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Biomedical subjects

S E Williams

Publications and source records attributed to S E Williams.

At least 19 recordsLinked to original sources
PubMed1998

Effective lipid modification by partial ileal bypass reduced long-term coronary heart disease mortality and morbidity: five-year posttrial follow-up report from the POSCH. Program on the Surgical Control of the Hyperlipidemias.

BACKGROUND: In 1990, when the Program on the Surgical Control of the Hyperlipidemias (POSCH) reported its in-trial results strongly supporting the conclusion that effective lipid modification reduces progression of atherosclerosis, the differences for the end points of overall mortality and mortality from atherosclerotic coronary heart disease (ACHD) did not reach statistical significance. METHODS: The Program on the Surgical Control of the Hyperlipidemias recruited men and women with a single documented myocardial infarction between the ages of 30 and 64 years who had a plasma cholesterol level higher than 5.69 mmol/L (220 mg/dL) or higher than 5.17 mmol/L (200 mg/dL) if the low-density lipoprotein cholesterol level was in excess of 3.62 mmol/L (140 mg/dL). Between 1975 and 1983, 838 patients were randomized: 417 to the diet control group and 421 to the diet plus partial ileal bypass intervention group. Mean patient follow-up for this 5-year posttrial report was 14.7 years (range, 12.2-20 years). RESULTS: At 5 years after the trial, statistical significance was obtained for differences in overall mortality (P = .049) and mortality from ACHD (P = .03). Other POSCH end points included overall mortality (left ventricular ejection fraction > or =50%) (P = .01), mortality from ACHD (left ventricular ejection fraction > or =50%) (P = .05), mortality from ACHD and confirmed nonfatal myocardial infarction (P<.001), confirmed nonfatal myocardial infarction (P<.001), mortality from ACHD, confirmed and suspected myocardial infarction and unstable angina (P<.001), incidence of coronary artery bypass grafting or percutaneous transluminal coronary angioplasty (P<.001), and onset of clinical peripheral vascular disease (P = .02). There were no statistically significant differences between groups for cerebrovascular events, mortality from non-ACHD, and cancer. All POSCH patients have been available for follow-up. CONCLUSION: At 5 years after the trial, all POSCH mortality and atherosclerosis end points, including overall mortality and mortality from ACHD, demonstrated statistically significant differences between the study groups.

Cholesterol, LDL↗
PubMed1998

Myocardial infarction and percent arteriographic stenosis of culprit lesion: report from the Program on the Surgical Control of the Hyperlipidemias (POSCH).

The objective of this study was to assess the percent stenosis of the culprit lesion responsible for subsequent myocardial infarction in the Program on the Surgical Control of the Hyperlipidemias (POSCH). It is unknown if the susceptible coronary artery culprit lesion responsible for an acute myocardial infarction is relatively large ( > or = 50% arteriographic stenosis) and hemodynamically significant ( > or = 70% stenosis), or small ( < 50%, stenosis) and asymptomatic. Certain necropsy and arteriography studies support the large progenitor lesion concept, and other arteriography studies support the small lesion hypothesis. We analyzed the coronary arteriogram immediately preceding a Q wave (transmural) myocardial infarction for the degree of stenosis of the suspected culprit lesion, which was selected by visual inspection of the coronary circulation supplying the electrocardiogram-defined area of myocardial infarction. There was no perceptible difference with respect to vessel segment distribution of culprit lesions or time to infarction between the 52 control-group patients and the 27 intervention-group patients. For the two groups combined (n=79), the predominantly involved segments were the middle right coronary artery and the proximal left anterior descending coronary artery. The time interval from the preceding coronary arteriogram closest to the index myocardial infarction ranged from 0 days to 10 years; however, 64.6% of the arteriograms were performed 2 years or less prior to the myocardial infarction. Only 5.1% of the patients in both groups combined had a culprit lesion stenosis < 50%, while 88.6% of the patients in both groups combined had a culprit lesion stenosis > or = 70%. The results strongly favor the large lesion hypothesis of causation for myocardial infarction. It is premature, however, to state that the relative size of the culprit lesion has been indisputably determined. The resolution of this problem has exceedingly important practical implications for the management of patients with known atherosclerotic coronary heart disease and for those asymptomatic individuals with silent atherosclerotic coronary heart disease.

Adult↗
PubMed1998

Recovery in pediatric brain injury: is psychostimulant medication beneficial?

OBJECTIVE: To assess the effects of methylphenidate on attention, memory, behavior, processing speed, and psychomotor skills of children with closed head injuries. DESIGN: Double-blind, placebo-controlled, crossover design. SETTING: An outpatient facility of a children's hospital medical center. PATIENTS: Ten pediatric subjects identified through chart review. Subjects met baseline scores for hyperactivity (Conner's Hyperactivity Index greater than or equal to 60) and intellectual functioning (Verbal Intelligence Quotient greather than or equal to 70) and achieved minimal scores on two psychometric tests. All subjects evidenced head injury by focal lesions on computed tomography scan and/or sequelae reported at the time of injury. Severity of injury ranged from mild to severe. All subjects were medically stable at the time of testing. Mean time post injury was 2 years, 8 months. INTERVENTION: Administration of methylphenidate and placebo. MAIN OUTCOME MEASURES: Percentage change in scores was calculated to assess differences between baseline and end of methylphenidate/placebo trials. RESULTS: No significant differences between methylphenidate and placebo on measures assessing behavior, attention, memory, and processing speed. CONCLUSIONS: The results of the study call into question the effectiveness of methylphenidate in the pediatric head injury population.

Adolescent↗
PubMed1998

Prediction of slaughter cow composition using live animal and carcass traits.

Slaughter cows (n = 120), representing four genotypes (British, continental, Bos indicus, and dairy) and three body condition classes (thin, moderate, and fat), n = 10 per subclass, were used to identify practical and accurate prediction equations for the yield of boneless manufacturing beef of specific fat percentages. Cows and their carcasses were weighed and evaluated for USDA yield and quality grade factors and for physical muscle and fat indicators. Carcass sides were fabricated; total fat percentage (TFP) was calculated as total fat (trimmed and chemical) divided by side weight, and tissue lean percentage (TLP) was calculated as boneless fat-free lean divided by soft tissue weight. Data were analyzed using maximum R2 multiple regression. The best live trait prediction model for TFP included live preliminary yield grade (LPYG), body condition score (LCOND), visual live muscle score (LMUSC), and live weight (LWT), R2 = .83. The best carcass trait TFP prediction model included adjusted preliminary yield grade (CPYGA); kidney, pelvic, and heart fat adjustment (CKPHADJ); marbling score (CMARB); and hot carcass weight (HCW), R2 = .92. The best live trait TLP prediction model included LPYG, LCOND, LMUSC, and LWT, R2 = .82. The best carcass trait TLP prediction model included CPYGA, CKPHADJ, CMARB, and lean maturity, R2 = .91. These data indicate that TFP and TLP of slaughter cows can be accurately and practically predicted using live animal and carcass traits.

Animals↗
PubMed1997

Historical rainforest contractions, localized extinctions and patterns of vertebrate endemism in the rainforests of Australia's wet tropics.

The spatial patterns in the distributions of vertebrates in the rainforests of the wet tropics biogeographic region of north-eastern Australia were examined to form hypotheses on the processes that have shaped vertebrate assemblages and patterns of species richness and regional endemism. These rainforests occur in a relatively narrow and discontinuous strip along the coast of north-eastern Australia. We found that the number of regionally endemic species and the proportion of regional endemics present in each subregion are both strongly related to the geographic shape of subregional patches of rainforest, independent of rainforest area, within Australian tropical rainforests. Shape has a more significant influence on regional endemism than area, and area has a stronger influence on species richness. These patterns were congruent for all terrestrial vertebrate classes manuals, birds, reptiles and frogst, and for the four groups combined. Our results suggest that the combination of current rainforest area and shape are an index of the relative susceptibility of each area of rainforest to historical contractions, with the implication that historical habitat fluctuations, coupled with subsequent localized extinctions species sifting; have been extremely important processes in determining current patterns of endemism in Australia's wet tropical rainforests. This hypothesis is supported by the highly nested structure of the subregional distribution patterns.

