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Allen D. Cooper - One of the best experts on this subject based on the ideXlab platform.
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Relative roles of the LDL Receptor, the LDL Receptor-like protein, and hepatic lipase in chylomicron remnant removal by the liver.
Journal of lipid research, 1996Co-Authors: E. C. De Faria, L G Fong, M C Komaromy, Allen D. CooperAbstract:Studies were carried out in mice utilizing inhibitors of several cell surface molecules to evaluate their relative roles in chylomicron remnant removal. Anti-LDL Receptor antibody inhibited approximately 45% of rapid remnant removal from plasma, prolonged their half life (63 s to 115 s) and reduced hepatic uptake by 45%. Receptor-associated protein (RAP) (1 mg/mouse), a high affinity inhibitor of the LDL Receptor-related protein (LRP) and a low affinity inhibitor of the LDL Receptor decreased remnant removal approximately 55%, prolonged the half life from 63 s to 230 s, and reduced hepatic uptake by 70%. RAP, but not anti-LDL Receptor antibody, inhibited splenic uptake. With both injected together, an incremental effect was seen; plasma removal decreased 60%, T1/2 increased to 290 s, and hepatic uptake decreased by 80%. Thus, it is likely that virtually all of the very rapid removal of remnants from the plasma by the liver requires the presence of at least one of these members of the LDL Receptor family. Anti-hepatic lipase antibody caused a small but significant delay in remnant removal from plasma and a larger decrease in hepatic uptake (22.5%). It doubled adrenal uptake. The anti-hepatic lipase antibody was not additive with either the anti-LDL Receptor antibody or RAP. Anti-rat hepatic lipase antibody did not inhibit lipolysis by mouse hepatic lipase, suggesting that lipolysis is not the way hepatic lipase enhances remnant uptake. Hepatic lipase bound to remnants to a greater degree than it bound to other lipoproteins. Together these data suggest that hepatic lipase may serve as a binding site for chylomicron remnants, thereby enhancing their affinity for the liver surface, and thus removal by the proteins of the LDL Receptor family. Other molecules may also play a role in removal from the circulation under conditions where the LDL Receptor family Receptors are absent or occupied.
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Activation of LDL Receptor gene expression in HepG2 cells by hepatocyte growth factor
Journal of lipid research, 1996Co-Authors: Youngmi Kim Pak, Allen D. Cooper, M P Kanuck, D Berrios, M R Briggs, Jeff L. EllsworthAbstract:The effect of recombinant human hepatocyte growth factor (HGF) on low density lipoprotein (LDL) Receptor gene expression was studied in the human hepatoma cell line HepG2. HepG2 cells were incubated with serum-free media in the presence and absence of HGF for various times and 125I-labeled LDL specific binding at 4 degrees C, uptake at 37 degrees C, and the levels of LDL Receptor mRNA were measured. Incubation with HGF produced time- and concentration-dependent increases in 125I-labeled LDL binding (2-fold), uptake (2.5-fold), and LDL Receptor mRNA (6-fold). HGF increased the rate of LDL Receptor gene transcription 4- to 5-fold relative to that of several "house-keeping" genes as measured by nuclear run-on transcription. The half-life of LDL Receptor mRNA, measured with actinomycin D, was not increased in HGF-treated cells. The stimulation of LDL Receptor expression occurred independently of changes in cellular cholesterol or DNA biosynthesis or total cell protein. HepG2 cells were transiently transfected with plasmids bearing either three copies of repeats 2 and 3 (pLDLR(23)3LUC) or one copy of the LDL Receptor promoter from -556 to +53 (pLDLR600LUC) linked to firefly luciferase. Incubation of pLDLR(23)3LUC, or pLDLR600LUC-transfected cells with HGF for 4 or 24 h at 37 degrees C produced a concentration-dependent increase in luciferase activity. A maximal stimulation of 3 to 6-fold was achieved for each construct at an HGF concentration of 100 ng/ml. In contrast, HGF had little or no effect on reporter activity in HepG2 cells transfected with a luciferase reporter plasmid bearing the HMG-CoA reductase promoter extending from -325 to +22. Thus, when compared to the native LDL Receptor promoter, multiple copies of repeats 2 and 3 of the LDL Receptor promoter can fully support activation of the luciferase reporter gene by HGF, demonstrating that the effect of HGF is mediated through the SRE-1. The lack of HGF effects mediated through the HMG-CoA reductase sterol regulatory element suggests, however, that sterol depletion may not be responsible for the induction of the LDL Receptor promoter by growth factors. The signalling pathways or effectors responsible for activation of the LDL Receptor and HMG-CoA reductase genes thus differ in their response to HGF. These data suggest that the level of SREBP's reaching the nucleus may be determined by as yet unidentified second messengers as well as by sterols.
