Lipoprotein Metabolism in Normal Volunteers and Hyperlipoproteinemic Patients

This study is currently recruiting patients.

Sponsored by

National Heart, Lung, and Blood Institute (NHLBI)

Purpose

The methodology utilized in this clinical protocol has been used for the investigation of in vivo lipoprotein metabolism in human subjects at the NIH for the past 26 years. Studies are designed to investigate the genetic defect in a lipid metabolic pathway to provide insight into normal and pathologic pathways. Dual-labeled iodinated apolipoproteins and lipoproteins are studied in dyslipidemic patients under controlled metabolic conditions. Kinetic data is quantitated by computer analysis and facilitate direct comparison of multiple studies. These studies have been significant in furthering our knowledge on the metabolism of apolipoprotein and lipoprotein in both dyslipidemic and normal states. The plasma kinetics of the major HDL apolipoproteins apoA-I and apoA-II have been extensively investigated in patients with extremely low HDL (less than 20mg/dl) or extremely high HDL (greater than 100 mg/dl). Hypoalphalipoproteinemia, or low HDL, is a disorder that is associated with early atherosclerosis in some patients but not in others. Hyperalphalipoproteinemia, or high level of HDL, is one of the few genetic longevity syndromes, however its molecular basis is largely unknown. The effect of HDL heterogeneity on its in vivo metabolism and physiologic functions plays an important role in the development of atherosclerosis and remains a topic of active investigation using this protocol. Other patients we are actively studying are patients with extremely low HDL (less than 10 mg/dl) Tangier disease, Lecithin Cholesteryl Acyltransferase (LCAT) deficiency, Fisheye Disease or patients with high HDL (greater than 85 mg/dl) Cholesteryl Ester Transfer Protein (CETP) deficiency. Patients with abnormalities of LDL including low LDL levels (less than 25 mg/dl) including abetalipoproteinemia and hypobetalipoproteinemia are also being studied.

MEDLINEplus related topics:  Circulatory Disorders

Study Type: Natural History

Official Title: Lipoprotein Metabolism in Normal Volunteers and Hyperlipoproteinemic Patients

Further Study Details: The metabolism of radioiodinated very low density lipoproteins (VLDL), low density lipoproteins (LDL), high density lipoproteins (HDL), and their associated apolipoproteins has been studied in normal and dyslipoproteinemic subjects. These studies were authorized by project number 68-H-0154 ("The Metabolism of Plasma Lipoproteins"), two amendments (71-H-0005, 76-H-0006), and project number 76-H-0030 ("Lipoprotein Metabolism in Type II Hyperlipoproteinemia"). Members of our branch have found that VLDL serves as a precursor for LDL, and during this conversion triglyceride and the apoC peptides are selectively removed. It has also been shown that the major defect in type II hyperlipoproteinemia appears to be decreased LDL catabolism. We have found that HDL concentration and catabolism are altered by changes in VLDL concentration (such as those induced by carbohydrate feeding and nicotinic acid).  The plasma kinetics of the major HDL apolipoproteins apoA-I and apoA-II have been extensively investigated in normal subjects. In vivo studies in patients with Tangier disease demonstrated markedly increased catabolic rates of these apolipoproteins. The kinetics of the conversion of pro-apoA-I to mature apo-I were elucidated in normal subjects and this process was shown to be normal in Tangier disease. More recently, the kinetics of subclasses of HDL have been investigated and it has been established that particles with different apolipoprotein composition have different in vivo metabolism. Two mutant forms of apoA-I, both associated with low levels of HDL, have been studied kinetically and found to be rapidly catabolized, establishing the basis for hypoalphalipoproteinemia in these kindreds. These studies also provided important information about the effect of single residue substitutions on the metabolism of apoA-I. Recently, a patient has been identified who has markedly elevated plasma HDL and a significant family history of longevity; she was demonstrated by in vivo turnover to have a selective and substantial increase in the apoA-I production rate. The in vivo metabolism of HDL and its associated apolipoproteins remains an active area of investigation in our branch.  The in vivo kinetics of apoE3 and its isoforms apoE2 and apoE4 have been thoroughly investigated in normal subjects and in subjects with Type III hyperlipoproteinemia. It has been shown that the apoE2 isoform is more slowly and the apoE4 isoform more rapidly catabolized than the apoE3 form, contributing greatly to the understanding of apoE metabolism and its importance in the pathogenesis of dyslipidemias. More recently, a mutation of apoE associated dominantly with Type III hyperlipoproteinemia was identified and the in vivo kinetics of this mutant apolipoprotein were found to be markedly abnormal.  Lp(a) is a plasma lipoprotein which is strongly associated with increased atherosclerotic risk. We investigated its kinetics in normal subjects and patients with homozygous familial hypercholesterolemia (FH) and found that its rate of catabolism is slower in FH, indicating that the LDL receptor has a role in the catabolism of Lp(a).  It is the purpose of this protocol to investigate in vivo lipoprotein and apolipoprotein metabolism in normal subjects and dyslipoproteinemic patients. Studies in normal subjects allow the elucidation of the normal physiologic pathways and regulation of lipoprotein metabolism. Studies in dyslipoproteinemic patients permit the investigation of pathophysiologic processes which disrupt normal lipoprotein metabolism and the study of structure-function relationships in the apolipoproteins. Kinetic studies performed under this protocol have contributed significantly to the understanding of lipoprotein metabolism; however there remain many important questions which can be answered through the in vivo investigation of lipoproteins and apolipoproteins.  

Eligibility

Genders Eligible for Study:  Both Criteria

Tangier Disease.

Lecithin Cholesteryl Acyltransferase (LCAT) deficiency, Fisheye disease.

Cholesteryl Ester Transfer Protein (CETP) deficiency.

Aetalipoproteinemia and hypobetalipoproteinemia or LDL less than 20 mg/dl.

Hypoalphalipoproteinemia with HDL less than 20 mg/dl.

Hyperalphalipoproteinemia with HDL greater than 85 mg/dl.

Location and Contact Information

Maryland

National Heart, Lung and Blood Institute (NHLBI), 9000 Rockville Pike   Bethesda,   Maryland,    20892,   United States; Recruiting

PRPL     Warren G. Magnuson Clinical Center National Institutes of Health   Bethesda,    Maryland,   20892-4754,   United States  1-800-411-1222    prpl@mail.cc.nih.gov  

More Information

Detailed Web Page

Publications that lead up to this study

Gregg. 1984. Apolipoprotein E metabolism in normolipoproteinemic human subjects, J Lipid Res, Vol. 25, p. 1167

Bojanovski. 1985. Human apolipoprotein A-I isoprotein metabolism: proapoA-I conversion to mature apoA-I, J Lipid Res, Vol. 26, p. 185

Gregg. 1986. Abnormal in vivo metabolism of apolipoprotein E(4) in humans, J Clin Invest, Vol. 78, p. 815

Study ID Numbers  76-H-0051

NLM Identifier  NCT00001154

Date study started March 3, 1976

Recruitment status verified  March 14, 2000

Last Updated  March 14, 2000

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