In 1929, Macheboeuf demonstrated that serum lipids do not’ circulate freely, but are bound to proteins in the form of large molecular complexes. Further investigations showed that these /ipoproteins are composed of varying proportions of triglycerides, cholesterol, and phospholipids, bound to a protein. By means of analytic ultracentrifugation, it is possible to separate different types of lipoproteins since these molecules have different density, and thus migrate at varying measureable rates under a great centrifugal force. With this technique it is possible to separate the serum lipoproteins into four major groups: (a) chylomicra, (b) very low density lipoproteins, (c) low density lipo- proteins, and (d) alpha lipoproteins?. It is also known that serum lipoproteins differ sufficiently, not only in density but also in electrostatic charges, to permit their separation by electrophoretic techniques. Fredrickson, Levy, and Lees?, utilizing paper electrophoresis with barbital buffer, pH 8.6 containing 1 per cent albumin*, were able to separate four distinct lipoprotein fractions, which were labelled as: chylomicra, beta, pre-beta, and alpha lipoproteins. These fractions correlate well with those separated by the ultracentrifuge. These lipoproteins have been isolated, and their lipid composition determined*. Based on the patterns of serum lipoproteins and serum lipid levels, Frederickson et a/.2 have been able to propose a new classification for familial hyperlipo- proteinemias. The determination of serum lipoprotein patterns is not only a diagnostic tool, but it may also give significant information as to the patho- physiologic mechanism of a particular lipid metabolic derangement. The in- crease in chylomicra is usually associated with hyperlipidemias of exogenous origin; the pre-beta lipoproteins are synthesized in the liver from free fatty acids, triglycerides, and carbohydrates, and are the expression of an endo- genous hyperlipidemia; beta lipoproteins are related to cholesterol metabolism, either of endogenous or exogenous origin. PLASMA LIPOPROTEINS Plasma triglycerides, cholesterol, and phospholipids do ELECTROPHORESIS CHYLOMICRA PRE-BETA BETA = © E VERY LOW DENSITY ———-——} Low DENSITY 1 HIGH DENSITY oO 10° 400 20 0 3 | ra oe sf = = Li © <= DENSITY —> 1.006 —> 1.063 P21 oi _ (__] TRIGLYCERIDES (J CHOLESTEROL HRB PHOSPHOLIPIDS WB PROTEINS MECHANISMS OF HYPERLIPIDEMIAS EXOGENOUS HYPERLIPIDEMIA FATTY MEAL > CHYLOMICRA LIPOPROTEIN LIPASE FATTY ACIDS + GLYCEROL HEPARIN HYPERTRIGLYCERIDEMIAS = INCREASE HYPERCHOLESTEROLEMIAS = INCREASE C_] TRIGLYCERIDES CHOLESTEROL PHOSPHOLIPIDS = PROTEINS ENDOGENOUS HYPERLIPIDEMIA TRIGLYCERIDES FREE FATTY ACIDS CARBOHYDRATES PRE-BETA CHYLOMICRA PRE-BETA CLASSIFICATION OF HYPERLIPOPROTEIN EMIAS Electrophoresis of a normal fasting plasma reveals the foliowing lipoproteins: Beta w 85%), Alpha (wv 15%), and small amounts of Pre-Beta. Chylomicra are absent. FASTING origin PLASMA T J ! i Normal CLEAR ! i Eo l 2 2a 5 a ae = = CHYLO CREAMY TYPE! _ EXOGENOUS HYPERLIPIDEMIA 2 aq 8 : = = | t a CLEAR I TYPE I ! HYPERCHOLESTEROLEMIA 2 2a 8 = = I | 5 TYPE Ill ABNORMALAL =| ouoy BROAD BETA L oe S I 1 _ ; | TYPE IV PRE-& “| cLoupy ENDOGENOUS HYPERLIPIDEMIA m chylo CHYLO TYPE V MIXED HYPERLIPIDEMIA PRE-f = — =a = a TYPE | SYNONYMS BURGER.GRUTZ DISEASE GENETICS AUTOSOMAL RECESSIVE. RARE XANTHOMAS ONSET CHILDHOOD, HEPATOSPLENOMEGALY, CLINICAL ABDOMINAL PAIN, (PANCREATITIS?) MANIFESTATIONS LIPEMIA RETINALIS. CARDIOVASCULAR DISEASE: LOW PLASMA LIPIDS CHO: NORMAL OR SLIGHTLY INCREASED TRI: MARKEDLY INCREASED. GLUCOSE TOLERANCE NORMAL LIPOPROTEIN ELECTROPHORESIS EXOGENOUS HYPERLIPIDEMIA, MECHANISM DECREASED ACTIVITY OF LIPOPROTEIN LIPASE TREATMENT LOW FAT DIET (A) SYSTEMIC LUPUS ERYTHEMATOSUS (B} LYMPHOMA SECONDARY FORMS TYPE Il TYPE ill ESSENTIAL FAMILIAL HYPERCHOLESTEROLEMIA IDIOPATHIC HYPERLIPIDEMIA SIMPLE MENDELIAN DOMINANT. COMMON RECESSIVE (?). LESS COMMON THAN It OR IV ONSET CHILDHOOD OR ADULTHOOD. ARCUS CORNEA, ACCELERATED ATHEROSCLEROSIS ONSET ADULTHOOD. HIGH INCIDENCE OF CARDIOVASCULAR DISEASE CHO: MARKEDLY INCREASED TRI: NORMAL OR SLIGHTLY INCREASED CHO: INCREASED TRI: INCREASED USUALLY NORMAL ABNORMAL T | | I J | I i UNKNOWN. DERANGEMENT IN CHOLESTEROL METABOLISM UNKNOWN. BETA LIPOPROTEINS WITH INCREASED CONTENT IN TRIGLYCERIDES. CARBOHYDRATE INDUCED CLOFIBRATE. ESTROGENS, D-THYROXINE, NICOTINIC ACID. CHOLESTYRAMINE, DIET: REDUCE CHOLESTEROL INTAKE. POLYUNSATURATED FATS. CLOFIBRATE AND LOW CARBOHYDRATE DIET, WEIGHT CONTROL (1) LIVER DISEASE (2) NEPHROTIC SYNDROME (3) HYPOTHYROIDISM (4) MYELOMA (5) MACROGLOBULINEMIA TYPE IV TYPE V IDIOPATHIC HYPERLIPIDEMIA DISEASE? SYNDROME? SIMPLE MENDELIAN DOMINANT (?). MOST COMMON ONSET ADULTHOOD, OBESITY FREQUENT, ABDOMINAL PAIN (PANCREATITIS?), CARDIOVASCULAR DISEASE. PROBABLY GENETIC VARIANT OF TYPE IV (2). RARE ONSET EARLY ADULTHOOD, HEPATOSPLENOMEGALY, OBESITY, ABDOMINAL PAIN, LIPEMIA RETINALIS, CARDIOVASCULAR DISEASE NOT FREQUENT CHO: NORMAL OR SLIGHTLY INCREASED ee Myce taememancit oT a TRI: MAL OR SLIGHTLY INCREASED ABNORMAL ABNORMAL ENDOGENOUS HYPERLIPIDEMIA, MAY BE CARBOHYDRATE INDUCED EXOGENOUS AND ENDOGENOUS HYPERLIPIDEMIA (MIXED FORM) LIPOPROTEIN LIPASE ACTIVITY MAY BE LOW WEIGHT CONTROL, RESTRICTION OF CARBOHYDRATES, CLOFIBRATE, NICOTINIC ACID I WEIGHT CONTROL, DIET LOW IN FAT AND CARBOHYDRATES, CLOFIBRATE, PROGESTATIONAL HORMONES (1) DIABETES MELLITUS (2) PANCREATITIS (3) GLYCOGEN STORAGE DISEASE (4) NEPHROTIC SYNDROME (5) PREGNANCY, GESTATIONAL HORMONES (6) MYELOMA (7) HYPOTHYROIDISM (8) PROGERIA (9) TOTAL LIPOATROPHY DIABETES MELLITUS INSULIN DEPENDENT, PANCREATITIS ALCOHOLISM LIFT HERE References: Lindgren, F. T., Elliot, H. A., and Gofman, J. W.: The ultracentrifugal charac- terization and isolation of human blood lipids and lipoproteins with applica- tions to the study of atherosclerosis, J. Physiol. Chem. 55:80 1951. . Fredrickson, D. S., Levy, R. I., and Lees, R. S.: Fat transport in lipoproteins — an integrated approach to mechanisms and disorders, New Eng. J. Med. 276:32-44 (Jan. 5), 94-103 (Jan. 12), 148-156 (Jan. 19), 215-226 QJan. 26), 273-281 (Feb. 2), 1967. Lees, R. S., and Hatch, F. T.: Sharper separation of lipoprotein species by paper electrophoresis in albumin-containing buffer, J. Lab. Clin. Med. 61: 518 1963. Bragdon, J. H., Havel, R. J., and Boyle, E.: Human serum lipoproteins. 1. Chemical composition of four fractions, J. Lab. Clin. Med. 42:48 1956. Fleischmajer, R.: The Dyslipidcses, Springfield, Ill., Charles C. Thomas, 1960. Fleischmajer, R.: Familial hyperlipoproteinemia Type Il}. Arch. Dermat., 100: 401, 1969.