Glycation and HMG-CoA Reductase Inhibitors: Implication in Diabetes and Associated Complications

Introduction: Diabetes Mellitus (DM) acts as an absolute mediator of cardiovascular risk, prompting the prolonged occurrence, size and intricacy of atherosclerotic plaques via enhanced Advanced Glycation Endproducts (AGEs) formation. Moreover, hyperglycemia is associated with enhanced glyco-oxidized and oxidized Low-Density Lipoprotein (LDL) possessing greater atherogenicity and decreased the ability to regulate HMG-CoA reductase (HMG-R). Although aminoguanidine (AG) prevents the AGE-induced protein cross-linking due to its anti-glycation potential, it exerts several unusual pharmaco-toxicological effects thus restraining its desirable therapeutic effects. HMG-R inhibitors/statins exhibit a variety of beneficial impacts in addition to the cholesterol-lowering effects. Objective: Inhibition of AGEs interaction with receptor for AGEs (RAGE) and glyco-oxidized-LDL by HMG-R inhibitors could decrease LDL uptake by LDL-receptor (LDL-R), regulate cholesterol synthesis via HMG-R, decrease oxidative and inflammatory stress to improve the diabetes-associated complications. Conclusion: Current article appraises the pathological AGE-RAGE concerns in diabetes and its associated complications, mainly focusing on the phenomenon of both circulatory AGEs and those accumulating in tissues in diabetic nephropathy, diabetic neuropathy, and diabetic retinopathy, discussing the potential protective role of HMG-R inhibitors against diabetic complications.

Download Full-text

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

Biochemical Journal ◽

10.1042/bj2720181 ◽

1990 ◽

Vol 272 (1) ◽

pp. 181-186 ◽

Cited By ~ 44

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.

Download Full-text

Short-term effects of ACTH on the low-density lipoprotein receptor mRNA level in rat and hamster adrenals

Journal of Molecular Endocrinology ◽

10.1677/jme.0.0060223 ◽

1991 ◽

Vol 6 (3) ◽

pp. 223-230 ◽

Cited By ~ 10

Author(s):

J.-G. Lehoux ◽

A. Lefebvre

Keyword(s):

Cholesterol Metabolism ◽

Low Density Lipoprotein ◽

Ldl Receptor ◽

Density Lipoprotein ◽

Cholesterol Content ◽

Low Density ◽

Short Term ◽

Hmg Coa Reductase ◽

Receptor Mrna ◽

Coa Reductase

ABSTRACT Low-density lipoprotein (LDL) receptor mRNA was found in both rat and hamster adrenals. Within 30 min after ACTH administration a significant increase in the levels of both LDL receptor and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) mRNAs was observed in rat adrenals; these levels remained increased for up to 240 min. The increase in the levels of LDL receptor and HMG-CoA reductase mRNAs produced by ACTH was reduced by co-administration of aminoglutethimide while, at the same time, the adrenal cholesterol content of rats treated with both aminoglutethimide and ACTH was significantly increased compared with that in groups treated with ACTH alone. Cycloheximide also induced increased levels of rat adrenal mRNAs for LDL receptor and HMG-CoA reductase, but this effect was not additive with that of ACTH. These results suggest that, in the rat, the short-term effect of ACTH on the levels of mRNAs for the LDL receptor and HMG-CoA reductase is similarly controlled and might be mediated through changes in the adrenal cholesterol content. In the hamster adrenal, however, no significant fluctuations were found in the level of LDL receptor mRNA, although a marked increase was found in the level of HMG-CoA reductase mRNA, 2 h after ACTH administration. This indicates that an important effect of ACTH on cholesterol metabolism in the hamster adrenal is at the level of HMG-CoA reductase. In the hamster, therefore, where the main source of cholesterol for the adrenal gland is de-novo synthesis, it seems that a complex mechanism is involved in the control of LDL receptor gene expression.

