Upregulation of acyl-CoA:cholesterol acyltransferase in chronic renal failure

2002 ◽  
Vol 283 (4) ◽  
pp. E676-E681 ◽  
Author(s):  
Kaihui Liang ◽  
N. D. Vaziri
Keyword(s):  
Renal Failure ◽  
Chronic Renal Failure ◽  
Free Cholesterol ◽  
Foam Cell ◽  
Cholesterol Concentration ◽  
Hepatic Tissue ◽  
Foam Cell Formation ◽  
Intracellular Enzyme ◽  
Hepatic Expression ◽  
Acat Activity

Chronic renal failure (CRF) is associated with profound abnormalities of lipid metabolism and accelerated arteriosclerotic cardiovascular disease. In a recent study, we found marked downregulation of hepatic lecithin-cholesterol acyltransferase, or LCAT, expression, which can account for impaired HDL maturation and depressed HDL cholesterol concentration in CRF. Here, we report on the effect of CRF on acyl-CoA:cholesterol acyltransferase (ACAT) expression. ACAT is an intracellular enzyme that catalyzes esterification of free cholesterol to cholesterol ester for storage or secretion. ACAT plays a major role in hepatic production and release of VLDL, intestinal absorption of cholesterol, foam cell formation, and atherogenesis. We examined hepatic expression of ACAT-1 and ACAT-2 mRNA (Northern blot) and protein (Western blot) abundance and total ACAT activity in male CRF rats (6 wk after 5/6 nephrectomy) and sham-operated controls. The CRF animals showed a significant reduction in creatinine clearance, marked hypertriglyceridemia, modest hypercholesterolemia, and significant upregulation of hepatic tissue ACAT-2 protein and mRNA abundance. In contrast, hepatic ACAT-1 mRNA and protein abundance were unaffected by CRF. Upregulation of ACAT-2 expression was accompanied by a significant increase in hepatic ACAT activity and a significant decrease in hepatic microsomal and whole liver free cholesterol concentration. Thus CRF results in significant upregulation of hepatic ACAT-2 (but not ACAT-1) expression and ACAT activity, which may, in part, contribute to the associated lipid disorders.

scholarly journals p38 Mitogen-activated Protein Kinase (MAPK) Promotes Cholesterol Ester Accumulation in Macrophages through Inhibition of Macroautophagy

2012 ◽  
Vol 287 (15) ◽  
pp. 11761-11768 ◽  
Author(s):  
Shuang Mei ◽  
Haihua Gu ◽  
Adam Ward ◽  
Xuefeng Yang ◽  
Huailan Guo ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Cholesterol Ester ◽  
Free Cholesterol ◽  
Ldl Cholesterol ◽  
Foam Cell ◽  
Cell Formation ◽  
Mitogen Activated Protein Kinase ◽  
Foam Cell Formation ◽  
Cholesterol Esters ◽  
Intracellular Accumulation

p38 MAPK has been strongly implicated in the development of atherosclerosis, but its role in cholesterol ester accumulation in macrophages and formation of foam cells, an early step in the development of atherosclerosis, has not been investigated. We addressed this issue and made some brand new observations. First, elevated intracellular cholesterol level induced by the exposure to LDL-activated p38 MAPK and activation of p38 MAPK with anisomycin increased the ratio of cholesterol esters over free cholesterol, whereas inhibition of p38 MAPK with SB203580 or siRNA reduced the LDL loading-induced intracellular accumulation of free cholesterol and cholesterol esters in macrophages. Second, exposure to LDL cholesterol inhibited autophagy in macrophages, and inhibition of autophagy with 3-methyladenine increased intracellular accumulation of cholesterol (free cholesterol and cholesterol esters), whereas activation of autophagy with rapamycin decreased intracellular accumulation of free cholesterol and cholesterol esters induced by the exposure to LDL cholesterol. Third, LDL cholesterol loading-induced inhibition of autophagy was prevented by blockade of p38 MAPK with SB203580 or siRNA. Neutral cholesterol ester hydrolase was co-localized with autophagosomes. Finally, LDL cholesterol loading and p38 activation suppressed expression of the key autophagy gene, ulk1, in macrophages. Together, our results provide brand new insight about cholesterol ester accumulation in macrophages and foam cell formation.

scholarly journals PCSK9 Functions in Atherosclerosis Are Not Limited to Plasmatic LDL-Cholesterol Regulation

