Unesterified Fatty Acids Inhibit the Binding of Low Density Lipoproteins to the Human Fibroblast Low Density Lipoprotein Receptor

Bihain, Bernard E.; Deckelbaum, Richard J.; Yen, Frances T; Gleeson, A. M.; Carpentier, Yvon; Witte, Larry

doi:10.1016/s0021-9258(18)71494-4

Cited by 38 publications

(11 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Also, no binding activity was observed in the absence of oleate. Further, we have previously shown that binding of LDL to the LDL receptor is inhibited by oleate (Bihain et al, 1989). Finally, the ligand blot was obtained in the absence of Ca2+, while binding of LDL to the LDL receptor is Ca2+-dependent (Goldstein et al, 1977).…”

Section: Resultsmentioning

confidence: 99%

Identification of a lipolysis-stimulated receptor that is distinct from the LDL receptor and the LDL receptor-related protein

Yen¹,

Mann²,

Guermani³

et al. 1994

Biochemistry

View full text Add to dashboard Cite

This paper provides further characterization of a receptor that, in cells lacking the LDL receptor (FH fibroblasts), mediates lipoprotein binding, uptake, and degradation when incubated with oleate at concentrations not exceeding albumin binding capacity. This oleate-activated receptor is genetically distinct from the LDL receptor and is hereafter referred to as the lipolysis-stimulated receptor (LSR). Its apparent affinity was higher for triglyceride-rich lipoproteins (chylomicrons, VLDL) and for lipid emulsions supplemented with recombinant apoE, than for LDL which contains solely apoB. In contrast, VLDL isolated from a Type III hyperlipidemic patient (apoE2/2 phenotype) failed to bind to the LSR. Five lines of evidence indicated that the LSR is distinct from the LDL receptor-related protein (LRP): (1) the LRP ligand, alpha 2-macroglobulin-methylamine (alpha 2-MG*), did not bind to the oleate-induced LDL binding site; (2) oleate had no effect on the binding of alpha 2-MG* to LRP; (3) the LRP-associated protein, RAP, which inhibits LRP, had no effect on the LSR; (4) binding of lipoproteins to LSR was independent of Ca2+; and (5) LSR activity resolved as two proteins smaller than LRP (apparent molecular masses as determined by ligand blots: 115 and 85 kDa). That LSR provides a new candidate receptor contributing to the clearance of chylomicron remnants (CMR) is supported by the observation that LSR was inhibited by lactoferrin, a milk protein that delays CMR clearance when injected in vivo. Furthermore, in primary cultures of rat hepatocytes, oleate stimulated binding, uptake, and degradation of LDL with kinetic characteristics similar to that of LSR expressed in FH fibroblasts.(ABSTRACT TRUNCATED AT 250 WORDS)

show abstract

Section: Resultsmentioning

confidence: 99%

Identification of a lipolysis-stimulated receptor that is distinct from the LDL receptor and the LDL receptor-related protein

Yen¹,

Mann²,

Guermani³

et al. 1994

Biochemistry

View full text Add to dashboard Cite

show abstract

“…We next tested whether the activation of LSR by FFA is a reversible process. Albumin provided the means to remove FFA from membranes after the FFA activation step (Bihain et al, 1989;Bihain & Yen, 1992).…”

Section: Resultsmentioning

confidence: 99%

Mechanism of Activation and Functional Significance of the Lipolysis-Stimulated Receptor. Evidence for a Role as Chylomicron Remnant Receptor

Mann¹,

Khallou²,

Chevreuil³

et al. 1995

Biochemistry

View full text Add to dashboard Cite

In cultured human and rat cells, the lipolysis-stimulated receptor (LSR), when activated by free fatty acids (FFA), mediates the binding of apoprotein B- and apoprotein E-containing lipoproteins and their subsequent internalization and degradation. To better understand the physiological role of LSR, we developed a biochemical assay that optimizes both the activation and binding steps and, thus, allows the estimation of the number of LSR binding sites expressed in the livers of living animals. With this technique, a strong inverse correlation was found in rats between the apparent number of LSR binding sites in liver and the postprandial plasma triglyceride concentration (r = -0.828, p < 0.001, n = 12). No correlation existed between the number of LSR and plasma triglycerides measured in the same animals after 24 h of fasting. The same membrane binding assay was used to elucidate the mechanism by which FFA induce lipoprotein binding to LSR. The LSR activation step was mediated by direct interaction of FFA with LSR candidate proteins of apparent molecular masses of 115 and 90 kDa and occurred independently of the membrane lipid environment. The FFA-induced conformational shift that revealed the lipoprotein binding site remained fully reversible upon removal of the FFA. However, occupancy of the site by the apoprotein ligand stabilized the active form of LSR. Comparison of the effect of different FFA alone or in combination indicated that the same binding site is revealed by different FFA and that the length and saturation of the FFA monomeric carbon chain are critical in determining the potency of the FFA activating effect. We propose that the LSR pathway represents a limiting step for the cellular uptake of intestinally derived triglyceride-rich lipoproteins and speculate that FFA liberated by lipolysis initiate this process by altering the conformation of LSR to reveal the lipoprotein binding site.