Download Full-text

Co-ordinate regulation of low-density-lipoprotein receptor and 3-hydroxy-3-methylglutaryl-CoA reductase and synthase gene expression in HepG2 cells

Biochemical Journal ◽

10.1042/bj2600731 ◽

1989 ◽

Vol 260 (3) ◽

pp. 731-736 ◽

Cited By ~ 41

Author(s):

D T Molowa ◽

G M Cimis

Keyword(s):

Hepg2 Cells ◽

Cholesterol Biosynthesis ◽

Hepatoma Cell ◽

Low Density Lipoprotein ◽

Ldl Receptor ◽

Density Lipoprotein ◽

Hepatoma Cell Line ◽

Low Density ◽

Hmg Coa Reductase ◽

Coa Reductase

Cellular processes responsible for maintaining cholesterol homoeostasis are highly regulated. To determine whether two of these processes, cholesterol biosynthesis and receptor-mediated uptake of low-density lipoprotein (LDL), are co-ordinately regulated in human liver, we employed a human hepatoma cell line (HepG2) and measured the accumulation of mRNA for LDL receptor, 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase and HMG-CoA synthase under a variety of conditions. Genomic Southern-blot analysis demonstrated that the integrity of these genes is maintained in the transformed cell. Treatment of HepG2 cells with mevalonate, 25-hydroxycholesterol, LDL, lovastatin or miconazole resulted in a similar effect on the accumulation of all three mRNAs at the concentrations tested. The onset of the response to drug, whether repression or induction of mRNA accumulation, occurred after approximately the same period of exposure for each mRNA. We conclude that the expression of the LDL receptor, HMG-CoA reductase and HMG-CoA synthase is co-ordinately regulated in HepG2 cells.

Download Full-text

Multilevel regulation of low-density lipoprotein receptor and 3-hydroxy- 3-methylglutaryl coenzyme A reductase gene expression in normal and leukemic cells

Blood ◽

10.1182/blood.v84.8.2689.2689 ◽

1994 ◽

Vol 84 (8) ◽

pp. 2689-2698 ◽

Cited By ~ 70

Author(s):

S Vitols ◽

S Norgren ◽

G Juliusson ◽

L Tatidis ◽

H Luthman

Keyword(s):

Low Density Lipoprotein ◽

Ldl Receptor ◽

Density Lipoprotein ◽

Receptor Activity ◽

Leukemic Cells ◽

Normal Cells ◽

Hmg Coa Reductase ◽

Coa Reductase ◽

Multilevel Regulation ◽

Rna Levels

Abstract Altered cholesterol homeostasis has been noted in malignant cells, which led us to explore the regulation of cholesterol metabolism in normal and leukemic cells. The mean low-density lipoprotein (LDL) receptor and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activities were fivefold and threefold higher in mononuclear blood cells from 33 patients with leukemia, compared with cells from 23 healthy subjects, whereas elevations in RNA levels were twofold and 40% only. The activities of the two proteins correlated in normal cells (r = .46), whereas an inverse correlation was found in leukemic cells (r = -.40). Relatively weak correlations were found between LDL receptor RNA levels and receptor activity in normal (r = .48) and leukemic cells (r = .49), and HMG-CoA reductase RNA levels correlated (r = .53) with reductase activity in leukemic cells only. The ratios of protein activities to RNA levels in cells were constant during consecutive blood samplings and similar in leukemic blood and bone marrow cells from the same individual. During cholesterol deprivation, protein activities increased more than RNA levels, and leukemic cells with high LDL receptor activity showed a partial resistance to the suppressing effect of sterols on LDL receptor gene expression. The results demonstrate that LDL receptor RNA levels alone can not explain variation in receptor activity, suggesting post-RNA regulation of LDL receptor expression, similar to what has been described for HMG-CoA reductase. Taken together, the present results suggest multilevel regulation of both proteins and demonstrate that each cell clone, normal or malignant, has a unique ratio of protein activity to RNA level. Leukemic cells, in contrast to normal cells, can meet increased cholesterol requirements by either elevated LDL receptor activity or increased cholesterol synthesis, which is of potential interest for diagnosis and specific treatment of leukemia.

