scholarly journals A simplified procedure to trace triglyceride‐rich lipoprotein metabolism in vivo

2021 ◽  
Vol 9 (8) ◽  
Author(s):  
Zhixiong Ying ◽  
Mariëtte R. Boon ◽  
Tamer Coskun ◽  
Sander Kooijman ◽  
Patrick C. N. Rensen
Keyword(s):  
Lipoprotein Metabolism ◽  
Triglyceride Rich Lipoprotein ◽  
Simplified Procedure

Dyslipidemia of chronic renal failure: the nature, mechanisms, and potential consequences

2006 ◽  
Vol 290 (2) ◽  
pp. F262-F272 ◽  
Author(s):  
N. D. Vaziri
Keyword(s):  
Renal Failure ◽  
Chronic Renal Failure ◽  
Hepatic Lipase ◽  
Low Density Lipoprotein ◽  
Plasma Concentrations ◽  
Cholesterol Acyltransferase ◽  
Lipoprotein Metabolism ◽  
Density Lipoprotein ◽  
Triglyceride Rich Lipoprotein ◽  
Density Lipoprotein Receptor

Chronic renal failure (CRF) results in profound lipid disorders, which stem largely from dysregulation of high-density lipoprotein (HDL) and triglyceride-rich lipoprotein metabolism. Specifically, maturation of HDL is impaired and its composition is altered in CRF. In addition, clearance of triglyceride-rich lipoproteins and their atherogenic remnants is impaired, their composition is altered, and their plasma concentrations are elevated in CRF. Impaired maturation of HDL in CRF is primarily due to downregulation of lecithin-cholesterol acyltransferase (LCAT) and, to a lesser extent, increased plasma cholesteryl ester transfer protein (CETP). Triglyceride enrichment of HDL in CRF is primarily due to hepatic lipase deficiency and elevated CETP activity. The CRF-induced hypertriglyceridemia, abnormal composition, and impaired clearance of triglyceride-rich lipoproteins and their remnants are primarily due to downregulation of lipoprotein lipase, hepatic lipase, and the very-low-density lipoprotein receptor, as well as, upregulation of hepatic acyl-CoA cholesterol acyltransferase (ACAT). In addition, impaired HDL metabolism contributes to the disturbances of triglyceride-rich lipoprotein metabolism. These abnormalities are compounded by downregulation of apolipoproteins apoA-I, apoA-II, and apoC-II in CRF. Together, these abnormalities may contribute to the risk of arteriosclerotic cardiovascular disease and may adversely affect progression of renal disease and energy metabolism in CRF.

scholarly journals Adiponectin and other Adipocytokines as Predictors of Markers of Triglyceride-Rich Lipoprotein Metabolism

2005 ◽  
Vol 51 (3) ◽  
pp. 578-585 ◽  
Author(s):  
Dick C Chan ◽  
Gerald F Watts ◽  
Theodore WK Ng ◽  
Yoshiaki Uchida ◽  
Naohiko Sakai ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Independent Predictor ◽  
Lipoprotein Metabolism ◽  
Bioelectrical Impedance ◽  
Apo B ◽  
Nonesterified Fatty Acids ◽  
Plasma Adiponectin ◽  
Tnf Α ◽  
Triglyceride Rich Lipoprotein