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A comparison of the roles of the low density lipoprotein (LDL) Receptor and the LDL Receptor-related protein/alpha 2-macroglobulin Receptor in chylomicron remnant removal in the mouse in vivo.
The Journal of biological chemistry, 1993Co-Authors: Sungshin Y. Choi, Allen D. CooperAbstract:Two cell surface molecules, the low density lipoprotein (LDL) Receptor and the LDL Receptor-related protein (LRP)/alpha 2-macroglobulin Receptor, have been found to have a role in the removal of apoE-rich lipoproteins. To further study this process and to assess the relative contributions of these proteins to the removal of chylomicron remnants, we used an anti-LDL Receptor antibody, activated alpha 2-macroglobulin and the 39-kDa Receptor-associated protein (RAP) as inhibitors of chylomicron remnant removal in intact mice. The advantage of this study is that we were able to use the same litters of animals and batches of lipoprotein for the experiment. In cultured Chinese hamster ovary cells, the anti-LDL Receptor antibody inhibited remnant uptake and degradation about 80% as well as did unlabeled remnants. It did not affect activated alpha 2-macroglobulin uptake or degradation. Activated alpha 2-macroglobulin did not inhibit remnant uptake in normal cells but is reported to block uptake in cells that lack LDL Receptors. Chylomicron remnants blocked activated alpha 2-macroglobulin uptake as effectively as unlabeled activated alpha 2-macroglobulin. This confirmed that the two ligands are cross-competitors but suggests that the LDL Receptor is the primary mediator of remnant uptake in cultured cells that express the LDL Receptor. In vivo, pretreatment with the anti-LDL Receptor antibody decreased remnant uptake 5 min after injection by one-third. The antibody did not affect the removal of activated alpha 2-macroglobulin. Activated alpha 2-macroglobulin had a small, but reproducible effect on remnant removal, decreasing it by about 7% at 5 min. Injection of chylomicron remnants affected activated alpha 2-macroglobulin removal slightly. A similar pattern, but somewhat greater effect was seen on the hepatic uptake of the ligands. Anti-LDL Receptor antibody reduced chylomicron remnant uptake by about half, and activated alpha 2-macroglobulin reduced it by about 15%. Studies with RAP provided results generally similar to those with activated alpha 2-macroglobulin, although RAP appears to bind to a site not recognized by either remnants or activated alpha 2-macroglobulin in addition to sharing a site with these ligands. Together, these results add support for the hypothesis that, although both Receptors can play a role in chylomicron remnant removal, in the normal mouse in vivo the LDL Receptor plays a substantially greater role, making the role of the LRP difficult to appreciate. The same is true in cells that express LDL Receptors.(ABSTRACT TRUNCATED AT 400 WORDS)
Dudley K. Strickland - One of the best experts on this subject based on the ideXlab platform.
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LDL Receptor related protein 1 unique tissue specific functions revealed by selective gene knockout studies
Physiological Reviews, 2008Co-Authors: Anna P Lillis, Lauren B Van Duyn, Joanne E Murphyullrich, Dudley K. StricklandAbstract:The LDL Receptor-related protein (originally called LRP, but now referred to as LRP1) is a large endocytic Receptor that is widely expressed in several tissues. LRP1 is a member of the LDL Receptor...
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the apoe isoform binding properties of the vLDL Receptor reveal marked differences from lrp and the LDL Receptor
Journal of Lipid Research, 2005Co-Authors: Jose Ruiz, Karl H Weisgraber, Diana V Kouiavskaia, Molly Migliorini, Susan Robinson, Evgueni L Saenko, Natalia Gorlatova, Daniel A Lawrence, Bradley T Hyman, Dudley K. StricklandAbstract:Apolipoprotein E (apoE) associates with lipoproteins and mediates their interaction with members of the LDL Receptor family. ApoE exists as three common isoforms that have important distinct functional and biological properties. Two apoE isoforms, apoE3 and apoE4, are recognized by the LDL Receptor, whereas apoE2 binds poorly to this Receptor and is associated with type III hyperlipidemia. In addition, the apoE4 isoform is associated with the common late-onset familial and sporadic forms of Alzheimer's disease. Although the interaction of apoE with the LDL Receptor is well characterized, the specificity of other members of this Receptor family for apoE is poorly understood. In the current investigation, we have characterized the binding of apoE to the VLDL Receptor and the LDL Receptor-related protein (LRP). Our results indicate that like the LDL Receptor, LRP prefers lipid-bound forms of apoE, but in contrast to the LDL Receptor, both LRP and the VLDL Receptor recognize all apoE isoforms. Interestingly, the VLDL Receptor does not require the association of apoE with lipid for optimal recognition and avidly binds lipid-free apoE. It is likely that this Receptor-dependent specificity for various apoE isoforms and for lipid-free versus lipid-bound forms of apoE is physiologically significant and is connected to distinct functions for these Receptors.