show abstract

“…On the other hand, there is also evidence that LDL receptor activity can be directly altered. Such a direct action may be one of the pathways by which triacylglycols and ketoconazole modulate LDL receptor function [18,22,23]. Bihain et al [23] have reported that unesterified fatty acids directly decrease the number of LDL receptors in human fibroblasts.…”

Section: Introductionmentioning

confidence: 99%

“…Such a direct action may be one of the pathways by which triacylglycols and ketoconazole modulate LDL receptor function [18,22,23]. Bihain et al [23] have reported that unesterified fatty acids directly decrease the number of LDL receptors in human fibroblasts. Ketoconazole has been shown to increase the number of LDLbinding sites in the human hepatoma cell line HepG2.…”

Section: Introductionmentioning

confidence: 99%

Ursodeoxycholic acid increases low-density lipoprotein binding, uptake and degradation in isolated hamster hepatocytes

Bouscarel

Fromm

Ceryak

et al. 1991

Biochemical Journal

View full text Add to dashboard Cite

Ursodeoxycholic acid (UDCA), in contrast to both chenodeoxycholic acid (CDCA), its 7 alpha-epimer, and lithocholic acid, enhanced receptor-dependent low-density lipoprotein (LDL) uptake and degradation in isolated hamster hepatocytes. The increase in cell-associated LDL was time- and concentration-dependent, with a maximum effect observed at approx. 60 min with 1 mM-UDCA. This increase was not associated with a detergent effect of UDCA, as no significant modifications were observed either in the cellular release of lactate dehydrogenase or in Trypan Blue exclusion. The effect of UDCA was not due to a modification of the LDL particle, but rather was receptor-related. UDCA (1 mM) maximally increased the number of 125I-LDL-binding sites (Bmax.) by 35%, from 176 to 240 ng/mg of protein, without a significant modification of the binding affinity. Furthermore, following proteolytic degradation of the LDL receptor with Pronase, specific LDL binding decreased to the level of non-specific binding, and the effect of UDCA was abolished. Conversely, the trihydroxy 7 beta-hydroxy bile acid ursocholic acid and its 7 alpha-epimer, cholic acid, induced a significant decrease in LDL binding by approx. 15%. The C23 analogue of UDCA (nor-UDCA) and CDCA did not affect LDL binding. On the other hand, UDCA conjugated with either glycine (GUDCA) or taurine (TUDCA), increased LDL binding to the same extent as did the free bile acid. The half maximum time (t1/2) to reach the full effect was 1-2 min for UDCA and TUDCA, while GUDCA had a much slower t1/2 of 8.3 min. Ketoconazole (50 microM), an antifungal agent, increased LDL binding, but this effect was not additive when tested in the presence of 0.7 mM-UDCA. The results of the studies indicate that, in isolated hamster hepatocytes, the UDCA-induced increase in receptor-dependent LDL binding and uptake represents a direct effect of this bile acid. The action of the bile acid is closely related to its specific structural conformation, since UDCA and its conjugates are the only bile acids shown to express this ability thus far. However, certain agents other than bile acids, such as ketoconazole, have a similar effect. Finally, the studies suggest that the recruitment of LDL receptors from a latent pool in the hepatocellular membrane may be the mechanism by which UDCA exerts its direct effect.

show abstract

Unesterified Fatty Acids Inhibit the Binding of Low Density Lipoproteins to the Human Fibroblast Low Density Lipoprotein Receptor

Cited by 38 publications

References 24 publications

Identification of a lipolysis-stimulated receptor that is distinct from the LDL receptor and the LDL receptor-related protein

Identification of a lipolysis-stimulated receptor that is distinct from the LDL receptor and the LDL receptor-related protein

Mechanism of Activation and Functional Significance of the Lipolysis-Stimulated Receptor. Evidence for a Role as Chylomicron Remnant Receptor

Ursodeoxycholic acid increases low-density lipoprotein binding, uptake and degradation in isolated hamster hepatocytes

Contact Info

Product

Resources

About