reduces Western diet-induced hypercholesterolemia and atherosclerosis in C57BL/6J and Apoe -/- mice with no obvious adverse effects by reducing hepatic lipoprotein production and lipid synthesis. Here, we tested the effect of miR-30c on plasma lipids, transaminases and hepatic lipids in five different mouse models. Hepatic delivery of miR-30c reduced MTP activity but did not affect plasma cholesterol, triglyceride and glucose in chow-fed C57Bl6J and streptozotocin-induced diabetic, normolipidemic mice. However, hepatic delivery of miR-30c to chow fed leptin deficient ( ob/ob ) and leptin receptor deficient ( db/db ) hypercholesterolemic and hyperglycemic type 2 diabetic mice reduced cholesterol in total plasma and VLDL/LDL by ~ 28%and ~ 25%, respectively, without affecting phospholipid, triglyceride and glucose levels. Interestingly, these mice had lower plasma transaminases and creatine kinases indicating possible beneficial effects. Mechanistic studies showed that miR-30c reduced hepatic MTP activity and lipid synthesis. Moreover, miR-30c significantly lowered plasma cholesterol and atherosclerosis in Western-diet fed low density lipoprotein receptor knockout mice with no effect on plasma triglyceride, glucose and transaminases, suggesting that miR-30c can be a potential therapeutic agent for homozygous familial hypercholesterolemia. In all these studies, hepatic lipid levels were similar in control and miR-30c injected mice. These studies indicate that miR-30c reduces plasma cholesterol in diet-induced and diabetic hyperholesterolemic mice but not in normocholesterolemic mice. Thus, miR-30c may be beneficial in lowering plasma cholesterol in different metabolic disorders independent of the origin of hypercholesterolemia.

scholarly journals The effect of (−)-hydroxycitrate on the activity of the low-density-lipoprotein receptor and 3-hydroxy-3-methylglutaryl-CoA reductase levels in the human hepatoma cell line Hep G2

1990 ◽  
Vol 272 (1) ◽  
pp. 181-186 ◽  
Author(s):  
T A Berkhout ◽  
L M Havekes ◽  
N J Pearce ◽  
P H E Groot
Keyword(s):  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Low Density ◽  
Hep G2 ◽  
Atp Citrate Lyase ◽  
Hmg Coa Reductase ◽  
Synthetic Pathway ◽  
Citrate Lyase ◽  
Coa Reductase

(-)-Hydroxycitrate, a potent inhibitor of ATP citrate-lyase, was tested in Hep G2 cells for effects on cholesterol homoeostasis. After 2.5 h and 18 h incubations with (-)-hydroxycitrate at concentrations of 0.5 mM or higher, incorporation of [1,5-14C]citrate into fatty acids and cholesterol was strongly inhibited. This most likely reflects an effective inhibition of ATP citrate-lyase. Cholesterol biosynthesis was decreased to 27% of the control value as measured by incorporations from 3H2O, indicating a decreased flux of carbon units through the cholesterol-synthetic pathway. After 18 h preincubation with 2 mM-(-)-hydroxycitrate, the cellular low-density-lipoprotein (LDL) receptor activity was increased by 50%, as determined by the receptor-mediated association and degradation. Measurements of receptor-mediated binding versus LDL concentration suggests that this increase was due to an increase in the numbers of LDL receptors. Simultaneously, enzyme levels of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase as determined by activity measurements increased 30-fold. Our results suggest that the increases in HMG-CoA reductase and the LDL receptor are initiated by the decreased flux of carbon units in the cholesterol-synthetic pathway, owing to inhibition of ATP citratelyase. A similar induction of HMG-CoA reductase and LDL receptor was also found after preincubations of cells with 0.3 microM-mevinolin, suggesting that the underlying mechanism for this induction is identical for both drugs.

scholarly journals Loss of TIMP4 (Tissue Inhibitor of Metalloproteinase 4) Promotes Atherosclerotic Plaque Deposition in the Abdominal Aorta Despite Suppressed Plasma Cholesterol Levels

