High density lipoprotein (HDL) is known to play an important role in protection from atherosclerosis. We investigated lipoprotein metabolism in two families with marked hyperalphalipoproteinemia. The probands were men, aged 43 and 34 years, respectively. None had clinical symptoms and signs of coronary heart disease. The serum HDL-cholesterol levels were extremely high (236, 279mg/dl) and the trait was considered to be inherited in each case. Serum total cholesterol levels were also elevated, and hypertriglyceridemia observed. Serum levels of apolipoprotein A-I, A-II, C-III and E were elevated, while serum apolipoprotein B concentrations were slightly decreased in both cases.
Sequential flotation-ultracentrifugation analysis disclosed that low density lipoprotein (LDL)-cholesterol was slightly lowered and that cholesteryl ester accumulated solely in the HDL fraction, which was also rich in apolipoprotein E. High performance liquid chromatography (HPLC) disclosed a very low peak of LDL and an extremely high peak of HDL. The elution position of patients' LDL shifted significantly to the right, and that of patients' HDL shifted markedly to the left. These data suggests a decrease in LDL particle size corresponding to a marked enlargement of HDL particle size. Analytical ultracentrifugation disclosed polydisperse LDL particles with the presence of small LDL subpopulations. The lipoprotein profiles of these patients were in part similar to those seen in rats, which are known to lack in cholesteryl ester transferr activity.
The activity of lipoprotein lipase (LPL) in postheparin plasma was high, while that of hepatic triglyceride lipase (HTGL) was within normal limits.
Cholesteryl ester transfer activity was measured using ³H-labeled-cholesteryl ester-HDL₃ and VLDL+LDL as a donor and acceptor, respectively. Activity was completely deficient in these cases, which was considered to be the cause of accumulation of cholesteryl ester in HDL₂ fraction. In conclusion, cholesteryl ester transfer protein (LTP-I) plays a physiologically important role in the distribution of cholesteryl ester and triglycerides among various lipoproteins modifying the physical and chemical properties of HDL and LDL. Hyperalphalipoproteinemia due to complete deficiency of cholesteryl ester transfer activity is characterized by the presence of both small polydisperse LDL and markedly large HDL enriched with cholesteryl ester and apolipoprotein E.

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Familial hypercholesterolemia (FH) is a genetic disorder caused by mutations in the gene encoding the low density lipoprotein (LDL) receptor. It is characterized by marked hypercholesterolemia, tendon xanthomas, and premature coronary heart disease (CHD). Homozygous cases of FH are generally resistant to diet and drug therapies. We report an unusual case of homozygous FH (LDL receptor-defective type): a 31-year-old woman with no complaints of angina pectoris. Coronary angiography showed no significant stenotic lesions. The concentration of serum total cholesterol was initially 600mg/dl. After treatment with probucol (1.5g/day), it fell to about 430mg/dl. When CS-514 was added (60mg/day), serum total cholesterol decreased markedly to 317mg/dl.
She developed aphasia because of transient cerebral ischemia in the region of right middle cerebral artery. Carotid angiography showed complete obstruction of bilateral internal carotid arteries and severe stenosis of left external carotid artery. She subsequently developed transient muscular weakness of right hand and leg, and thromboendoarterectomy was performed for the lesion of left external carotid artery. Blood transfusions were performed during the operation. One month later she suffered from acute viral hepatitis, and liver function was extremely damaged. The concentration of serum total cholesterol decreased to almost normal level (237mg/dl), while that of serum triglyceride slightly increased during hepatitis. The concentrations of apolipoproteins A-I, A-II, and B decreased reflecting the reduction of apolipoprotein synthesis by the liver. Laparoscopic findings were consistent with posttransfusion hepatitis rather than drug-induced hepatitis.
Ultracentrifugation analysis disclosed a marked decrease in LDL-cholesterol and HDL-cholesterol, and an increase in IDL₂-cholesterol and HDL₃-cholesterol. LDL fraction was poor in cholesterol and enriched with triglycerides. These changes in the lipoprotein profiles are thought to be caused by the reduction of cholesterol synthesis in the liver due to severe liver dysfunction. It has been generally accepted that serum cholesterol level in FH is largely determined by the catabolic rate of LDL through LDL receptor pathway, however, these data show that cholesterol synthesis in the liver is also of great importance for the regulation of serum cholesterol level in FH-homozygote.
In conclusion, we report an unusual case of FH-homozygote, showing marked atherosclerosis in the carotid arteries without significant lesions in the coronary arteries. The marked reduction of serum total cholesterol by CS-514 and liver dysfunction due to posttransfusion hepatitis might suggest that serum total cholesterol can be lowered by the strong inhibition of cholesterol synthesis in the liver, even in FH-homozygotes who lack LDL-receptors.

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