Animals↗
PubMed1997

Serum concentrations of insulin-like growth factors and placental lactogen during gestation in cattle. I. Fetal profiles.

Sixty crossbred beef heifers pregnant with fetuses of either high (H; n = 30) or low (L; n = 30) genetic potential for growth were used to establish fetal serum profiles of insulin-like growth factor (IGF)-I, IGF-II, and placental lactogen (PL), and to examine relationships between serum hormone concentrations and fetal growth parameters. Three H and three L fetuses were collected by caesarean section at 21-d intervals from Day 85 through Day 274 of gestation. Arterial, venous, and mixed umbilical blood samples were collected during surgery. Fetal body weight, crown-rump length, hip height, and heart girth were measured. Serum concentrations of IGF-I and IGF-II increased (P < 0.0001) with advancing gestational age, whereas serum PL declined (P < 0.0001) linearly (P < 0.01) throughout gestation. Serum concentrations were greater in the umbilical vein compared with the umbilical artery for IGF-II (P < 0.0001) and PL (P < 0.05), but not IGF-I. Fetal IGF-I, IGF-II, and PL serum concentrations were not correlated with serum concentrations of the respective maternal hormones. Fetal serum IGF-I concentrations were correlated to fetal body weight (r = 0.66), growth rate (r = 0.72), crown-rump length (r = 0.20), hip height (r = 0.17), and heart girth (r = 0.20). Correlations between fetal serum IGF-II concentrations and the same parameters were 0.60, 0.62, 0.39, 0.34, and 0.37, respectively. Fetal serum PL concentrations were negatively correlated to body weight (r = -0.40) and growth rate (r = -0.40) and not correlated with any fetal linear measure. Fetal genotype (L vs. H) differences were detected for IGF-I (P < 0.05) and PL (P = 0.09) concentrations. Fetal sex effects were not observed for any hormone. Maternal sire breed, hip height, and body condition score did not influence fetal serum hormone concentrations.

Animals↗
PubMed1997

Serum concentrations of insulin-like growth factors and placental lactogen during gestation in cattle. II. Maternal profiles.

This study was designed to examine the effects of fetal growth potential on maternal hormones and lipid metabolism. Sixty beef heifers were inseminated with semen from sires with high (H) or low (L) expected progeny differences for birth weight. Maternal serum was collected at 21-d intervals from Day 85 to Day 274 of gestation. Serum concentrations of insulin-like growth factor (IGF)-I, IGF-II, placental lactogen (PL), and nonesterified fatty acids (NEFA) were determined and correlated to fetal and maternal characteristics. Maternal serum IGF-I declined throughout pregnancy, whereas IGF-II was relatively constant and PL tended to increase. Maternal serum NEFA was low and invariant through Day 211 of gestation when it rose 3.5 times to peak levels at Day 253 and declined at Day 274. PL was positively correlated to NEFA (r = 0.37, P < 0.01), IGF-I was negatively correlated (P < 0.01) to NEFA and PL (r = -0.59, and -0.35, respectively), and IGF-II was negatively correlated to NEFA (r = -0.35, P < 0.01). Dams pregnant with H fetuses had lower (P = 0.02) serum IGF-I and tended to have higher (P = 0.09) serum PL concentrations than dams carrying L fetuses. Additionally, dams pregnant with L fetuses had higher (P < 0.03) serum IGF-II concentrations than dams with H fetuses (175.6 vs. 145.0 ng/ml) during the third trimester. Fetal sex had no effect on any maternal serum parameter. Fetal weight and instantaneous growth rate (IGR) were positively correlated to maternal NEFA and PL and negatively correlated to maternal IGF-I and IGF-II. Independent IGR effects were detected for PL (P < 0.06) and IGF-I (P < 0.0005) concentrations. Maternal hip height was negatively related to serum IGF-I and positively related to serum PL concentrations. Maternal body weight and body condition score were correlated with several serum parameters but were confounded by day of gestation. Correlation analysis of serum concentrations of IGF-I, IGF-II, and PL did not support the hypothesis that PL regulates IGF concentrations.

