Postprandial dyslipidemia in men with visceral obesity: an effect of reduced LDL receptor expression?

2001 ◽  
Vol 281 (3) ◽  
pp. E626-E632 ◽  
Author(s):  
John C. L. Mamo ◽  
Gerald F. Watts ◽  
P. Hugh R. Barrett ◽  
Darrin Smith ◽  
Anthony P. James ◽  
...  
Keyword(s):  
Plasma Cholesterol ◽  
Hydrolytic Enzyme ◽  
Ldl Receptor ◽  
Surrogate Marker ◽  
Visceral Obesity ◽  
Receptor Expression ◽  
Cell Protein ◽  
Insulin Resistant ◽  
Postprandial Triglyceride ◽  
Obese Subjects

Postprandial lipemia after an oral fat challenge was studied in middle-aged men with visceral obesity. The two groups had similar plasma cholesterol levels, but obese subjects had higher levels of plasma triglyceride and reduced amounts of high-density cholesterol. Fasting plasma insulin was fourfold greater in obese subjects because of concomitant insulin resistance, with a calculated HOMA score of 3.1 ± 0.6 vs. 0.8 ± 0.2, respectively. Plasma apolipoprotein B48(apoB48) and retinyl palmitate (RP) after an oral fat challenge were used to monitor chylomicron metabolism. Compared with lean subjects, the fasting concentration of apoB48 was more than twofold greater in obese individuals, suggestive of an accumulation of posthydrolyzed particles. After the oral lipid load, the incremental areas under the apoB48 and RP curves (IAUC) were both significantly greater in obese subjects (apoB48: 97 ± 17 vs. 44 ± 12 μg · ml−1 · h; RP: 3,120 ± 511 vs. 1,308 ± 177 U · ml−1 · h, respectively). A delay in the conversion of chylomicrons to remnants probably contributed to postprandial dyslipidemia in viscerally obese subjects. The triglyceride IAUC was 68% greater in obese subjects (4.7 ± 0.6 vs. 2.8 ± 0.8 mM · h, P< 0.06). Moreover, peak postprandial triglyceride was delayed by ∼2 h in obese subjects. The reduction in triglyceride lipolysis in vivo did not appear to reflect changes in hydrolytic enzyme activities. Postheparin plasma lipase rates were found to be similar for lean and obese subjects. In this study, low-density lipoprotein (LDL) receptor expression on monunuclear cells was used as a surrogate marker of hepatic activity. We found that, in obese subjects, the binding of LDL was reduced by one-half compared with lean controls (70.9 ± 15.07 vs. 38.9 ± 4.6 ng LDL bound/μg cell protein, P = 0.02). Because the LDL receptor is involved in the removal of proatherogenic chylomicron remnants, we suggest that the hepatic clearance of these particles might be compromised in insulin-resistant obese subjects. Premature and accelerated atherogenesis in viscerally obese, insulin-resistant subjects may in part reflect delayed clearance of postprandial lipoprotein remnants.

Abstract 13801: The p.Leu167del Mutation in APOE Gene causes Autosomal Dominant Hypercholesterolemia by Down-Regulation of LDL Receptor Expression in Hepatocytes

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Ana Cenarro ◽  
César Martín ◽  
Marianne Stef ◽  
Isabel de Castro-Orós ◽  
Aitor Etxebarria ◽  
...  
Keyword(s):  
Hepg2 Cells ◽  
Autosomal Dominant ◽  
Plasma Cholesterol ◽  
Family Members ◽  
Ldl Receptor ◽  
Receptor Expression ◽  
Apoe Gene ◽  
Control Group ◽  
Down Regulation ◽  
Mutation Carriers