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The cytoplasmic domain of the low density lipoprotein (LDL) Receptor-related protein, but not that of the LDL Receptor, triggers phagocytosis.
The Journal of biological chemistry, 2003Co-Authors: Mintoo Patel, Dudley K. Strickland, John P. Morrow, Frederick R. Maxfield, Steven Greenberg, Ira TabasAbstract:The macrophage LDL Receptor and LDL Receptor-related protein (LRP, CD91) mediate the phagocytic-like uptake of atherogenic lipoproteins and apoptotic cells, yet the structural basis of their phagocytic functions is not known. To address this issue, we transfected macrophages with chimeric proteins containing the cytoplasmic tails and transmembrane regions of the LDL Receptor or LRP and the ectodomain of CD2, which can bind non-opsonized sheep red blood cells (SRBCs). Macrophages expressing Receptors containing the LDL Receptor domains were able to bind but not internalize SRBCs. In contrast, macrophages expressing Receptors containing the cytoplasmic tail of LRP were able to bind and internalize SRBCs. Chimeras in which the LRP cytoplasmic tail was mutated in two di-leucine motifs and a tyrosine in an NPXYXXL motif were able to endocytose anti-CD2 antibody and bind SRBCs, but SRBC phagocytosis was decreased by 70%. Thus, the phagocytic-like functions of LRP, but not those of the LDL Receptor, can be explained by the ability of the LRP cytoplasmic tail to trigger phagocytosis. These findings have important implications for atherogenesis and apoptotic cell clearance and for a fundamental cell biological understanding of how the LDL Receptor and LRP function in internalization processes.
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Diverse roles for the LDL Receptor family
Trends in endocrinology and metabolism: TEM, 2002Co-Authors: Dudley K. Strickland, Steven L. Gonias, W. Scott ArgravesAbstract:The low-density lipoprotein (LDL) Receptor family consists of several related scavenger Receptors that not only function as important cargo transporters, but also inform the cell of changes in its environment by mediating signaling responses. The LDL Receptor was the first family member to be characterized and its function seems to be restricted to lipoprotein metabolism. By contrast, lipoprotein metabolism does not appear to be the exclusive function of the other characterized LDL Receptor family members. It is now apparent that cargo transport by members of the LDL Receptor family is closely associated with regulation of cellular physiology and cellular signaling events. Here, we focus on the diverse biological activities of certain members of this family.
Theodore Mazzone - One of the best experts on this subject based on the ideXlab platform.
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Regulation of macrophage apoE secretion and sterol efflux by the LDL Receptor.
Journal of lipid research, 2006Co-Authors: Danijela Lucic, Zhi Hua Huang, De Sheng Gu, Michael K. Altenburg, Nobuyo Maeda, Theodore MazzoneAbstract:Factors that regulate apolipoprotein E (apoE) secretion by macrophages will have important effects on vessel wall lipid flux and atherosclerosis. Macrophages express the LDL Receptor, which binds apoE with high affinity and could thereby affect the net secretion of apoE from macrophages. In these studies, we demonstrate that treatment of J774 macrophages transfected to constitutively express a human apoE3 cDNA with simvastatin, to increase LDL Receptor activity, reduces the secretion of apoE. To further examine the relationship between LDL Receptor expression and apoE secretion from macrophages, mouse peritoneal macrophages (MPMs) were isolated from mice with constitutively high expression of human LDL Receptor to increase overall LDL Receptor expression by 2- to 3-fold. Cells with increased LDL Receptor expression also showed reduced apoE secretion compared with MPMs with basal LDL Receptor expression. The effect of changes in LDL Receptor expression on apoE secretion was isoform-specific, with greater reduction of apoE4 compared with apoE3 secretion and no reduction of apoE2 secretion, paralleling the known affinity of each isoform for LDL Receptor binding. The effect of the LDL Receptor on apoE secretion for each isoform was further reflected in LDL Receptor-dependent changes in apoE-mediated cholesterol efflux. These results establish a regulatory interaction between two branches of macrophage sterol homeostatic pathways that could facilitate a rapid response to changes in macrophage sterol content relative to need.