Animals↗
PubMed1997

Adult psychosocial outcome in early-treated phenylketonuria.

Concerns about the psychosocial risk of adults with early-treated phenylketonuria (ETPKU) are predicated on four sources of scientific data: (1) consistent documentation of increased behavioural risk in children with ETPKU; (2) recent evidence of neurocognitive impairment in adults with ETPKU; (3) reports of neuroimaging abnormalities in adults with ETPKU; and (4) preliminary evidence of increased rates of psychiatric disturbance in this population. We studied the psychosocial adjustment of 25 patients, aged 18 years and older, with ETPKU. On most psychosocial outcome measures, patients were indistinguishable from 15 sibling controls. However, on a self-report inventory of psychiatric symptoms, 20% of the patients demonstrated significant morbidity. Psychosocial outcome of these patients was unrelated to concurrent or historical biological dietary disease factors, unlike neurocognitive outcome. A strong relationship was demonstrated, however, between neurocognitive measures and psychosocial morbidity. These findings indicate that a significant minority of patients with ETPKU develop psychosocial difficulties with multiple clinical elevations on a psychiatric inventory. However, most adults with ETPKU cope with the challenges of young adulthood with the same degree of success as their unaffected siblings. Neuropsychological surveillance during childhood and adolescence is important in identifying patients at risk for both neurocognitive and psychosocial morbidity.

Adult↗
PubMed1997

HIV-1 induction of CD40 on endothelial cells promotes the outgrowth of AIDS-associated B-cell lymphomas.

Human immunodeficiency virus (HIV)-1 infection is associated with the development of aggressive extranodal B-cell non-Hodgkin's lymphomas. Using microvascular endothelial cell (MVEC)-enriched bone marrow stromal cultures, HIV infection of stromal MVECs from lymphoma patients induced the outgrowth of malignant B cells. MVECs were the only HIV-infected cells in the stroma, and purified brain MVECs also induced a phenotype supportive of neoplastic B-cell attachment and proliferation. HIV infection of MVECs stimulated surface expression of CD40 and allowed preferential induction of the vascular cell adhesion molecule VCAM-1 after CD40 triggering. B-lymphoma cells expressed the CD40 ligand (CD40L), and blocking of CD40-CD40L interactions between HIV-infected MVECs and B-lymphoma cells inhibited B-cell attachment and proliferation. These observations suggest that HIV promotes B-lymphoma cell growth through facilitating attachment of lymphoma cells to HIV-infected MVECs and represent a novel mechanism through which viruses may induce malignancies.

CD40 Antigens↗
PubMed1997

Carcass characteristics, the calpain proteinase system, and aged tenderness of Angus and Brahman crossbred steers.