Download Full-text

Multilevel regulation of low-density lipoprotein receptor and 3-hydroxy- 3-methylglutaryl coenzyme A reductase gene expression in normal and leukemic cells

Blood ◽

10.1182/blood.v84.8.2689.bloodjournal8482689 ◽

1994 ◽

Vol 84 (8) ◽

pp. 2689-2698 ◽

Cited By ~ 1

Author(s):

S Vitols ◽

S Norgren ◽

G Juliusson ◽

L Tatidis ◽

H Luthman

Keyword(s):

Low Density Lipoprotein ◽

Ldl Receptor ◽

Density Lipoprotein ◽

Receptor Activity ◽

Leukemic Cells ◽

Normal Cells ◽

Hmg Coa Reductase ◽

Coa Reductase ◽

Multilevel Regulation ◽

Rna Levels

Altered cholesterol homeostasis has been noted in malignant cells, which led us to explore the regulation of cholesterol metabolism in normal and leukemic cells. The mean low-density lipoprotein (LDL) receptor and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activities were fivefold and threefold higher in mononuclear blood cells from 33 patients with leukemia, compared with cells from 23 healthy subjects, whereas elevations in RNA levels were twofold and 40% only. The activities of the two proteins correlated in normal cells (r = .46), whereas an inverse correlation was found in leukemic cells (r = -.40). Relatively weak correlations were found between LDL receptor RNA levels and receptor activity in normal (r = .48) and leukemic cells (r = .49), and HMG-CoA reductase RNA levels correlated (r = .53) with reductase activity in leukemic cells only. The ratios of protein activities to RNA levels in cells were constant during consecutive blood samplings and similar in leukemic blood and bone marrow cells from the same individual. During cholesterol deprivation, protein activities increased more than RNA levels, and leukemic cells with high LDL receptor activity showed a partial resistance to the suppressing effect of sterols on LDL receptor gene expression. The results demonstrate that LDL receptor RNA levels alone can not explain variation in receptor activity, suggesting post-RNA regulation of LDL receptor expression, similar to what has been described for HMG-CoA reductase. Taken together, the present results suggest multilevel regulation of both proteins and demonstrate that each cell clone, normal or malignant, has a unique ratio of protein activity to RNA level. Leukemic cells, in contrast to normal cells, can meet increased cholesterol requirements by either elevated LDL receptor activity or increased cholesterol synthesis, which is of potential interest for diagnosis and specific treatment of leukemia.

Download Full-text

Circadian rhythm in hepatic low-density-lipoprotein (LDL)-receptor expression and plasma LDL levels

Biochemical Journal ◽

10.1042/bj2980039 ◽

1994 ◽

Vol 298 (1) ◽

pp. 39-43 ◽

Cited By ~ 28

Author(s):

S Balasubramaniam ◽

A Szanto ◽

P D Roach

Keyword(s):

Low Density Lipoprotein ◽

Circadian Variation ◽

Ldl Receptor ◽

Density Lipoprotein ◽

Receptor Expression ◽

Receptor Protein ◽

Low Density ◽

Hmg Coa Reductase ◽

Cultured Fibroblasts ◽

Coa Reductase

On the basis of studies in vivo and in vitro that involved the use of pharmacological amounts of drugs and hormones or excess cholesterol supplementation, the expression of the low-density lipoprotein (LDL) receptor appears to be tightly coupled to the regulation of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase activity and to extracellular levels of LDL. The present study was undertaken to see how these three entities are regulated under normal physiological conditions over a 24 h period. The results show that, in the rat, hepatic LDL-receptor expression and plasma LDL levels exhibit diurnal periodicity, with a 2-3-fold difference between the peak and trough of each rhythm. Both rhythms showed high inverse correlation (r = -0.86, P < 0.01), plasma LDL levels being lowest at the onset of darkness when LDL-receptor expression was at its peak. The results also showed that the LDL-receptor protein in rat liver has a shorter half-life than that reported for cultured fibroblasts or HepG2 cells. The maximal expression of the LDL receptor occurred several hours before the peak activity of HMG-CoA reductase and appeared not to be influenced by cellular or membrane cholesterol levels during the 24 h cycle. Treatment with dexamethasone increased the LDL-receptor activity significantly at both the lowest and highest points of the rhythm, but the receptor rhythm was still maintained, suggesting that the signal for the circadian variation of the receptor expression is not mediated by adrenal hormones.

Download Full-text

Oxidized LDL but not angiotensin II induces the interaction between LOX-1 and AT1 receptors

10.1101/2020.12.14.422633 ◽

2020 ◽

Author(s):

Li Lin ◽

Ning Zhou ◽

Le Kang ◽

Qi Wang ◽

Jian Wu ◽

...