Introduction: The p.Leu167del mutation in APOE gene has been associated to different hyperlipidemias. However, the frequency of this mutation in autosomal dominant hypercholesterolemia and the mechanism of this association is not known. Objectives: To establish the frequency of p.Leu167del mutation in APOE gene in subjects with clinical diagnosis of Autosomal Dominant Hypercholesterolemia (ADH) non-dependent of LDLR, APOB nor PCSK9 genes, and to investigate the mechanism by which this mutation associates to ADH. Methods: We selected 288 unrelated subjects with ADH non-dependent of LDLR, APOB nor PCSK9 genes, and 220 unrelated normolipidemic subjects (control group). All available family members of mutation carrier subjects were also studied. Exon 4 of APOE gene was sequenced in all subjects. VLDL and LDL were isolated from p.Leu167del carriers and E3/E3 control subjects by ultracentrifugation. Quantification of lipoprotein uptake in HepG2 and THP-1 cells and LDL receptor membrane-expression in HepG2 cells were carried out by flow cytometry. Results: In the ADH group, 9 unrelated subjects (3.1%) were carriers of the p.Leu167del mutation in APOE gene and none in the control group. Eleven family members were carriers of the mutation, 7 with isolated hypercholesterolemia and 4 with mixed hyperlipidemia. A clear co-segregation of p.Leu167del mutation with elevated plasma cholesterol levels in the families was found. VLDL isolated from p.Leu167del mutation carriers had a significantly higher uptake by HepG2 and THP-1 cells compared to VLDL isolated from E3/E3 subjects (p<0.01). When increasing incubation times of HepG2 cells with VLDL from p.Leu167del carriers, the LDL receptor expression in surface membrane diminished, in contrast with the VLDL from E3/E3 subjects. When pre-incubating HepG2 cells with VLDL from p.Leu167del mutation carriers, the percentage of LDL internalisation was significantly lower than when incubating with VLDL from E3/E3 subject (p<0.01). Conclusion: The p.Leu167del mutation in APOE gene is associated to ADH in 3.1% of studied subjects. The mechanism of this association is higher uptake of VLDL, down regulation of the LDLR expression and decrease of LDL internalisation in hepatocytes.

scholarly journals Isoproterenol decreases LDL receptor expression in rat adipose cells: activation of cyclic AMP-dependent proteolysis

1996 ◽  
Vol 37 (2) ◽  
pp. 237-249
Author(s):  
F B Kraemer ◽  
V Natu ◽  
A Singh-Bist ◽  
S Patel ◽  
M C Komaromy ◽  
...  
Keyword(s):  
Cyclic Amp ◽  
Ldl Receptor ◽  
Receptor Expression ◽  
Adipose Cells

Sterol regulation of human LDL receptor expression in gene therapy

2000 ◽  
Vol 151 (1) ◽  
pp. 102-103
Author(s):  
J. Heeren ◽  
F. Schnieders ◽  
U. Beisiegel
Keyword(s):  
Gene Therapy ◽  
Ldl Receptor ◽  
Receptor Expression

Increased LDL receptor mRNA expression in colon cancer is correlated with a rise in plasma cholesterol levels after curative surgery

1995 ◽  
Vol 61 (4) ◽  
pp. 461-464 ◽  
Author(s):  
Axel Niendorf ◽  
Herbert Nägele ◽  
Daisy Gerding ◽  
Udo Meyer-Pannwitt ◽  
Angelika Gebhardt
Keyword(s):  
Colon Cancer ◽  
Mrna Expression ◽  
Plasma Cholesterol ◽  
Ldl Receptor ◽  
Curative Surgery ◽  
Receptor Mrna ◽  
Cholesterol Levels

Enhanced endothelin-1 response and receptor expression in small mesenteric arteries of insulin-resistant rats

2001 ◽  
Vol 280 (2) ◽  
pp. H522-H527 ◽  
Author(s):  
Prasad V. G. Katakam ◽  
Jennifer S. Pollock ◽  
David M. Pollock ◽  
Michael R. Ujhelyi ◽  
Allison W. Miller
Keyword(s):  
Receptor Expression ◽  
Mesenteric Arteries ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Binding Characteristics ◽  
Endothelin 1 ◽  
Insulin Resistant ◽  
Vasoconstrictor Response ◽  
Enhanced Expression

Hyperinsulinemia, a primary feature of insulin resistance, is associated with increased endothelin-1 (ET-1) activity. This study determined the vascular response to ET-1 and receptor binding characteristics in small mesenteric arteries of insulin-resistant (IR) rats. Rats were randomized to control (C) ( n = 32) or IR ( n = 32) groups. The response to ET-1 was assessed (in vitro) in arteries with (Endo+) and without (Endo−) endothelium. In addition, arteries (Endo+) were pretreated with the ETBantagonist A-192621 or the ETA antagonist A-127722. Finally, binding characteristics of [125I]ET-1 were determined. Results showed that in Endo+ arteries the maximal relaxation ( E max) to ET-1 was similar between C and IR groups; however, the concentration at 50% of maximum relaxation (EC50) was decreased in IR arteries. In Endo− arteries, the E max to ET-1 was enhanced in both groups. Pretreatment with A-192621 enhanced the E max and EC50 to ET-1 in both groups. In contrast, A-127722 inhibited the ET-1 response in all arteries in a concentration-dependent manner; however, a greater ET-1 response was seen at each concentration in IR arteries. Maximal binding of [125I]ET-1 was increased in IR versus C arteries although the dissociation constant values were similar. In conclusion, we found the vasoconstrictor response to ET-1 is enhanced in IR arteries due to an enhanced expression of ET receptors and underlying endothelial dysfunction.