We used 69 steers of varying percentage Brahman (B) breeding (0% B, n = 11; 25% B, n = 13; 37% B, n = 10; 50% B, n = 12; 75% B, n = 12; 100% B, n = 11) to study the relationship between carcass traits, the calpain proteinase system, and aged meat tenderness in intermediate B crosses. Calpains and calpastatin activities were determined on fresh longissimus muscle samples using anion-exchange chromatography. The USDA yield and quality grade data (24 h) were collected for each carcass. Longissimus steaks were removed and aged for 5 or 14 d for determination of shear force and 5 d for sensory panel evaluation. Even though some yield grade factors were affected by the percentage of B breeding, USDA yield grades did not differ (P > .15) between breed types. Marbling score and USDA quality grade decreased linearly (P < .01) with increasing percentage of B breeding. Shear force after 5 and 14 d of aging was higher (P < .05) in the 100% B steers than in all other breed types, which were not significantly different. Sensory panel tenderness and connective tissue scores decreased linearly (P < .05) with increasing B breeding. A quadratic effect was also noted for tenderness and connective tissue scores; 37% B steers received the highest scores. A similar response was found in mu-calpain activities; the 37% B steers had the highest activities. Conversely, calpastatin activity increased linearly (P < .01) with increasing percentage B breeding. These data show strong linear relationships between calpastatin activity (positive), marbling score (negative), and percentage B breeding, suggesting a possible combined effect of these traits on aged tenderness of intermediate Brahman crosses.

Animals↗
PubMed1997

Biceps femoris and rump fat as additional ultrasound measurements for predicting retail product and trimmable fat in beef carcasses.

One hundred ninety-eight steers of Angus and Hereford breeding were evaluated ultrasonically for fat thickness over the 12-13th rib (UFAT), fat thickness over the rump (URUMP), 12-13th longissimus muscle area (UREA), and depth of the biceps femoris (UROUND) before slaughter. Carcass measurements associated with the USDA yield grade were also obtained. Carcasses were fabricated into closely trimmed (.32 cm fat), boneless subprimals. Regression procedures were used to predict weight and the percentages of retail product and trimmable fat. Final weight (FINALWT) accounted for most of the variation when predicting kilograms of retail product and trimmable fat, with R2 values of .836 and .435, respectively. As single predictors URUMP and UFAT accounted for most of the variation when predicting the percentages of retail product and trimmable fat with R2 values of .244 and .220, respectively. Adding URUMP to equations that included FINALWT, UREA, and UFAT increased R2 values for percentage of retail product from .175 to .318 and for weight of retail product from .847 to .865, whereas the addition of UROUND did not appreciably increase R2 values for the same models. Adding URUMP and UROUND to the model of FINALWT, UREA, and UFAT to predict kilograms and the percentage of trimmable fat increased R2 values from .530 to .610 and from .254 to .360, respectively. Models using live-animal measurements to predict weight and the percentage of retail product gave R2 values equal to models using the actual measurements found in the USDA Yield Grade equation.

Animals↗
PubMed1996

Vitreous hemorrhage as an ophthalmic complication of galactosemia.

A major complication of galactosemia is cataracts. This is usually considered to be the sole ophthalmic feature of this disorder. However, we have encountered vitreous hemorrhage, a very rare ophthalmic finding, in five neonates with galactosemia and have found four probable additional cases in the literature. All of these infants had severe neonatal manifestations of galactosemia and were discovered to have vitreous hemorrhage by ophthalmologic examination initiated by the observation of clouding of the eye or on a routine basis. The infants lost most or all vision from the affected eye. Retinal abnormalities were present in the involved eyes of the five neonates of whom we have direct knowledge. Thus we believe that retinal hemorrhage is the most likely source of the vitreous hemorrhage and that the coagulopathy associated with neonatal disease in galactosemia leads to vitreous hemorrhage. Prompt recognition and therapy for the coagulopathy would likely prevent vitreous hemorrhage in galactosemia.

Female↗
PubMed1996

Impact of cholesterol reduction on peripheral arterial disease in the Program on the Surgical Control of the Hyperlipidemias (POSCH).