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Platelet-Derived Growth Factor Enhances Sp1 Binding to the LDL Receptor Gene
Arteriosclerosis thrombosis and vascular biology, 1995Co-Authors: Khaja Basheeruddin, Carol Rechtoris, Theodore MazzoneAbstract:Abstract We have previously demonstrated that growth activation of quiescent cells enhances LDL Receptor gene transcription and that the proximal 5′ flanking region of the LDL Receptor gene could transduce a platelet-derived growth factor (PDGF) response. This portion of the LDL Receptor gene encompasses a previously characterized sterol response element and an adjacent Sp1 binding site. By use of mobility shift analyses we show that PDGF activation of quiescent cells enhances binding of Sp1 to the LDL Receptor gene. Transfection analyses indicated that the Sp1 site, but not the sterol response element binding protein site, could confer PDGF responsiveness to a heterologous promoter in quiescent cells. Furthermore, cotransfection of an LDL Receptor reporter gene (containing −141 to +35 bp of the LDL Receptor gene promoter) along with an expression construct coding for high-level constitutive expression of an Sp1 cDNA led to marked enhancement in expression of the LDL Receptor reporter gene in quiescent cells. Increased Sp1 binding due to PDGF could be due to enhanced production of Sp1; alternatively, posttranslational activation of binding could be involved. Western blot analysis showed no difference in Sp1 abundance in quiescent cells versus PDGF-stimulated cells, suggesting a posttranslational mechanism for activation of Sp1 binding by growth induction. Our data demonstrate that PDGF stimulation of quiescent cells leads to enhanced Sp1 binding to the LDL Receptor gene. This enhanced binding could participate in PDGF induction of LDL Receptor gene transcription.
Dayami Lopez - One of the best experts on this subject based on the ideXlab platform.
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Preparation of a Functional Rat LDL Receptor Minigene.
International journal of biomedical investigation, 2019Co-Authors: Catherine J. Wooten, Dayami LopezAbstract:The majority of the low-density lipoprotein (LDL) Receptors present in the body are expressed in the liver. Therefore, plasma LDL levels significantly correlate with changes in the activity of the hepatic LDL Receptor. Based on this, there is a need to understand the regulatory mechanisms that control the hepatic expression of the low-density lipoprotein (LDL) Receptor. Herein, we have prepared a functional rat LDL Receptor minigene construct that can produce mRNA after splicing. Sequence analysis suggests that this construct has the potential to code for a truncated version of LDL Receptor protein. This minigene could be used as a research tool to identify small molecules, natural products, and regulators of the LDL Receptor gene that could be developed into LDL Receptor-specific activators for therapeutic use.
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Distribution of the LDL Receptor within clathrin-coated pits and caveolae in rat and human liver.
Biochemical and biophysical research communications, 2014Co-Authors: Soumya Ivaturi, Catherine J. Wooten, Gene C. Ness, Maikhanh D. Nguyen, Dayami LopezAbstract:Several findings suggest that the low-density lipoprotein (LDL) Receptor may internalize different lipoprotein particles via diverse pathways. Using a combination of discontinuous sucrose gradients and Triton solubilization studies, we demonstrated that the LDL Receptor could be located simultaneously in clathrin-coated pits and caveolae in rat and human liver and in human hepatocyte-like C3A cells. Treatment with the cholesterol biosynthesis inhibitor, zaragozic acid A, shifted the distribution of the LDL Receptor to clathrin containing fractions, whereas treatment with cholesterol or LDL shifted the Receptor distribution towards caveolin-1 containing fractions. The LDL-dependent shift of the LDL Receptor to caveolae coincided with a reduction in internalization of Bodipy-LDL. Redistribution within plasma membrane microdomains in response to specific treatments resulting in changes in LDL Receptor function represents a novel paradigm that could be exploited in the development of a new class of therapeutic drugs.