Flow cytometry with a monoclonal antibody to the low density lipoprotein receptor compared with gene mutation detection in diagnosis of heterozygous familial hypercholesterolemia

1998 ◽  
Vol 44 (5) ◽  
pp. 966-972 ◽  
Author(s):  
Bent Raungaard ◽  
Finn Heath ◽  
Jens Uffe Brorholt-Petersen ◽  
Henrik Kjærulf Jensen ◽  
Ole Faergeman
Keyword(s):  
Flow Cytometry ◽  
T Lymphocytes ◽  
Receptor Gene ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Receptor Expression ◽  
Low Density ◽  
Flow Cytometry Assay ◽  
Stop Mutation

Abstract We used a fluorescence flow cytometry assay with a monoclonal low density lipoprotein (LDL) receptor-specific antibody to detect LDL receptor expression on blood T lymphocytes and monocytes. We prepared peripheral blood mononuclear cells from patients with genetically verified LDL receptor-defective (Trp66-Gly mutation, n = 17) or receptor-negative (Trp23-stop mutation, n = 17) heterozygous familial hypercholesterolemia (FH) and from healthy individuals (n = 24). The cells were stimulated to express the maximum amount of LDL receptor by preincubation in lipoprotein-deficient medium. A dual-labeling technique allowed flow cytometric analysis of LDL receptor expression on cells identified by fluorescently conjugated surface marker antibodies. Knowing the LDL receptor gene mutation of the FH patients allowed us to compare the diagnostic capability of this functional assay with the DNA diagnosis and to validate the assay with molecular genetics instead of clinical indices of heterozygous FH. T lymphocytes expressed more LDL receptors and gave better diagnostic results than monocytes, and cells from patients with either the Trp66-Gly or the Trp23-stop mutation had variable but significantly reduced LDL receptor expression. The data indicate that this fluorescence flow cytometry assay is unsuitable for diagnosis of individual cases of heterozygous FH but that it may be useful for functionally characterizing mutations in the LDL receptor gene.

scholarly journals Oxidized LDL Modify the Human Adipocyte Phenotype to an Insulin Resistant, Proinflamatory and Proapoptotic Profile

Biomolecules ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 534 ◽  
Author(s):  
Concepción Santiago-Fernández ◽  
Flores Martin-Reyes ◽  
Mónica Tome ◽  
Luis Ocaña-Wilhelmi ◽  
Jose Rivas-Becerra ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Morbidly Obese ◽  
Insulin Resistant ◽  
Tnf Α ◽  
Obese Subjects ◽  
Factor Α ◽  
Visceral Adipose

Little information exists in humans on the regulation that oxidized low-density lipoprotein (oxLDL) exerts on adipocyte metabolism, which is associated with obesity and type 2 diabetes. The aim was to analyze the oxLDL effects on adipocytokine secretion and scavenger receptors (SRs) and cell death markers in human visceral adipocytes. Human differentiated adipocytes from visceral adipose tissue from non-obese and morbidly obese subjects were incubated with increasing oxLDL concentrations. mRNA expression of SRs, markers of apoptosis and autophagy, secretion of adipocytokines, and glucose uptake were analyzed. In non-obese and in morbidly obese subjects, oxLDL produced a decrease in insulin-induced glucose uptake, a significant dose-dependent increase in tumor necrosis factor-α (TNF-α), IL-6, and adiponectin secretion, and a decrease in leptin secretion. OxLDL produced a significant increase of Lox-1 and a decrease in Cxcl16 and Cl-p1 expression. The expression of Bnip3 (marker of apoptosis, necrosis and autophagy) was significantly increased and Bcl2 (antiapoptotic marker) was decreased. OxLDL could sensitize adipocytes to a lower insulin-induced glucose uptake, a more proinflammatory phenotype, and could modify the gene expression involved in apoptosis, autophagy, necrosis, and mitophagy. OxLDL can upregulate Lox-1, and this could lead to a possible amplification of proinflammatory and proapoptotic effects of oxLDL.

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