2021 ◽  
Vol 8 ◽  
Author(s):  
Aureli Luquero ◽  
Lina Badimon ◽  
Maria Borrell-Pages
Keyword(s):  
Ldl Cholesterol ◽  
Foam Cell ◽  
Vascular Inflammation ◽  
Cell Formation ◽  
Plasma Lipid ◽  
Lipid Lowering ◽  
Foam Cell Formation ◽  
Hepatic Expression ◽  
Atherosclerosis Progression ◽  
The Impact

The relevance of PCSK9 in atherosclerosis progression is demonstrated by the benefits observed in patients that have followed PCSK9-targeted therapies. The impact of these therapies is attributed to the plasma lipid-lowering effect induced when LDLR hepatic expression levels are recovered after the suppression of soluble PCSK9. Different studies show that PCSK9 is involved in other mechanisms that take place at different stages during atherosclerosis development. Indeed, PCSK9 regulates the expression of key receptors expressed in macrophages that contribute to lipid-loading, foam cell formation and atherosclerotic plaque formation. PCSK9 is also a regulator of vascular inflammation and its expression correlates with pro-inflammatory cytokines release, inflammatory cell recruitment and plaque destabilization. Furthermore, anti-PCSK9 approaches have demonstrated that by inhibiting PCSK9 activity, the progression of atherosclerotic disease is diminished. PCSK9 also modulates thrombosis by modifying platelets steady-state, leukocyte recruitment and clot formation. In this review we evaluate recent findings on PCSK9 functions in cardiovascular diseases beyond LDL-cholesterol plasma levels regulation.

Correction by insulin of disturbed TG-rich LP metabolism in rats with chronic renal failure

1986 ◽  
Vol 250 (4) ◽  
pp. E373-E376 ◽  
Author(s):  
J. B. Roullet ◽  
B. Lacour ◽  
J. P. Yvert ◽  
T. Drueke
Keyword(s):  
Renal Failure ◽  
Adipose Tissue ◽  
Chronic Renal Failure ◽  
Insulin Infusion ◽  
Insulin Treatment ◽  
Serum Insulin ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Experimental Period ◽  
Cholesterol Concentration

To define the role of insulin in lipid disturbances of chronic renal failure, chronically uremic rats (U+) were supplemented by continuous insulin infusion over a 35-day experimental period and compared with control ad libitum-fed rats (C) and uremic rats without insulin (U). Uremic rats were characterized by hypoinsulinemia, an increase in both circulating very low-density lipoprotein (VLDL) and their cholesterol concentration, a normal hepatic triglyceride secretion rate (TGSR) determined with Triton WR 1339, and a low adipose tissue lipoprotein lipase (LPL) activity. Chronic insulin infusion at low rate (0.5 IU/24 h) to U+ rats normalized serum insulin (from 17.0 +/- 0.6 mU/l in U rats to 23.4 +/- 1.7 mU/l in U+ rats), serum VLDL triglycerides (from 804 +/- 65 to 410 +/- 36 mg/l), and serum VLDL cholesterol (from 43 +/- 8 to 16 +/- 3 mg/l). Hepatic TGSR decreased significantly after insulin treatment (from 0.58 +/- 0.03 to 0.44 +/- 0.03 mumol/min). Moreover, adipose tissue LPL was restored to normal by insulin supplementation (from 460 +/- 60 to 860 +/- 150 mU per total epididymal fat in U and U+ rats, respectively). Correction of the disturbed VLDL metabolism was associated with multiple actions of insulin including 1) a decrease of peripheral lipolysis, 2) a decrease of hepatic TGSR, and 3) an increase of adipose tissue LPL activity. Because cholesterol-rich VLDL are potentially atherogenic, their normalization with insulin treatment in this animal model suggests a viable area of investigation for the prevention of accelerated atherogenesis in chronic renal failure.