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Osmotic Stress Modulates the Expression and Function of the Human LDL Receptor
Cell & Developmental Biology, 2014Co-Authors: Catherine J. Wooten, Ayodele Fakayode, Audrey F. Adcock, Kendra M Davis, Raven S King, Denika D Rhodes, Dayami LopezAbstract:The purpose of this study was to determine whether the Low-Density Lipoprotein (LDL) Receptor could be directly regulated by high glucose (HG) in human hepatocyte-like C3A cells. C3A cells were cultured in a medium supplemented with BD™ MITO+ serum extender (MITO+ medium), a serum-free, cholesterol deficient medium. We found that HG reduced Receptor mRNA levels without significantly affecting overall or plasma membrane Receptor protein expression. Interestingly, these effects were also seen in the presence of low glucose + high mannitol (LG +HM). LDL Receptor protein synthesis, protein degradation, and Receptor function (LDL internalization) were increased by HG and LG+HM. However, no changes in protein expression of proprotein convertase subtilisin kexin type 9 (PCSK9) or the inducible degrader of LDL Receptors (IDOL), the known degraders of the LDL Receptor, were seen under the same conditions. These results implied that the effects of HG and LG+HM on the expression/ function of the LDL Receptor were mostly due to an osmotic stress induced by the high levels of these monosaccharides. Further studies are required to determine how other factors found in diabetic patients, such as high cholesterol and/or high fatty acid levels, may influence the osmotic- dependent regulation of the LDL Receptor expression/function due to hyperglycemia.
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Diabetes alters LDL Receptor and PCSK9 expression in rat liver
Archives of biochemistry and biophysics, 2007Co-Authors: Melissa I. Niesen, Mohini Bedi, Dayami LopezAbstract:Since the hepatic LDL Receptor is regarded as a major determinant of plasma LDL levels, the effect of diabetes on the expression of this Receptor was examined in rat liver. Inducing diabetes with streptozotocin caused a significant reduction in hepatic LDL Receptor mRNA levels in concert with an increase in serum cholesterol levels. However, LDL Receptor protein levels were unaffected by the diabetic state. Further investigation revealed that protein levels of PCSK9, which has been shown to enhance the degradation of the LDL Receptor protein, were significantly decreased in the diabetic rats explaining the lack of reduction in LDL Receptor protein levels. These observations indicate that the rate of LDL Receptor cycling (function) in diabetic rats is decreased resulting in higher serum LDL levels.
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Activation of the hepatic LDL Receptor promoter by thyroid hormone
Biochimica et biophysica acta, 2007Co-Authors: Dayami Lopez, Mohini Bedi, Jose F. Abisambra Socarrás, Gene C. NessAbstract:Abstract The question of whether mature sterol regulatory element binding protein-2 (SREBP-2) mediates transcriptional activation of the hepatic low density lipoprotein (LDL) Receptor by thyroid hormone was investigated. Western blotting analysis and electrophoretic mobility shift assays demonstrated that mature nuclear SREBP-2 protein could be detected in liver nuclear extracts prepared from normal animals but not in extracts prepared from rats rendered hypothyroid either by hypophysectomy (Hx) or thyroidectomy (Tx). Treatment of Hx rats with T3 restored LDL Receptor mRNA levels in about 1 h and caused a 6-fold increase 2.5 h after T3 administration. However, no detectable mature SREBP-2 was seen in this time period despite a substantial reduction in serum cholesterol levels caused by the T3 treatment. Deletion of the SRE region from the LDL Receptor promoter did not decrease the T3 response. Thus, the possibility that T3 may be mediating LDL Receptor induction directly via a thyroid response element (TRE) was investigated. Reporter gene analysis and electrophoretic mobility shift assays demonstrated that the rat LDL Receptor promoter contains two functional TREs (US-TRE and 2H-TRE). Either one of these elements could support T3 induction. However, the stronger of these elements is US-TRE at-612 which binds TRβ1 more tightly and when mutated results in a diminished T3 response. These results indicate that the rapid induction of the hepatic LDL Receptor by thyroid hormone is likely due to direct interaction with TREs rather than indirectly by a mechanism involving SREBP-2.
Gene C. Ness - One of the best experts on this subject based on the ideXlab platform.
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Distribution of the LDL Receptor within clathrin-coated pits and caveolae in rat and human liver.