Abstract Background: Adipocytokines are bioactive peptides that may play an important role in the regulation of glucose and lipid metabolism. In this study, we investigated the association of plasma adipocytokine concentrations with markers of triglyceride-rich lipoprotein (TRL) metabolism in men. Methods: Fasting adiponectin, leptin, resistin, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), apolipoprotein (apo) B-48, apo C-III, and remnant-like particle (RLP)-cholesterol concentrations were measured by immunoassays and insulin resistance by homeostasis assessment (HOMA) score in 41 nondiabetic men with a body mass index of 22–35 kg/m2. Visceral and subcutaneous adipose tissue masses (ATMs) were determined by magnetic resonance imaging and total ATM by bioelectrical impedance. Results: In univariate regression, plasma adiponectin and leptin concentrations were inversely and directly associated with plasma apoB-48, apoC-III, RLP-cholesterol, triglycerides, VLDL-apoB, and VLDL-triglycerides (P <0.05). Resistin, IL-6, and TNF-α were not significantly associated with any of these variables, except for a direct correction between apoC-III and IL-6 (P <0.05). In multivariate regression including HOMA, age, nonesterified fatty acids, and adipose tissue compartment, adiponectin was an independent predictor of plasma apoB-48 (β coefficient = −0.354; P = 0.048), apoC-III (β coefficient = −0.406; P = 0.012), RLP-cholesterol (β coefficient = −0.377; P = 0.016), and triglycerides (β coefficient = −0.374; P = 0.013). By contrast, leptin was not an independent predictor of these TRL markers. Plasma apoB-48, apoC-III, RLP-cholesterol, and triglycerides were all significantly and positively associated with plasma insulin, HOMA, and visceral, subcutaneous, and total ATMs (P <0.05). Conclusions: These data suggest that the plasma adiponectin concentration may not only link abdominal fat, insulin resistance, and dyslipidemia, but may also exert an independent role in regulating TRL metabolism.

Real-time magnetic resonance imaging and quantification of lipoprotein metabolism in vivo using nanocrystals

2009 ◽  
Vol 4 (3) ◽  
pp. 193-201 ◽  
Author(s):  
Oliver T. Bruns ◽  
Harald Ittrich ◽  
Kersten Peldschus ◽  
Michael G. Kaul ◽  
Ulrich I. Tromsdorf ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Magnetic Resonance ◽  
Real Time ◽  
Lipoprotein Metabolism ◽  
Resonance Imaging

Abstract 76: MicroRNA-144 Regulates Hepatic ABCA1 and Plasma HDL Following Activation of the Nuclear Receptor FXR

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Thomas Vallim ◽  
Elizabeth Tarling ◽  
Tammy Kim ◽  
Mete Civelek ◽  
Angel Baldan ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Nuclear Receptor ◽  
Molecular Mechanisms ◽  
Lipoprotein Metabolism ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Farnesoid X Receptor ◽  
Abca1 Protein

Rationale The bile acid receptor Farnesoid-X-Receptor (FXR) regulates many aspects of lipid metabolism by various complex and not fully understood molecular mechanisms. We set out to investigate the molecular mechanisms for FXR-dependent regulation of lipid and lipoprotein metabolism. Objective To identify FXR-regulated microRNAs that were subsequently involved in regulating lipid metabolism. Methods and Results ATP binding cassette transporter A1 (ABCA1) is a major determinant of plasma High Density Lipoprotein (HDL)-cholesterol levels. Here we show that activation of the nuclear receptor FXR in vivo increases hepatic levels of miR-144, which in turn lower hepatic ABCA1 and plasma HDL levels. We identified two complementary sequences to miR-144 in the 3’ untranslated region (UTR) of ABCA1 mRNA that are necessary for miR-144-dependent regulation. Overexpression of miR-144 in vitro decreased both cellular ABCA1 protein and cholesterol efflux to lipid-poor apolipoprotein A-I (ApoA-I) protein, whilst overexpression in vivo reduced hepatic ABCA1 protein and plasma HDL- cholesterol. Conversely, silencing miR-144 in mice increased hepatic ABCA1 protein and HDL- cholesterol. In addition, we utilized tissue-specific FXR deficient mice to show that induction of miR-144 and FXR-dependent hypolipidemia requires hepatic, but not intestinal FXR. Finally, we identified functional FXR response elements (FXREs) upstream of the miR-144 locus, consistent with direct FXR regulation. Conclusion In conclusion, we have identified a pathway involving FXR, miR-144 and ABCA1 that together regulate plasma HDL cholesterol. This pathway may be therapeutically targeted in the future in order to increase HDL levels.

