scholarly journals Loss-of-function mutation in Pcsk1 increases serum APOA1 level and LCAT activity in mice

2022 ◽  
Vol 38 (1) ◽  
Author(s):  
Aleksandra Aljakna Khan ◽  
Nakyung Kim ◽  
Ron Korstanje ◽  
Seungbum Choi
Keyword(s):  
Cholesterol Metabolism ◽  
Wide Spectrum ◽  
Hdl Cholesterol ◽  
Apolipoprotein A1 ◽  
Cholesterol Concentration ◽  
Lcat Activity ◽  
Loss Of Function ◽  
Nucleotide Mutation ◽  
Hdl Metabolism

Abstract Background The convertase subtilisin/kexin family 1 gene (PCSK1) has been associated in various human genetics studies with a wide spectrum of metabolic phenotypes, including early-onset obesity, hyperphagia, diabetes insipidus, and others. Despite the evident influence of PCSK1 on obesity and the known functions of other PCSKs in lipid metabolism, the role of PCSK1 specifically in lipid and cholesterol metabolism remains unclear. This study evaluated the effect of loss of PCSK1 function on high-density lipoprotein (HDL) metabolism in mice. Results HDL cholesterol, apolipoprotein A1 (APOA1) levels in serum and liver, and the activities of two enzymes (lecithin-cholesterol acyltransferase, LCAT and phospholipid transfer protein, PLTP) were evaluated in 8-week-old mice with a non-synonymous single nucleotide mutation leading to an amino acid substitution in PCSK1, which results in a loss of protein’s function. Mutant mice had similar serum HDL cholesterol concentration but increased levels of serum total and mature APOA1, and LCAT activity in comparison to controls. Conclusions This study presents the first evaluation of the role of PCSK1 in HDL metabolism using a loss-of-function mutant mouse model. Further investigations will be needed to determine the underlying molecular mechanism.

scholarly journals Evolutionary Conservation of MKRN3 and Other Makorins and Their Roles in Puberty Initiation and Endocrine Functions

2019 ◽  
Vol 37 (04) ◽  
pp. 166-173 ◽  
Author(s):  
Lydie Naulé ◽  
Ursula B. Kaiser
Keyword(s):  
Wide Spectrum ◽  
Pubertal Timing ◽  
Pubertal Development ◽  
Protein Structures ◽  
Ring Finger ◽  
Central Precocious Puberty ◽  
Evolutionary Conservation ◽  
Loss Of Function ◽  
Underlying Mechanisms

AbstractPuberty is a critical period of development regulated by genetic, nutritional, and environmental factors. The role of makorin ring finger protein 3 (MKRN3) in the regulation of pubertal timing was revealed when loss-of-function mutations were identified in patients with central precocious puberty (CPP). To date, MKRN3 mutations are the most common known genetic cause of CPP. MKRN3 is a member of the makorin family of ubiquitin ligases, together with MKRN1 and MKRN2. The Mkrn genes have been identified in both vertebrates and invertebrates and show high evolutionary conservation of their gene and protein structures. While the existence of Mkrn orthologues in a wide spectrum of species suggests a vital cellular role of the makorins, their role in puberty initiation and endocrine functions is just beginning to be investigated. In this review, we discuss recent studies that have shown the involvement of Mkrn3 and other makorins in the regulation of pubertal development and other endocrine functions, including metabolism and fertility, as well as their underlying mechanisms of action.

scholarly journals Genetic deletion of Abcc6 disturbs cholesterol homeostasis in mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Bettina Ibold ◽  
Janina Tiemann ◽  
Isabel Faust ◽  
Uta Ceglarek ◽  
Julia Dittrich ◽  
...  
Keyword(s):  
Cholesterol Metabolism ◽  
Cholesterol Biosynthesis ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Pseudoxanthoma Elasticum ◽  
Serum Levels ◽  
Cholesterol Homeostasis ◽  
Cholesterol Depletion ◽  
Transferase Activity

AbstractGenetic studies link adenosine triphosphate-binding cassette transporter C6 (ABCC6) mutations to pseudoxanthoma elasticum (PXE). ABCC6 sequence variations are correlated with altered HDL cholesterol levels and an elevated risk of coronary artery diseases. However, the role of ABCC6 in cholesterol homeostasis is not widely known. Here, we report reduced serum cholesterol and phytosterol levels in Abcc6-deficient mice, indicating an impaired sterol absorption. Ratios of cholesterol precursors to cholesterol were increased, confirmed by upregulation of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase (Hmgcr) expression, suggesting activation of cholesterol biosynthesis in Abcc6−/− mice. We found that cholesterol depletion was accompanied by a substantial decrease in HDL cholesterol mediated by lowered ApoA-I and ApoA-II protein levels and not by inhibited lecithin-cholesterol transferase activity. Additionally, higher proprotein convertase subtilisin/kexin type 9 (Pcsk9) serum levels in Abcc6−/− mice and PXE patients and elevated ApoB level in knockout mice were observed, suggesting a potentially altered very low-density lipoprotein synthesis. Our results underline the role of Abcc6 in cholesterol homeostasis and indicate impaired cholesterol metabolism as an important pathomechanism involved in PXE manifestation.