2021 ◽  
Author(s):  
Mei Hu ◽  
Sayantan Jana ◽  
Tolga Kilic ◽  
Faqi Wang ◽  
Mengcheng Shen ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Thoracic Aorta ◽  
Abdominal Aorta ◽  
Plasma Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Plaque Deposition ◽  
Cholesterol Levels

Objective: Atherosclerosis is accumulation of lipids and extracellular matrix in the arterial wall. TIMPs (tissue inhibitor of metalloproteinases) can impact plaque deposition by regulating ECM (extracellular matrix) turnover. TIMP4 also influences lipid metabolism and smooth muscle cell (SMC) proliferation. We investigated the role of TIMP4 in atherosclerosis. Approach and Results: Mice lacking low-density lipoprotein receptor ( Ldlr −/− ) and Timp4 ( Timp4 −/− / Ldlr −/− ) were fed high-fat diet (HFD) or regular laboratory diet. After 3 or 6 months, HFD-fed male and female Timp4 −/− / Ldlr −/− mice exhibited higher plaque density in the abdominal aorta (but not in aortic valves, arch, thoracic aorta) compared with Ldlr −/− mice. Although plasma lipid and cholesterol levels were lower in Timp4 −/− / Ldlr −/− -HFD, cholesterol content in the abdominal aorta was higher along with elevated inflammatory cytokines, MMP (matrix metalloproteinase) activities, CD68 + /calponin + macrophage-like SMCs in Timp4 −/− / Ldlr −/− -HFD compared with Ldlr −/− -HFD mice. In vitro, oxidized LDL (low-density lipoprotein) markedly increased CD68 expression, reduced SMC markers, increased lipid uptake, and reduced cholesterol efflux protein ABCA1 (ATP-binding cassette transporter A1) in Timp4 −/− / Ldlr −/− compared with Ldlr −/− primary SMCs from abdominal, but not thoracic aorta. TIMP4 expression in the abdominal aorta (in vivo) and its corresponding SMCs (in vitro) was ≈2-fold higher than in the thoracic aorta and SMCs; TIMP4 levels decreased following HFD. Timp4 -deficiency in bone marrow–derived macrophages did not alter their foam cell formation capacity. Conclusions: TIMP4 protects against plaque deposition in the abdominal aorta independent of plasma cholesterol levels. TIMP4 prevents proteolytic degradation of ABCA1 in SMCs, hindering cholesterol accumulation and transdifferentiation to macrophage-like foam cells, representing a novel negative regulator of atherosclerosis.

scholarly journals (Pro)renin Receptor Inhibition Reduces Plasma Cholesterol and Triglycerides but Does Not Attenuate Atherosclerosis in Atherosclerotic Mice

2021 ◽  
Vol 8 ◽  
Author(s):  
Dien Ye ◽  
Xiaofei Yang ◽  
Liwei Ren ◽  
Hong S. Lu ◽  
Yuan Sun ◽  
...  
Keyword(s):  
Plasma Lipids ◽  
Inflammatory Responses ◽  
Plasma Cholesterol ◽  
Low Density Lipoprotein ◽  
Plasma Lipid ◽  
Density Lipoprotein ◽  
Low Density ◽  
Beneficial Effects ◽  
Receptor Inhibition ◽  
Density Lipoprotein Receptor