Transcriptomic therapy for dyslipidemias utilizing nucleic acids targeted at ANGPTL3

2021 ◽  
Author(s):  
Gerald F Watts ◽  
Frederick J Raal ◽  
Dick C Chan
Keyword(s):  
Clinical Trials ◽  
Plasma Lipid ◽  
Lipoprotein Metabolism ◽  
New Approach ◽  
Cholesterol Levels ◽  
Ldl Particles ◽  
Severe Hypertriglyceridemia ◽  
Triglyceride Rich Lipoprotein ◽  
Mixed Hyperlipidemia

Angiopoietin-like protein 3 (ANGPTL3) is a key physiological regulator of plasma lipid and lipoprotein metabolism that involves the control of enzymes, lipoprotein and endothelial lipases. Inhibition of ANGPTL3 offers a new approach for correcting the health risks of dyslipidemia, including familial hypercholesterolemia, mixed hyperlipidemia, metabolic syndrome and/or severe hypertriglyceridemia. ANGPTL3 inhibition with nucleic acid-based antisense oligonucleotide and siRNA can correct dyslipidemia chiefly by reducing production and increasing catabolism of triglyceride-rich lipoprotein and LDL particles. Early clinical trials have demonstrated that these agents can safely and effectively lower plasma triglyceride and LDL-cholesterol levels by up to 70 and 50%, respectively. However, the long-term safety and cost–effectiveness of these agents await to be confirmed in an ongoing and future clinical trials.

scholarly journals Triglyceride-rich lipoprotein binding and uptake by heparan sulfate proteoglycan receptors in a CRISPR/Cas9 library of Hep3B mutants

Glycobiology ◽  
2019 ◽  
Vol 29 (8) ◽  
pp. 582-592 ◽  
Author(s):  
Ferdous Anower-E-Khuda ◽  
Gagandeep Singh ◽  
Yiping Deng ◽  
Philip L S M Gordts ◽  
Jeffrey D Esko
Keyword(s):  
Heparan Sulfate ◽  
Hepatoma Cell ◽  
Lipoprotein Metabolism ◽  
Hepatoma Cell Line ◽  
Human Hepatoma Cell ◽  
Triglyceride Rich Lipoprotein ◽  
Hep3b Cells ◽  
Lipoprotein Binding ◽  
Genetic Deletion ◽  
Uptake Studies

Abstract Binding and uptake of triglyceride-rich lipoproteins (TRLs) in mice depend on heparan sulfate and the hepatic proteoglycan, syndecan-1 (SDC1). Alteration of glucosamine N-sulfation by deletion of glucosamine N-deacetylase-N-sulfotransferase 1 (Ndst1) and 2-O-sulfation of uronic acids by deletion of uronyl 2-O-sulfotransferase (Hs2st) led to diminished lipoprotein metabolism, whereas inactivation of glucosaminyl 6-O-sulfotransferase 1 (Hs6st1), which encodes one of the three 6-O-sulfotransferases, had little effect on lipoprotein binding. However, other studies have suggested that 6-O-sulfation may be important for TRL binding and uptake. In order to explain these discrepant findings, we used CRISPR/Cas9 gene editing to create a library of mutants in the human hepatoma cell line, Hep3B. Inactivation of EXT1 encoding the heparan sulfate copolymerase, NDST1 and HS2ST dramatically reduced binding of TRLs. Inactivation of HS6ST1 had no effect, but deletion of HS6ST2 reduced TRL binding. Compounding mutations in HS6ST1 and HS6ST2 did not exacerbate this effect indicating that HS6ST2 is the dominant 6-O-sulfotransferase and that binding of TRLs indeed depends on 6-O-sulfation of glucosamine residues. Uptake studies showed that TRL internalization was also affected in 6-O-sulfation deficient cells. Interestingly, genetic deletion of SDC1 only marginally impacted binding of TRLs but reduced TRL uptake to the same extent as treating the cells with heparin lyases. These findings confirm that SDC1 is the dominant endocytic proteoglycan receptor for TRLs in human Hep3B cells and that binding and uptake of TRLs depend on SDC1 and N- and 2-O-sulfation as well as 6-O-sulfation of heparan sulfate chains catalyzed by HS6ST2.

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