scholarly journals Dietary myristic acid modifies the HDL-cholesterol concentration and liver scavenger receptor BI expression in the hamster

2002 ◽  
Vol 87 (3) ◽  
pp. 199-210 ◽  
Author(s):  
Carole Loison ◽  
François Mendy ◽  
Colette Sérougne ◽  
Claude Lutton
Keyword(s):  
Myristic Acid ◽  
Cholesterol Metabolism ◽  
Scavenger Receptor ◽  
Hdl Cholesterol ◽  
Test Period ◽  
Cholesterol Concentration ◽  
Scavenger Receptor Bi ◽  
Hepatic Expression ◽  
Hepatic Mass ◽  
Post Period

The influence of myristic acid in a narrow physiological range (0·5 to 2·4 % of total dietary energy) on the plasma and hepatic cholesterol metabolism was investigated in the hamster. The hamsters were fed on a diet containing 12·5 g fat/100 g and 0·05 g cholesterol/100 g with 0·5 % myristic acid (LA diet) for 3 weeks (pre-period). During the following 3 weeks (test period), they were divided into four dietary groups with 0·5 % (LA), 1·2 % (LM), 1·8 % (ML) or 2·4 % (M) myristic acid. Finally, half the hamsters in each group were again fed the LA diet for another 3 weeks (post-period). At the end of the test period, the hepatic expression of the scavenger receptor BI (SR-BI) was lower in the LM, ML and M groups than in the LA group whereas the hepatic cholesteryl ester concentration was higher. Cholesterol 7α hydroxylase activity was lower in the ML and M groups than in the LA and LM groups while the sterol 27 hydroxylase and 3-hydroxy-3-methyl glutaryl coenzyme A reductase activities were not modulated by dietary myristic acid. This is the first time a negative correlation has been observed between the HDL-cholesterol concentration and the hepatic mass of SR-BI (r-0·69;P<0·0001) under physiological conditions. An inverse linear regression was also shown between SR-BI and the percentage of myristic acid in the diet (r-0·75;P<0·0001). The hepatic mass of SR-BI in the M group had increased at the end of the post-period compared with the test-period values. The present investigation shows that myristic acid modulates HDL-cholesterol via a regulation of the SR-BI expression.

scholarly journals Inhibition of Bromodomain and Extraterminal Domain (BET) Proteins by JQ1 Unravels a Novel Epigenetic Modulation to Control Lipid Homeostasis

2020 ◽  
Vol 21 (4) ◽  
pp. 1297 ◽  
Author(s):  
Claudia Tonini ◽  
Mayra Colardo ◽  
Barbara Colella ◽  
Sabrina Di Bartolomeo ◽  
Francesco Berardinelli ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Cholesterol Metabolism ◽  
Deep Understanding ◽  
Epigenetic Mechanism ◽  
Lipid Homeostasis ◽  
Loss Of Function ◽  
Bet Inhibitor ◽  
Physiological Processes ◽  
Epigenetic Modulation

The homeostatic control of lipid metabolism is essential for many fundamental physiological processes. A deep understanding of its regulatory mechanisms is pivotal to unravel prospective physiopathological factors and to identify novel molecular targets that could be employed to design promising therapies in the management of lipid disorders. Here, we investigated the role of bromodomain and extraterminal domain (BET) proteins in the regulation of lipid metabolism. To reach this aim, we used a loss-of-function approach by treating HepG2 cells with JQ1, a powerful and selective BET inhibitor. The main results demonstrated that BET inhibition by JQ1 efficiently decreases intracellular lipid content, determining a significant modulation of proteins involved in lipid biosynthesis, uptake and intracellular trafficking. Importantly, the capability of BET inhibition to slow down cell proliferation is dependent on the modulation of cholesterol metabolism. Taken together, these data highlight a novel epigenetic mechanism involved in the regulation of lipid homeostasis.