Su1680 Effect of Chronic Renal Failure on the Hepatic Expression of Bile Acid Transporters

2013 ◽  
Vol 144 (5) ◽  
pp. S-996
Author(s):  
Gai Zhibo ◽  
Chu Lei ◽  
Jean-Pierre Montani ◽  
Gerd A. Kullak-Ublick
Keyword(s):  
Renal Failure ◽  
Bile Acid ◽  
Chronic Renal Failure ◽  
Hepatic Expression ◽  
Bile Acid Transporters

scholarly journals Foam cell formation containing lipid droplets enriched with free cholesterol by hyperlipidemic serum

2001 ◽  
Vol 42 (11) ◽  
pp. 1771-1781 ◽  
Author(s):  
Masahiro Mori ◽  
Hiroyuki Itabe ◽  
Yusuke Higashi ◽  
Yasuyuki Fujimoto ◽  
Masahiro Shiomi ◽  
...  
Keyword(s):  
Lipid Droplets ◽  
Free Cholesterol ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cell Formation

LncRNA DYNLRB2-2 inhibits THP-1 macrophage foam cell formation by enhancing autophagy

2019 ◽  
Vol 400 (8) ◽  
pp. 1047-1057 ◽  
Author(s):  
Yongqiang Li ◽  
Tao Sun ◽  
Shuxin Shen ◽  
Lixia Wang ◽  
Jifeng Yan
Keyword(s):  
Signaling Pathway ◽  
Western Blotting ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cells ◽  
Cholesterol Concentration ◽  
Inflammatory Factors ◽  
Foam Cell Formation ◽  
Enzyme Linked Immunosorbent Assay ◽  
Compound C

Abstract The aim of this study was to investigate whether long non-coding RNA (lncRNA) DYNLRB2-2 can inhibit foam cell formation by activating autophagy. The location of DYNLRB2-2 in THP-1-derived macrophages was analyzed by fluorescence in situ hybridization (FISH). Oxidized-low-density lipoprotein (ox-LDL) was used to induce the formation of foam cells, Oil Red O (ORO) staining and high-performance liquid chromatography (HPLC) were performed to detect accumulation of lipid droplets and the level of cholesterol concentration, respectively. The mRNA and protein level of ATP-binding cassette transporter A1 (ABCA1) were examined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blotting. Relative protein levels of (p-) liver kinase B1 (LKB1), (p-) AMP-activated protein kinase (AMPK), (p-) the mammalian target of rapamycin (mTOR) and autophagy markers (LC3 II, Beclin-1 and p62) in THP-1 macrophage-derived foam cells were analyzed by Western blotting. The levels of inflammatory factors [tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β] in THP-1 macrophage-derived foam cells were detected by enzyme-linked immunosorbent assay (ELISA). 3-MA and compound C were used to block autophagy. Our data show that DYNLRB2-2 inhibited the formation of THP-1 macrophage-derived foam cells and promotes cholesterol efflux (CE) by activating autophagy. DYNLRB2-2 caused autophagy by activating the signaling pathway of LKB1/AMPK/mTOR in foam cells. DYNLRB2-2 activated the LKB1/AMPK/mTOR signaling pathway via the miR-298/Sirtuin 3 (SIRT3) axis. Our data indicated that DYNLRB2-2 enhanced CE by regulating the LKB1/AMPK/mTOR autophagy signaling pathway through the miR-298/SIRT3 axis, thereby blocking the formation of foam cells from THP-1 macrophages.

EM of human atherosclerosis: Aortic fatty streaks with transitional lesion features

1992 ◽  
Vol 50 (1) ◽  
pp. 622-623
Author(s):  
K. Florian Klemp ◽  
J.R. Guyton
Keyword(s):  
Foam Cell ◽  
Cell Formation ◽  
Processing Technique ◽  
Foam Cell Formation ◽  
Tissue Preparation ◽  
Electron Microscopic ◽  
Extracellular Lipid ◽  
Electron Microscopic Cytochemistry ◽  
Human Atherosclerosis ◽  
Clinically Significant

The earliest distinctive lesions in human atherosclerosis are fatty streaks (FS), characterized initially by lipid-laden foam cell formation. Fibrous plaques (FP), the clinically significant lesions, differ from FS in several respects. In addition to foam cells, the FP also exhibit fibromuscular proliferation and a necrotic core region rich in extracellular lipid. The possible transition of FS into mature FP has long been debated, however. A subset of FS described by Katz etal., was intermediate in lipid composition between ordinary FS and FP. We investigated this hypothesis by electron microscopic cytochemistry by employing a tissue processing technique previously described by our laboratory. Osmium-tannic acid-paraphenylenediamine (OTAP) tissue preparation enabled ultrastructural analysis of lipid deposits to discern features characteristic of mature fibrous plaques.

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