Keyword(s):

Angiotensin Ii ◽

Oxidized Ldl ◽

Low Density Lipoprotein ◽

Ldl Receptor ◽

Density Lipoprotein ◽

Direct Interaction ◽

Cardiomyocyte Hypertrophy ◽

Oxidized Low Density Lipoprotein ◽

Protein Activation

Oxidized low-density lipoprotein (Ox-LDL) can induce cardiac hypertrophy, but the mechanism is still unclear. Here we elucidate the role of angiotensin II (AngII) receptor (AT1-R) in Ox-LDL-induced cardiomycyte hypertrophy. Inhibition of Ox-LDL receptor LOX-1 and AT1-R rather than AngII abolished Ox-LDL-induced hypertrophic responses. Similar results were obtained from the heart of mice lacking endogenous Ang II and their cardiomyocytes. Ox-LDL but not AngII induced binding of LOX-1 to AT1-R, and the inhibition of LOX-1 or AT1-R rather than AngII abolished the association of these two receptors. Ox-LDL-induced ERKs phosphorylation in LOX-1 and AT1-R-overexpression cells and the binding of both receptors were suppressed by the mutants of LOX-1 (Lys266Ala/Lys267Ala) or AT1-R (Glu257Ala), however, the AT1-R mutant lacking Gq protein-coupling ability only abolished the ERKs phosphorylation. The phosphorylation of ERKs induced by Ox-LDL in LOX-1 and AT1-R-overexpression cells was abrogated by Gq protein inhibitor but not by Jak2, Rac1 and RhoA inhibitors. Therefore, the direct interaction between LOX-1 and AT1-R and the downstream Gq protein activation are important mechanisms for Ox-LDL- but not AngII-induced cardiomyocyte hypertrophy

Download Full-text

Electronegative LDL from Rabbits Fed with Atherogenic Diet Is Highly Proinflammatory

Mediators of Inflammation ◽

10.1155/2019/6163130 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 3

Author(s):

Po-Yuan Chang ◽

Jou-Hsiang Pai ◽

Yu-Sheng Lai ◽

Shao-Chun Lu

Keyword(s):

Tumor Necrosis ◽

Culture Medium ◽

Oxidized Ldl ◽

Low Density Lipoprotein ◽

Ldl Receptor ◽

Density Lipoprotein ◽

Anion Exchange Chromatography ◽

Atherogenic Diet ◽

Exchange Chromatography ◽

Necrosis Factor

Electronegative low-density lipoprotein (LDL(-)) has been found in the plasma of familial hypercholesterolemia and acute myocardial infarction and has been implicated in atherosclerosis and cardiovascular disease. However, less is known about the involvement of LDL(-) in atherosclerosis-related inflammation. This study aims at investigating the inducibility of LDL(-) by atherogenic diet in rabbits and at exploring the proinflammatory potential of the diet-induced LDL(-) in macrophages. Rabbits were fed with an atherogenic diet; LDL was isolated from plasma by NaBr density gradient ultracentrifugation and was then resolved into nLDL and LDL(-) by anion-exchange chromatography. Isolated nLDL and LDL(-) were directly used or incubated with 10 μM CuSO4 for 24 h to produce copper- (Cu-) ox-nLDL and Cu-ox-LDL(-). The effects of these LDLs on inflammation were evaluated in THP-1-derived macrophages. Macrophages were treated with nLDL, LDL(-), and extensively oxidized LDL (ox-LDL), then the levels of interleukin- (IL-) 1β, IL-6, and tumor necrosis factor- (TNF-) α in a culture medium were determined by ELISA, and the levels of total and phosphorylated IκB, p65, p38, JNK, and ERK in cell lysates were determined by Western blotting. The LDL(-) induced significantly higher levels of IL-1β, IL-6, and TNF-α in the medium. The levels of phosphorylated/total IκB, p65, p38, JNK, and ERK were also upregulated by LDL(-). In contrast, nLDL, Cu-ox-nLDL, and Cu-ox-LDL(-) exhibited much less effect. Knockdown of lectin-type oxidized LDL receptor- (LOX-) 1 resulted in significant reduction in LDL(-)-induced IL-1β, IL-6, and TNF-α. In addition, these LDL(-) effects were also markedly attenuated by inhibition of NF-κB and ERK1/2. The data suggested that LDL(-) induced inflammation through LOX-1-, NF-κB-, and ERK1/2-dependent pathways. Taken together, our results show that rabbits fed with atherogenic diet produce a highly proinflammatory LDL(-) that is more potent in inducing inflammation than nLDL and extensively oxidize LDL in macrophages. The results thus provide a novel link between diet-induced hypercholesterolemia and inflammation.

