Atherosclerotic disease in marked hyperalphalipoproteinemia. Combined reduction of cholesteryl ester transfer protein and hepatic triglyceride lipase.

Hyperalphalipoproteinemia (HALP) has been regarded as a beneficial state accompanied by a longevity syndrome. However, we reported the cases of markedly hyperalphalipoproteinemic subjects with juvenile corneal opacification. The patients had reduced postheparin hepatic triglyceride lipase (HTGL) activities, and one of them has recently been identified to be homozygous for a missense mutation in exon 15 (D442: G) in the cholesteryl ester transfer protein (CETP) gene. In the current study, to elucidate the clinical significance of and atherogenicity in marked HALP, we determined the incidence of atherosclerotic cardiovascular disease (ACD) in patients with marked HALP and characterized the lipoprotein abnormalities in those who had ACD, focusing especially on CETP and HTGL. The subjects were 201 patients (111 males and 90 females) with marked HALP ( > or = 2.58 mmol/L [100 mg/dL]), 67% of whom were demonstrated to have the CETP gene mutations in the intron 14 splice donor site or in exon 15. Their mean age was 54 +/- 15 years. Plasma levels of total cholesterol, HDL cholesterol, and triglyceride in all subjects were 6.28 +/- 1.78, 3.15 +/- 0.90, and 1.08 +/- 0.53 mmol/L, respectively. Ten of the male patients (9.0%) and two of the female patients (2.2%) had apparent ACD such as myocardial infarction, angina pectoris, and peripheral vascular diseases. Ten patients with HALP who had ACD were identified to be heterozygotes for CETP deficiency. To further clarify the characteristics of marked HALP in patients with ACD, we compared the plasma lipids, lipoproteins, CETP, and HTGL activities between heterozygotes for CETP deficiency who were with and without ACD.

[1]  S. Yamashita,et al.  Marked hyper-HDL2-cholesterolemia associated with premature corneal opacity. A case report. , 1984, Atherosclerosis.

[2]  G. Schmitz,et al.  High-density lipoprotein metabolism, reverse cholesterol transport and membrane protection , 1991 .

[3]  A. Tall,et al.  Increased high-density lipoprotein levels caused by a common cholesteryl-ester transfer protein gene mutation. , 1990, The New England journal of medicine.

[4]  J. Ordovás,et al.  Familial apolipoprotein A-I, C-III, and A-IV deficiency and premature atherosclerosis due to deletion of a gene complex on chromosome 11. , 1989, The Journal of biological chemistry.

[5]  G. Miller,et al.  PLASMA-HIGH-DENSITY-LIPOPROTEIN CONCENTRATION AND DEVELOPMENT OF ISCHÆMIC HEART-DISEASE , 1975, The Lancet.

[6]  N. Miller,et al.  Pathophysiology of reverse cholesterol transport. Insights from inherited disorders of lipoprotein metabolism. , 1989, Arteriosclerosis.

[7]  W. Willett,et al.  A prospective study of cholesterol, apolipoproteins, and the risk of myocardial infarction. , 1991, The New England journal of medicine.

[8]  V. Fuster,et al.  Regression of atherosclerotic lesions by high density lipoprotein plasma fraction in the cholesterol-fed rabbit. , 1990, The Journal of clinical investigation.

[9]  P. Barter,et al.  Synergistic effects of lipid transfers and hepatic lipase in the formation of very small high-density lipoproteins during incubation of human plasma. , 1990, Biochimica et biophysica acta.

[10]  P. Wilson,et al.  High density lipoprotein cholesterol and mortality. The Framingham Heart Study. , 1988, Arteriosclerosis.

[11]  A. Tall,et al.  Molecular basis of lipid transfer protein deficiency in a family with increased high-density lipoproteins , 1989, Nature.

[12]  B. Rosner,et al.  Plasma lipoprotein levels in vegetarians. The effect of ingestion of fats from dairy products. , 1985, JAMA.

[13]  S. Yamashita,et al.  Detection of two species of low density lipoprotein particles in cholesteryl ester transfer protein deficiency. , 1991, Arteriosclerosis and thrombosis : a journal of vascular biology.

[14]  S. Yamashita,et al.  Small polydisperse low density lipoproteins in familial hyperalphalipoproteinemia with complete deficiency of cholesteryl ester transfer activity. , 1988, Atherosclerosis.

[15]  M. Hayden,et al.  A lipoprotein lipase mutation (Asn291Ser) is associated with reduced HDL cholesterol levels in premature atherosclerosis , 1995, Nature Genetics.

[16]  S. Grundy,et al.  Activities of lipoprotein lipase and hepatic triglyceride lipase in postheparin plasma of patients with low concentrations of HDL cholesterol. , 1993, Arteriosclerosis and thrombosis : a journal of vascular biology.

[17]  C. Sing,et al.  Apolipoprotein E phenotyping with a single gel method: application to the study of informative matings. , 1983, Journal of lipid research.

[18]  Y. Matsuzawa,et al.  Sensitive non-radioisotopic method for measuring lipoprotein lipase and hepatic triglyceride lipase in post-heparin plasma. , 1984, Clinical chemistry.

[19]  A. Takagi,et al.  A sandwich-enzyme immunoassay for the quantification of lipoprotein lipase and hepatic triglyceride lipase in human postheparin plasma using monoclonal antibodies to the corresponding enzymes. , 1990, Journal of lipid research.

