Resistant Hypertriglyceridemia in a Patient With High Plasma Levels of Apolipoprotein CII
To the Editor:
Human apolipoprotein CII (apo CII) consists of 79 amino acid residues and is required as a cofactor in the hydrolysis of triacylglycerides of chylomicrons and VLDL by lipoprotein lipase.1 2 Familial apo CII deficiency is an autosomal recessive genetic disorder characterized by fasting hypertriglyceridemia and an accumulation of chylomicrons in the plasma.3 Shachter et al4 generated transgenic mice overexpressing human apo CII, and these authors reported the unexpected observation of marked hypertriglyceridemia with an accumulation of triglyceride-enriched VLDL in the plasma. We are the first to report a case of resistant hypertriglyceridemia in a young man with high plasma levels of apo CII (turbidimetric method by Alpha-Biotech, Milan, Italy).
A 42-year-old white man was referred to our lipid clinic for diet- and drug-resistant hypertriglyceridemia. His familial history was positive for cardiovascular diseases (father with hypercholesterolemia and myocardial infarction). He had stopped smoking 9 years ago. He presented a history of chest pain, but the baseline ECG and a strength test were normal. He also underwent an ultrasound scan of the abdomen, which showed normal morphology of the liver and gallbladder. His blood pressure was normal (120/80 mm Hg), and he usually performed adequate physical activity. The Table⇓ shows the lipid profile of the patient at the first visit, after 1 month of diet therapy (1800 kcal/d and total abstention from alcohol consumption), and after 1 month of diet plus 400 mg of fenofibrate. We also treated the patient with 1200 mg×3/d of gemfibrozil without changes in the lipid profile. No floating chylomicrons were detected in the plasma sample after 24 hours at 4.0°C, although the plasma remained turbid. The results of laboratory tests included a fasting plasma glucose of 82 mg/dL, an alanine aminotransferase level of 23 IU/L, an aspartate aminotransferase of 13 IU/L, and a γ-glutamyl transpeptidase of 30 IU/L. Considering the lack of results with drug therapy, the patient is currently being treated with diet only.
The molecular mechanisms of hypertriglyceridemia are not well understood; however, it is well known that apo CII stimulates lipoprotein lipase. The possibility that the high plasma levels of triglycerides described in this case were related to impaired remnant particle removal could be ruled out, considering the normal plasma cholesterol levels; we can argue that the defect could be in the lipolysis. Furthermore, it has been shown that high levels of apo CII directly inhibit lipoprotein lipase5 and that a high level of human apo CII is inhibitory to mouse lipoprotein lipase.4 It has been considered that an excess of apo CII may impair lipolysis by decreasing the access of lipoprotein particles to lipases; in fact, apo CII has been shown to decrease the association of lipoprotein lipase with phospholipid vesicles, and thus, excess apo CII may interfere with the association of triglyceride-rich lipoproteins with glycosaminoglycans, thereby impairing both lipolysis and particle clearance.4 This case raises the possibility that overexpression of apo CII could have a different role in the catabolism of triglyceride-rich lipoproteins, leading to increased levels of several atherogenic species, including cholesterol-enriched VLDL.
Olivecrona G, Beisiegel U. Lipid binding of apolipoprotein CII is required for stimulation of lipoprotein lipase activity against apolipoprotein CII–deficient chylomicrons. Arterioscler Thromb Vasc Biol. 1997;17:1545–1549.
Okubo M, Hasegawa Y, Aoyama Y, Murase T. A G+1 to C mutation in a donor splice site of intron 2 in the apolipoprotein (apo) CII gene in a patient with apo CII deficiency: a possible interaction between apo CII deficiency and apo E4 in a severely hypertriglyceridemic patient. Atherosclerosis. 1997;130:153–160.
Shachter NS, Hayek T, Leff T, Smith JD, Rosenberg DW, Walsh A, Ramakrishnan R, Goldberg IJ, Ginsberg HN, Breslow JL. Overexpression of apolipoprotein CII causes hypertriglyceridemia in transgenic mice. J Clin Invest. 1994;93:1683–1690.