Biochemical and biophysical research communications, 2014Co-Authors: Soumya Ivaturi, Catherine J. Wooten, Gene C. Ness, Maikhanh D. Nguyen, Dayami LopezAbstract:Several findings suggest that the low-density lipoprotein (LDL) Receptor may internalize different lipoprotein particles via diverse pathways. Using a combination of discontinuous sucrose gradients and Triton solubilization studies, we demonstrated that the LDL Receptor could be located simultaneously in clathrin-coated pits and caveolae in rat and human liver and in human hepatocyte-like C3A cells. Treatment with the cholesterol biosynthesis inhibitor, zaragozic acid A, shifted the distribution of the LDL Receptor to clathrin containing fractions, whereas treatment with cholesterol or LDL shifted the Receptor distribution towards caveolin-1 containing fractions. The LDL-dependent shift of the LDL Receptor to caveolae coincided with a reduction in internalization of Bodipy-LDL. Redistribution within plasma membrane microdomains in response to specific treatments resulting in changes in LDL Receptor function represents a novel paradigm that could be exploited in the development of a new class of therapeutic drugs.
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Activation of the hepatic LDL Receptor promoter by thyroid hormone
Biochimica et biophysica acta, 2007Co-Authors: Dayami Lopez, Mohini Bedi, Jose F. Abisambra Socarrás, Gene C. NessAbstract:Abstract The question of whether mature sterol regulatory element binding protein-2 (SREBP-2) mediates transcriptional activation of the hepatic low density lipoprotein (LDL) Receptor by thyroid hormone was investigated. Western blotting analysis and electrophoretic mobility shift assays demonstrated that mature nuclear SREBP-2 protein could be detected in liver nuclear extracts prepared from normal animals but not in extracts prepared from rats rendered hypothyroid either by hypophysectomy (Hx) or thyroidectomy (Tx). Treatment of Hx rats with T3 restored LDL Receptor mRNA levels in about 1 h and caused a 6-fold increase 2.5 h after T3 administration. However, no detectable mature SREBP-2 was seen in this time period despite a substantial reduction in serum cholesterol levels caused by the T3 treatment. Deletion of the SRE region from the LDL Receptor promoter did not decrease the T3 response. Thus, the possibility that T3 may be mediating LDL Receptor induction directly via a thyroid response element (TRE) was investigated. Reporter gene analysis and electrophoretic mobility shift assays demonstrated that the rat LDL Receptor promoter contains two functional TREs (US-TRE and 2H-TRE). Either one of these elements could support T3 induction. However, the stronger of these elements is US-TRE at-612 which binds TRβ1 more tightly and when mutated results in a diminished T3 response. These results indicate that the rapid induction of the hepatic LDL Receptor by thyroid hormone is likely due to direct interaction with TREs rather than indirectly by a mechanism involving SREBP-2.
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Characterization of the rat LDL Receptor 5′-flanking region
Biochimica et biophysica acta, 2006Co-Authors: Dayami Lopez, Gene C. NessAbstract:A 1.5-kb genomic DNA fragment corresponding to the 5'-flanking region of the rat LDL Receptor gene was cloned and putative regulatory regions were identified. A major transcription start site was identified at -154 bp relative to the ATG translation initiation codon, within a region containing two thyroid hormone response element half-site motifs (2H-TRE). Binding of thyroid hormone Receptors alpha and beta1 to this element was demonstrated. Mutations within this 2H-TRE region abolished basal transcription levels of the rat LDL Receptor gene. Reporter gene studies indicated that the promoter region between -300 and -200 bp, which contains one sterol response element (SRE) and two specificity protein-1 sites (Sp1) sites, is crucial for basal transcription of the rat LDL Receptor gene. The functionality of the SRE motif was confirmed using electrophoretic mobility shift assays and reporter gene studies.
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Thyroid hormone rapidly induces hepatic LDL Receptor mRNA levels in hypophysectomized rats.
Archives of biochemistry and biophysics, 1994Co-Authors: Gene C. Ness, Zhihong ZhaoAbstract:Abstract The effects of hypophysectomy and thyroid hormone treatment on the expression of the hepatic LDL Receptor gene was studied in young male rats. Hypophysectomy lowered levels of LDL Receptor mRNA and protein. It was found that increased levels of LDL Receptor mRNA could be detected 30 min after giving hypophysectomized rats an intramuscular injection of 10 μg of L-triiodothyronine (T 3 ) per 100 g of body weight. This dose of T 3 also increased hepatic LDL Receptor protein levels within 1 h. A T 3 dose of only 0.25 μg per 100 g increased LDL Receptor mRNA levels more than threefold. The half-life of the hepatic LDL Receptor mRNA was found to be about 30 min and was unaffected by T 3 . The data suggests that thyroid hormone acts physiologically to induce hepatic LDL Receptor expression. This action may explain, in part, the hypocholesterolemic effect of the hormone.