Lipid composition of Kupffer cells

1959 ◽  
Vol 196 (4) ◽  
pp. 884-886 ◽  
Author(s):  
N. R. Di Luzio
Keyword(s):  
Kupffer Cells ◽  
Cholesterol Metabolism ◽  
Parenchymal Cell ◽  
Cholesterol Concentration ◽  
Iron Particles ◽  
Phagocytic Cells ◽  
Elevated Cholesterol ◽  
Acute Injection ◽  
Parenchymal Cells

The St. George procedure was modified to permit the isolation of large quantities of viable, highly purified Kupffer cells and parenchymal cells. Phagocytic cells were isolated from normal dogs and rats by magnetic means following the acute injection of 3-micron spherical iron particles. The phospholipid, total, free and ester cholesterol and total lipids were determined in Kupffer and parenchymal cells. In contrast to the noniron-containing or parenchymal cells, the Kupffer cells of both the dog and rat were characterized by an elevated cholesterol concentration. This difference in cholesterol concentration is due to elevation in both the free and ester fractions. However, the ratio between free, ester and total cholesterol was identical in both the RE cell and the parenchymal cell. These findings suggest a specialized role of reticuloendothelial cells in cholesterol metabolism.

scholarly journals Role of GPR109A Receptor in the Efficacy of Nicotinic Acid

2021 ◽  
Vol 04 (05) ◽  
Author(s):  
Virendra Tangri ◽  
Keyword(s):  
Nicotinic Acid ◽  
Mechanism Of Action ◽  
Hdl Cholesterol ◽  
Underlying Mechanism ◽  
Cholesterol Concentration ◽  
Pharmacological Effects ◽  
Unwanted Side Effect ◽  
The Past ◽  
G Protein Coupled

Nicotinic acid is used to treat dyslipidemia from the past few decades. Nicotinic acid has the capability to increase plasma HDL cholesterol concentration, and so it is being used as a potential pharmacological agent. Nicotinic acid has an unwanted side effect called flushing, which effect the patients compliance as this is unpleasant . With the help of receptor GPR109A for nicotinic acid it is possible to understand the underlying mechanism of action and effects of nicotinic acid, and this helped in maximizing the potential pharmacological effects of nicotinic acid and reducing the flushing side effects.GPR109A is a G protein coupled receptor which is activated by nicotinic acid (NA).The role of GPR109A receptor in the efficacy of nicotinic acid is discussed in this paper.

scholarly journals Hypocholesterolemic Activity of Kedawung (Parkia roxburghii)

2021 ◽  
Vol 6 (2) ◽  
pp. 353-360
Author(s):  
Nurul Isnaini Fitriyana ◽  
Kosuke Nishi ◽  
Takuya Sugahara
Keyword(s):  
Total Cholesterol ◽  
Ldl Cholesterol ◽  
Phenolic Content ◽  
Cholesterol Metabolism ◽  
Day Treatment ◽  
Hdl Cholesterol ◽  
Cholesterol Concentration ◽  
Total Phenol Content ◽  
Food Material ◽  
Cholesterol Levels

The purpose of this study is to investigate the hypocholesterolemic activity of kedawung (Parkia roxburghii), an underutilized and lesss-known tree nut. Kedawung was prepared into kedawung powder (BK), kedawung extract (SK) and hydrolyzed kedawung (HK) and then analyzed for its proximate and total phenol content. Furthermore, SK and HK were administered to rats to evaluate their effects on the lipid profile. Oral administration of HK at 160 mg/kg body weight increased the HDL cholesterol level and lowered the LDL and total cholesterol levels in blood of the administered rats. Among groups of the administered rats that completed the 35-day treatment, total cholesterol and LDL cholesterol were significantly reduced (p0.01). The present data showed that kedawung has a hypocholesterolemic activity because of its phenolic content that acts as antioxidant that can bind cholesterol in blood; composition and distribution of amino acid in HK that changed the cholesterol metabolism (reduced cholesterol concentration); protein content in HK that increased the production of lipoprotein that plays a role in suppression of plaque and atherosclerosis. Therefore, hydrolyzed kedawung can be used as an hypocholesterolemic food material.

scholarly journals Asialoglycoprotein receptor 1 is a novel PCSK9-independent ligand of liver LDLR that is shed by Furin

2021 ◽  
Author(s):  
Delia Susan-Resiga ◽  
Emmanuelle Girard ◽  
Rachid Essalmani ◽  
Anna Roubtsova ◽  
Jadwiga Marcinkiewicz ◽  
...  
Keyword(s):  
Cell Surface ◽  
Hdl Cholesterol ◽  
Asialoglycoprotein Receptor ◽  
Carbohydrate Binding ◽  
Loss Of Function ◽  
Novel Approach ◽  
Terminal Galactose ◽  
Ldl Uptake ◽  
Artery Disease