BACKGROUND: Few lipid/atherosclerosis intervention trials have assessed the impact of cholesterol reduction on peripheral arterial disease. The 838 patients evaluated in the Program on the Surgical Control of the Hyperlipidemias (POSCH) trial represent more than the total number of patients in the seven previously reported studies. METHODS: Peripheral arterial disease in POSCH was assessed by progression of clinical disease, serial changes in the systolic blood pressure ankle/brachial index (ABI), and changes on sequential peripheral arteriograms. RESULTS: At the time of formal closure of the POSCH trial on July 19, 1990, claudication or limb-threatening ischemia was exhibited in 72 of 417 control group (CG) patients and in 54 of 421 intervention group (IG) patients (IG relative risk [RR] 0.702, 95% confidence interval [CI] 0.169 to 1.000, p = 0.049). With additional follow-up evaluation to September 30, 1994, clinical peripheral arterial disease was evident in 91 CG patients and 64 IG patients (RR 0.656, 95% CI 0.200 to 0.903, p = 0.009). At the 5-year follow-up evaluation, an ABI of less than 0.95 was present in 41 of 120 CG patients and in 24 of 126 IG patients, all of whom had an ABI of 0.95 or greater at baseline (RR in the IG of 0.557, 95% CI 0.360 to 0.863, p < 0.01). No appreciable differences were noted in the progression or regression of arteriographic peripheral arterial disease between the two groups. CONCLUSIONS: Effective cholesterol reduction in POSCH led to statistically significant differences between the control and the intervention groups in the development of clinically evident peripheral arterial disease and in the ABI values, but not in the peripheral arteriograms. Additional studies need to assess the correlation between peripheral arterial changes and coronary arterial changes and clinical atherosclerosis events. Intervention trials that study peripheral arterial disease have intrinsic value in the evaluation of the impact of risk factor modification on progression of atherosclerotic peripheral arterial disease.

Angiography↗
PubMed1996

Gender-based mortality follow-up from the Program on the Surgical Control of the Hyperlipidemias (POSCH) and meta-analysis of lipid intervention trials. Women in POSCH and other lipid trials.

OBJECTIVE: The authors assessed the clinical results of lipid-lowering therapy in women. SUMMARY BACKGROUND DATA: The Program on the Surgical Control of the Hyperlipidemias (POSCH) has demonstrated that effective lowering of total cholesterol and low-density lipoprotein cholesterol in a postmyocardial infarction population significantly reduces atherosclerotic coronary heart disease (ACHD) mortality, ACHD mortality combined with a new confirmed nonfatal myocardial infarction, and the number of coronary artery bypass grafting and angioplasty procedures performed. METHODS: A review and meta-analysis were performed of the seven primary or secondary lipid/ atherosclerosis intervention trials-including POSCH-published in the English-language literature that included women and published results in women separate from the results in men or in the entire trial population. The main outcome measure analyzed was overall mortality. RESULTS: The Scottish Physicians Clofibrate Study, the Newcastle upon Tyne Clofibrate Study, and the Pravastatin Limitation of Atherosclerosis in the Coronary Arteries (PLAC I) Trial may have demonstrated a possible benefit in ACHD prognosis from effective lipid intervention in women. The other four available trials did not. The Minnesota Coronary Survey reported a 15.6% increase in overall mortality rate and a 30.6% increase in a combined cardiovascular endpoint rate in the lipid-intervention group. The Upjohn Colestipol Study demonstrated statistically significant reductions in overall and ACHD mortality in the men, but not in the women. The Scandinavian.

Cholesterol↗
PubMed1995

The effects of topic and listener familiarity on discourse variables in procedural and narrative discourse tasks.

This study investigated the effects of listener and topic familiarity on procedural and narrative discourse variables. Twenty-two aphasic patients (5 Broca's, 7 conduction, and 10 anomic aphasics) and 10 normal speakers served as subjects. Topic familiarity influenced discourse production in both procedural discourse and story retell situations. In procedural discourse, a greater number of optional steps were provided with familiar topics. During retelling of familiar topic stories, a greater proportion of action and resolution clauses were included. Listener familiarity affected the story retell task only. A greater percentage of subjects provided the setting when the listener was familiar.

