Response to the Letter by Ebara et al
As highlighted by Dr Ebara et al, there are key differences in lipoprotein metabolism between mice and humans. In humans, lipoprotein lipase (LPL) deficiency with severe hypertriglyceridemia was originally reported to be nonatherogenic.1 However, in 1996, Benlian et al presented 4 French cases of LPL deficiency with severe hypertriglyceridemia who all displayed various degrees of angiographically defined coronary or carotid atherosclerosis.2 One of them had bypass surgery at age 65, and during the surgery, atherosclerotic lesions of all grades (from fatty streaks to calcified and hemorrhagic atherosclerotic plaques) were noted all along the aorta and iliac and femoral arteries. The patient died suddenly 2 years after surgery. These 4 cases not only exhibited severe hypertriglyceridemia, but they also had high cholesterol levels, which were elevated 3- to 4-fold over the normal range, because even in triglyceride-rich lipoproteins, there is a certain portion of cholesterol and its esters consisting of lipid core.
Over the past decade, there have been several case reports of LPL-deficient patients with or without detectable lesions of atherosclerosis.3,4 Therefore, humans with LPL-deficient hypertriglyceridemia appear to be prone to atherosclerosis in certain circumstances. As discussed in our article,5 such discrepancies between different individuals may be partially explained by the presence or absence of noncatalytic LPL protein. The catalytically inactive LPL protein could act as a molecular bridge between proteoglycans and different lipoprotein receptors to facilitate lipoprotein uptake by cells such as macrophages. Therefore, if macrophage secrete inactive LPL protein, such molecules may then enhance foam cell formation through increased uptake of atherogenic lipoproteins.
We also found that LPL-deficient mice developed spontaneous atherosclerosis only at a very old age. The extent of lesions in these mice were equivalent to those of apolipoprotein E–null mice at ≈3 months of age (G. Liu, personal communication, 2005). Similarly, the patients with LPL-deficient hypertriglyceridemia reported by Benlian et al manifested signs of peripheral atherosclerosis or CAD at age 50, which is in contrast to familial hypercholesterolemia patients who have signs of atherosclerosis at very early age.6
In the aged LPL-deficient mice, there was a marked increase in oxidative susceptibility of chylomicrons, and in vitro evidence that these chylomicrons increased the expression of vascular cell adhesion molecules. Although the spontaneous atherosclerosis found in old LPL-deficient mice in our study may not directly extrapolate to humans with LPL deficiency, these results provide insight into the potential mechanisms of the variable susceptibility to atherosclerosis in LPL-deficient patients.
Regarding the nature of accumulated triglyceride-rich lipoproteins in LPL-deficient mice, these particles do not consist of very-low-density lipoprotein alone, but instead they are a mixture of chylomicrons, chylomicron remnants, and very-low-density lipoprotein, because a large portion of these lipoproteins could be floated by centrifugation in a Hitachi P42AT rotor at 25 000 rpm (75 700g) for 20 minutes at 15°C, as described in the expanded Materials and Methods section in the online data supplement of our article.5 The fractions isolated by this way are mainly composed of chylomicrons and chylomicron remnants.7 Although these lipoproteins may not enter arterial wall, modified chylomicron and remnants, especially oxidized forms of these triglyceride-rich lipoproteins, will activate endothelial cells, which will ultimately result in development of atherosclerosis, as evidenced by our experiments. Although HDL cholesterol levels in these mice are extremely low, their LDL cholesterol levels are similar to wild type as a barely discernable peak in fast protein liquid chromatography profile.
Therefore, the message from our article and from this discussion is that patients with LPL deficiency are not free of atherosclerotic disorders. They may actually well be at increased risk of atherosclerosis, especially at later stages of life.
Sources of Funding
Supported by Canadian Institutes of Health Research (CIHR), China-Canada Collaboration.
Brunzell JD. Familial lipoprotein lipase deficiency and other causes of the chylomicronemia syndrome. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic Basis of Inherited Disease. Vol 2. New York: McGraw-Hill; 1995: 1913–1932.
Saika Y, Sakai N, Takahashi M, Maruyama T, Kihara S, Ouchi N, Ishigami M, Hiraoka H, Nakamura T, Yamashita S, Matsuzawa Y. Novel LPL mutation (L303F) found in a patient associated with coronary artery disease and severe systemic atherosclerosis. Eur J Clin Invest. 2003; 33: 216–222.
Zhang X, Qi R, Xian X, Yang F, Blackstein M, Deng X, Fan J, Ross C, Karasinska J, Hayden MR, Liu G. Spontaneous atherosclerosis in aged lipoprotein lipase-deficient mice with severe hypertriglyceridemia on a normal chow diet. Circ Res. 2008; 102: 250–256.
Bhattacharya S, Redgrave TG. The content of apolipoprotein B in chylomicron particles. J Lipid Res. 1981; 22: 820–828.