Objective: Elevated plasma cholesterol concentrations contributes to ischemic cardiovascular diseases. Recently, we showed that inhibiting hepatic (pro)renin receptor [(P)RR] attenuated diet-induced hypercholesterolemia and hypertriglyceridemia in low-density lipoprotein receptor (LDLR) deficient mice. The purpose of this study was to determine whether inhibiting hepatic (P)RR could attenuate atherosclerosis.Approach and Results: Eight-week-old male LDLR−/− mice were injected with either saline or N-acetylgalactosamine-modified antisense oligonucleotides (G-ASOs) primarily targeting hepatic (P)RR and were fed a western-type diet (WTD) for 16 weeks. (P)RR G-ASOs markedly reduced plasma cholesterol concentrations from 2,211 ± 146 to 1,128 ± 121 mg/dL. Fast protein liquid chromatography (FPLC) analyses revealed that cholesterol in very low-density lipoprotein (VLDL) and intermediate density lipoprotein (IDL)/LDL fraction were potently reduced by (P)RR G-ASOs. Moreover, (P)RR G-ASOs reduced plasma triglyceride concentrations by more than 80%. Strikingly, despite marked reduction in plasma lipid concentrations, atherosclerosis was not reduced but rather increased in these mice. Further testing in ApoE−/− mice confirmed that (P)RR G-ASOs reduced plasma lipid concentrations but not atherosclerosis. Transcriptomic analysis of the aortas revealed that (P)RR G-ASOs induced the expression of the genes involved in immune responses and inflammation. Further investigation revealed that (P)RR G-ASOs also inhibited (P)RR in macrophages and in enhanced inflammatory responses to exogenous stimuli. Moreover, deleting the (P)RR in macrophages resulted in accelerated atherosclerosis in WTD fed ApoE−/− mice.Conclusion: (P)RR G-ASOs reduced the plasma lipids in atherosclerotic mice due to hepatic (P)RR deficiency. However, augmented pro-inflammatory responses in macrophages due to (P)RR downregulation counteracted the beneficial effects of lowered plasma lipid concentrations on atherosclerosis. Our study demonstrated that hepatic (P)RR and macrophage (P)RR played a counteracting role in atherosclerosis.

scholarly journals Performance characteristics, plasma lipids and copper residue in organs and tissues of cockerel chickens fed dietary organic and inorganic copper

2020 ◽  
Vol 42 (1) ◽  
pp. 85-92
Author(s):  
A. V. Jegede ◽  
O. O. Oduguwa ◽  
A. O. Fafiolu ◽  
O. O. Ibitoye ◽  
I. A. Ogunsola ◽  
...  
Keyword(s):  
Copper Sulphate ◽  
Plasma Lipids ◽  
Plasma Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Live Weight ◽  
Basal Diet ◽  
Feed Conversion ◽  
Total Weight Gain ◽  
Dietary Treatments

A 112-day study was conducted to determine the effect of dietary organic (Copper proteinate) and inorganic (Copper sulphate) Cu source on growth performance, plasma lipids and copper residue in organs and tissues of cockerel chickens. 240 day-old commercial Black-Harco cockerel chicks were randomly distributed to 6 dietary treatments of 40 birds each. Each treatment group was randomly allocated to 4 replicates of 10 birds each. The diets were formulated to contain a basal diet (containing 30.62 and 29.71 mg/kg Cu for starter and finisher phases respectively) supplemented with organic Cu (Cu proteinate; Cu-P) or inorganic Cu (Cu sulphate; CuSO ) fed at 3 dietary levels (50, 100 and 4 150 mg/kg). The birds were fed chicks mash and grower mash at 1-56 days and 57-112 days respectively in a deep litter pen at floor space of 0.06 m2/bird. Cu-P supplementation resulted in significantly higher (P<0.05) final live weight (FLW) and total weight gain (TWG) compared to CuSO at starter phase. Better feed conversion ratio was noticed in birds fed 4 Cu-P supplemented diets compared to CuSO at 150mg/kg Cu concentration at both starter 4 and finisher phases. Birds fed 150 mg/kg Cu recorded the highest (P<0.05) feed intake value at starter phase. There was significantly higher (P<0.05) accumulation of Cu in the blood, heart, lung, liver and thigh of birds fed Cu-P than those fed CuSO . The liver Cu 4 concentration increased as dietary Cu concentration increased. Cu-P supplementation resulted in significant reduction (P<0.05) in plasma cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL) and triglyceride in comparison to CuSO . The blood 4 cholesterol, LDL and triglyceride decreased with increased copper concentration. Organic form of copper promotes growth, more bioavailable and more effective in reducing cholesterol than copper sulphate.

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