Aged↗
PubMed1995

Disease-free intervals after partial ileal bypass in patients with coronary heart disease and hypercholesterolemia: report from the Program on the Surgical Control of the Hyperlipidemias (POSCH).

OBJECTIVES: We sought to analyze the disease-free intervals and calculate the freedom from atherosclerosis events in the Program on the Surgical Control of the Hyperlipidemias (POSCH). BACKGROUND: The POSCH study was a randomized, secondary lipid/atherosclerosis intervention trial that provided strong evidence for reduction in atherosclerosis progression as demonstrated by clinical and arteriographic end points. The 417 control group patients received American Heart Association phase II diet instruction, and the 421 intervention group patients received identical dietary instruction and underwent a partial ileal bypass operation. METHODS: Four outcome measures were determined: 1) overall mortality, 2) coronary heart disease mortality, 3) coronary heart disease mortality and confirmed nonfatal myocardial infarction, and 4) coronary/cardiac interventions. RESULTS: An overall mortality rate of 10% occurred at 6.7 years in the control group and 9.4 years in the intervention group, for a gain in disease-free interval of 2.7 years in the intervention group (p = 0.032). A coronary heart disease mortality rate of 8% occurred at 7.2 years in the control group and 11 years in the intervention group, for a gain of 3.8 years (p = 0.046). Twenty percent of patients demonstrated the combined end point of coronary heart disease mortality and confirmed nonfatal myocardial infarction at 5.9 years in the control group and 11.4 years in the intervention group, for a gain of 5.5 years (p < 0.001). Twenty-five percent of patients underwent either coronary artery bypass graft surgery, percutaneous transluminal coronary angioplasty or heart transplantation at 5.4 years in the control group and 12.4 years in the intervention group, for a gain of 7 years (p < 0.001). CONCLUSIONS: The marked lipid modification achieved by partial ileal bypass in the POSCH trial led to demonstrable increases in the disease-free intervals for overall mortality, coronary heart disease mortality, coronary heart disease mortality and confirmed nonfatal myocardial infarction, and coronary intervention procedures. For the clinician and the patient, estimation of disease-free intervals may be more relevant than assessment of differences in incidence rates and risk ratios.

Adult↗
PubMed1994

The carboxyl-terminal domain of lipoprotein lipase binds to the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor (LRP) and mediates binding of normal very low density lipoproteins to LRP.

Lipoprotein lipase (LPL) binds with high affinity to the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor (LRP) and promotes binding, uptake, and degradation of normal triglyceride-rich lipoproteins in a process mediated by LRP (Chappell, D. A., Fry, G. L., Naknitx, M.A., Muhonen, L. E., Pladet, M. W., Iverius, P-H., and Strickland, D. K. (1993) J. Biol. Chem. 268, 14168-14175). To localize the portion of LPL that is responsible for interacting with LRP, fragments of LPL were expressed in bacteria. A fragment of human LPL containing the COOH-terminal domain (residues 313-448, designated LPLC) which lacks the catalytic site was able to bind to LRP. Purified LRP bound specifically to microtiter wells coated with LPL or LPLC with KD values of 2.8 and 5 nM, respectively. The effects of several mutations of LPLC were tested. Mutation of Lys407 to Ala reduced the affinity of LPLC for LRP by approximately 10-fold. Like native LPL, LPLC prevented the binding of activated alpha 2-macroglobulin and the 39-kDa receptor-associated protein to LRP and inhibited the internalization and degradation of activated alpha 2-macroglobulin and receptor-associated protein in cultured fibroblasts. LPLC also bound to 125I-labeled human normal triglyceride-rich lipoproteins and promoted their binding to purified LRP and to cultured cells. Mutation of Trp393 and Trp394 to Ala completely abolished the ability of LPLC to bind to lipoproteins, but had little effect on its interaction with LRP. These data indicate that the COOH-terminal domain of LPL may function both in binding lipoproteins and mediating their interaction with LRP.

Amino Acid Sequence↗