ABSTRACTThe hepatic carbohydrate-recognizing asialoglycoprotein receptor (ASGR1) mediates the endocytosis/lysosomal degradation of desialylated glycoproteins following binding to terminal galactose/N-acetylgalactosamine. Human heterozygote-carriers of ASGR1-deletions exhibited ~34% lower risk of coronary artery disease and ~10-14% non-HDL-cholesterol reduction. Since PCSK9 is a major degrader of LDLR, we examined the regulation of LDLR and/or PCSK9 by ASGR1. We investigated the role of endogenous/overexpressed ASGR1 on LDLR degradation and functionality in naïve HepG2 and HepG2-PCSK9-knockout cells by Western-blot and immunofluorescence.ASGR1, like PCSK9, targets LDLR and both interact with/enhance the degradation of the receptor independently. The lack of cooperativity between PCSK9 and ASGR1 on LDLR expression was confirmed in livers of wild-type (WT) versus Pcsk9-/- mice. ASGR1-knockdown in naïve HepG2 cells significantly increased total (~1.2-fold) and cell-surface (~4-fold) LDLR protein. In HepG2-PCSK9-knockout cells ASGR1-silencing led to ~2-fold higher levels of LDLR protein and DiI-LDL uptake associated with ~4-fold increased cell-surface LDLR. Overexpression of WT-ASGR1 reduced primarily the immature non-O-glycosylated LDLR (~110 kDa), whereas the triple Gln240/Trp244/Glu253 Ala-mutant (loss of carbohydrate-binding) reduced the mature form of the LDLR (~150 kDa), suggesting that ASGR1 binds the LDLR in sugar-dependent and -independent fashion. Furin sheds ASGR1 at RKMK103↓ into a secreted form, likely resulting in a loss-of-function on LDLR. LDLR is the first example of a liver-receptor ligand of ASGR1. Additionally, we demonstrate that lack of ASGR1 enhances LDLR levels and DiI-LDL incorporation, independently of PCSK9. Overall, silencing of ASGR1 and PCSK9 may lead to higher LDL-uptake by hepatocytes, thereby providing a novel approach to further reduce LDL-cholesterol.

The Effect of n-3 Fatty Acids on Lipids and Haemostasis in Patients with Type lla and Type IV Hyperlipidaemia

1989 ◽  
Vol 62 (02) ◽  
pp. 797-801 ◽  
Author(s):  
E Berg Schmidt ◽  
E Ernst ◽  
K Varming ◽  
J O Pedersen ◽  
J Dyerberg
Keyword(s):  
Fatty Acids ◽  
Plasma Lipids ◽  
Plasma Cholesterol ◽  
Hdl Cholesterol ◽  
Apolipoprotein A1 ◽  
Type Iv ◽  
Before And After ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Factor Antigen

SummaryPlasma lipids and haemostasis were investigated in 17 patients with hyperlipidaemia before and after 6 weeks supplementation with 6 g n-3 fatty acids. Nine of the patients had type IIa and 8 had type IV hyperlipidaemia. No effect on plasma cholesterol, LDL- or HDL-cholesterol were seen, but plasma triglycerides decreased after n-3 supplementation. Apolipoprotein B increased and apolipoprotein A1 decreased after the oil supplement. The bleeding time was prolonged, but platelet aggregation was unaltered by n-3 fatty acids. Protein C activity increased in type II a and decreased in type IV after the supplement. Fibrinolysis was markedly depressed while von Willebrand factor antigen was reduced after intake of n-3 fatty acids.

Platelet Aggregation and Plasma Lipoproteins in Alcoholics During Alcohol Withdrawal

1986 ◽  
Vol 55 (02) ◽  
pp. 173-177 ◽  
Author(s):  
K Desai ◽  
J S Owen ◽  
D T Wilson ◽  
R A Hutton
Keyword(s):  
Platelet Aggregation ◽  
Alcohol Withdrawal ◽  
Ldl Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Plasma Lipoprotein ◽  
Cholesterol Concentration ◽  
Arachidonic Acid Content ◽  
Low Density

SummaryPlatelet aggregation, platelet lipid composition and plasma lipoprotein concentrations were measured each week in a group of seventeen alcoholics, without overt liver disease, for one month, following acute, total alcohol withdrawal. The platelets were initially hypoaggregable but, within 1-2 weeks of cessation of drinking, they became hyperaggregable and then gradually returned towards normal values. Hyperaggregability could not be explained by increases in either the cholesterol or the arachidonic acid content of the platelets. Plasma very-low-density lipoprotein cholesterol levels remained high throughout the study, but the initially raised levels of high-density lipoprotein (HDL) cholesterol fell by 26%. Low-density lipoprotein (LDL) cholesterol concentration rose by 10% after two weeks of withdrawal but then returned to about the starting level. The resulting changes in the plasma LDL-cholesterol: HDL-cholesterol ratio, which had increased by more than 50% after two weeks of abstinence, essentially paralleled the time course of enhanced platelet reactivity in all but four of the alcoholics. These findings suggest that alterations in plasma lipoprotein concentrations during acute alcohol withdrawal may be a contributory factor to the haemostatic disorders present in such patients.

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