[20]  J. Sasaki,et al.  Detection of a point mutation in cholesteryl ester transfer protein gene by polymerase chain reaction-mediated site-directed mutagenesis. , 1993, Biochimica et biophysica acta.

[21]  R. Havel,et al.  The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum. , 1955, The Journal of clinical investigation.

[22]  Matsuzawa Yuji,et al.  Extralysosomal degradation of high-density lipoproteins in a human hepatoma cell line, Mahlavu , 1993 .

[23]  S. Yamashita,et al.  Accumulation of apolipoprotein E-rich high density lipoproteins in hyperalphalipoproteinemic human subjects with plasma cholesteryl ester transfer protein deficiency. , 1990, The Journal of clinical investigation.

[24]  M. Burstein,et al.  Lipoprotein-polyanion-metal interactions. , 1973, Advances in lipid research.

[25]  M. Taskinen,et al.  Post-heparin plasma lipoprotein and hepatic lipases. Relationships to high density lipoprotein cholesterol and to apolipoprotein CII in familial hyperalphalipoproteinemic and in normal subjects. , 1980, Atherosclerosis.

[26]  L. Kunkel,et al.  Analysis of human Y-chromosome-specific reiterated DNA in chromosome variants. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[27]  S. Yamashita,et al.  Plasma cholesteryl ester transfer protein (CETP) induces very high density lipoproteins (VHDL) with a potent anti-atherogenic function , 1994 .

[28]  R. Hegele,et al.  A hepatic lipase gene mutation associated with heritable lipolytic deficiency. , 1991, The Journal of clinical endocrinology and metabolism.

[29]  K. Dugi,et al.  Structure, function and role of lipoprotein lipase in lipoprotein metabolism. , 1994, Current opinion in lipidology.

[30]  S. Yamashita,et al.  Decrease of hepatic triglyceride lipase levels and increase of cholesteryl ester transfer protein levels in patients with primary biliary cirrhosis: Relationship to abnormalities in high‐density lipoprotein , 1993, Hepatology.

[31]  Y. Matsuzawa,et al.  Determination by the SRID Method of Normal Values of Serum Apolipoproteins (A-I, A-II, B, C-II, C-III, and E) in Normolipidemic Healthy Japanese Subjects , 1986 .

[32]  E. Vartiainen,et al.  Postheparin plasma lipoprotein and hepatic lipase are determinants of hypo- and hyperalphalipoproteinemia. , 1989, Journal of lipid research.

[33]  V. Dole,et al.  Microdetermination of long-chain fatty acids in plasma and tissues. , 1960, The Journal of biological chemistry.

[34]  F. Chollet,et al.  Uptake of HDL unesterified and esterified cholesterol by human endothelial cells. Modulation by HDL phospholipolysis and cell cholesterol content. , 1988, Biochimica et biophysica acta.

[35]  A. von Eckardstein,et al.  Apolipoprotein C-III(Lys58----Glu). Identification of an apolipoprotein C-III variant in a family with hyperalphalipoproteinemia. , 1991, The Journal of clinical investigation.

[36]  A. Tall.  Plasma cholesteryl ester transfer protein. , 1993, Journal of lipid research.

[37]  D. Comings.  Metabolic basis of inherited disease , 1983 .

[38]  S. Yamashita,et al.  Frequency of exon 15 missense mutation (442D:G) in cholesteryl ester transfer protein gene in hyperalphalipoproteinemic Japanese subjects. , 1995, Atherosclerosis.

[39]  S. Yamashita,et al.  Frequency of intron 14 splicing defect of cholesteryl ester transfer protein gene in the Japanese general population--relation between the mutation and hyperalphalipoproteinemia. , 1993, Atherosclerosis.

[40]  O. H. Lowry,et al.  Protein measurement with the Folin phenol reagent. , 1951, The Journal of biological chemistry.

[41]  S. Yamashita,et al.  Large and cholesteryl ester-rich high-density lipoproteins in cholesteryl ester transfer protein (CETP) deficiency can not protect macrophages from cholesterol accumulation induced by acetylated low-density lipoproteins. , 1994, Journal of biochemistry.

[42]  D. Gordon,et al.  High-density lipoprotein--the clinical implications of recent studies. , 1989, The New England journal of medicine.

[43]  A. von Eckardstein,et al.  A frameshift mutation in the human apolipoprotein A-I gene causes high density lipoprotein deficiency, partial lecithin: cholesterol-acyltransferase deficiency, and corneal opacities. , 1991, The Journal of clinical investigation.

[44]  H. Arai,et al.  Purification, microheterogeneity, and stability of human lipid transfer protein. , 1989, The Journal of biological chemistry.

[45]  A. Tall.  Plasma high density lipoproteins. Metabolism and relationship to atherogenesis. , 1990, The Journal of clinical investigation.

[46]  T. Sumiyoshi,et al.  New mutants of apolipoprotein E associated with atherosclerotic diseases but not to type III hyperlipoproteinemia. , 1984, The Journal of clinical investigation.

[47]  J. Hokanson,et al.  Large Buoyant LDL‐like Particles in Hepatic Lipase Deficiency , 1989, Arteriosclerosis.

[48]  S. Yamashita,et al.  Selective reduction of cholesterol in HDL2 fraction by probucol in familial hypercholesterolemia and hyperHDL2 cholesterolemia with abnormal cholesteryl ester transfer. , 1988, The American journal of cardiology.

[49]  O. Williams,et al.  The association of plasma high-density lipoprotein cholesterol with dietary intake and alcohol consumption. The Lipid Research Clinics Prevalence Study. , 1980, Circulation.