Download Full-text

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1): a crucial driver of atherosclerotic cardiovascular disease

European Heart Journal ◽

10.1093/eurheartj/ehaa770 ◽

2020 ◽

Author(s):

Alexander Akhmedov ◽

Tatsuya Sawamura ◽

Chu-Huang Chen ◽

Simon Kraler ◽

Daria Vdovenko ◽

...

Keyword(s):

Oxidized Ldl ◽

Low Density Lipoprotein ◽

Ldl Receptor ◽

Density Lipoprotein ◽

Basic Research ◽

Plaque Formation ◽

Atherosclerotic Cardiovascular Disease ◽

Low Density ◽

Oxidized Low Density Lipoprotein ◽

Atheromatous Plaques

Abstract Cardiovascular diseases (CVDs), specifically lipid-driven atherosclerotic CVDs, remain the number one cause of death worldwide. The lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1), a scavenger receptor that promotes endothelial dysfunction by inducing pro-atherogenic signalling and plaque formation via the endothelial uptake of oxidized LDL (oxLDL) and electronegative LDL, contributes to the initiation, progression, and destabilization of atheromatous plaques, eventually leading to the development of myocardial infarction and certain forms of stroke. In addition to its expression in endothelial cells, LOX-1 is expressed in macrophages, cardiomyocytes, fibroblasts, dendritic cells, lymphocytes, and neutrophils, further implicating this receptor in multiple aspects of atherosclerotic plaque formation. LOX-1 holds promise as a novel diagnostic and therapeutic target for certain CVDs; therefore, understanding the molecular structure and function of LOX-1 is of critical importance. In this review, we highlight the latest scientific findings related to LOX-1, its ligands, and their roles in the broad spectrum of CVDs. We describe recent findings from basic research, delineate their translational value, and discuss the potential of LOX-1 as a novel target for the prevention, diagnosis, and treatment of related CVDs.

Download Full-text

PCSK9 and inflammation: role of shear stress, pro-inflammatory cytokines, and LOX-1

Cardiovascular Research ◽

10.1093/cvr/cvz313 ◽

2019 ◽

Vol 116 (5) ◽

pp. 908-915 ◽

Cited By ~ 12

Author(s):

Zufeng Ding ◽

Naga Venkata K Pothineni ◽

Akshay Goel ◽

Thomas F Lüscher ◽

Jawahar L Mehta

Keyword(s):

Inflammatory Cytokines ◽

Ldl Cholesterol ◽

Vascular Endothelial Cells ◽

Oxidized Ldl ◽

Low Density Lipoprotein ◽

Ldl Receptor ◽

Density Lipoprotein ◽

Pcsk9 Inhibitors ◽

Prevention Of Atherosclerosis ◽

Pro Inflammatory Cytokines

Abstract PCSK9 degrades low-density lipoprotein cholesterol (LDL) receptors and subsequently increases serum LDL cholesterol. Clinical trials show that inhibition of PCSK9 efficiently lowers LDL cholesterol levels and reduces cardiovascular events. PCSK9 inhibitors also reduce the extent of atherosclerosis. Recent studies show that PCSK9 is secreted by vascular endothelial cells, smooth muscle cells, and macrophages. PCSK9 induces secretion of pro-inflammatory cytokines in macrophages, liver cells, and in a variety of tissues. PCSK9 regulates toll-like receptor 4 expression and NF-κB activation as well as development of apoptosis and autophagy. PCSK9 also interacts with oxidized-LDL receptor-1 (LOX-1) in a mutually facilitative fashion. These observations suggest that PCSK9 is inter-twined with inflammation with implications in atherosclerosis and its major consequence—myocardial ischaemia. This relationship provides a basis for the use of PCSK9 inhibitors in prevention of atherosclerosis and related clinical events.

Download Full-text