It is widely accepted that high density lipoprotein (HDL) is the "good" cholesterol that protects an individual from developing heart disease. However, in a new study of transgenic mice, LBL researchers have demonstrated that not all HDLs provide the same degree of protection.
There are two major forms of HDL in the bloodstream of any individual human. One is called AI-HDL (or LpA-I) because it contains the protein apolipoprotein A-I (apoA-I), and the other is called AI/AII-HDL (or LpA-I, A-II) because it contains both apoA-I and the protein apolipoprotein A-II (apoA-II). The LBL researchers genetically altered mice so that they carried almost exclusively one or the other form of these human HDLs.
Following a high-fat, high-cholesterol diet, despite similar total cholesterol and HDL-cholesterol levels, the development of atherosclerotic lesions was 15 times greater in the mice that carried human AI/AII-HDL than in those that carried human AI-HDL.
"AI-HDL appears to be the antiatherogenic form of HDL while AI/AII-HDL is much less efficient in protecting an organism from developing heart disease," says Edward Rubin, of LBL's Life Sciences Division, who led this research. Working with Rubin on the study were Joshua Schultz, Judy Verstuyft, Elaine Gong, and Alex Nichols. Their findings were reported in the October 21, 1993 issue of the science magazine Nature.
Heart disease remains the leading cause of death in the United States and the majority of these deaths are the result of atherosclerosis -- the hardening of arteries through the buildup of plaque deposited primarily by low density lipoprotein (LDL) or "bad cholesterol." Numerous studies have suggested that HDLs remove plaque from arterial walls, however, it is also known that some people with low HDL levels show no signs of atherosclerosis.
Recent reports comparing the respective merits of AI-HDLs and AI/AII-HDLs for preventing heart disease, based on human studies, have been conflicting. In part, this is due to the difficulty of conducting a proper study with human subjects who have a mixture of both forms of HDLs as well as differing total HDL levels.
Rubin and colleagues introduced the human genes that express HDL proteins into an atherosclerosis susceptible strain of mice. Because HDL formed from human proteins differs significantly in size and structure from HDL formed from mouse proteins, the researchers were able to determine that the HDL in their transgenic mice resembled one form or the other of the HDL seen in humans but not normally found in mice.
Says Schultz, "The fact that the HDL particles in the transgenic mice looked like human HDL told us that we could use the mice to model the effects of human HDL proteins on atherosclerosis."
Groups of mice bearing each form of human HDL were fed an atherogenic diet for 36 weeks, as was a control group bearing only mouse HDLs. Both the control group and the group of transgenics with AI/AII-HDL developed extensive atherosclerotic lesions. AI-HDL transgenics were almost completely protected, only developing a limited number of small early atherosclerosis lesions.
Explains Schultz, "One way of looking at the data is that AI-HDL is like an industrial vacuum cleaner, moving through the arteries, collecting cholesterol and transporting it to the liver where it can be disposed of. In contrast, AI/AII-HDL is more like a dust buster. It may offer some protection (compared to the control group), but not to a significant degree."
The LBL study suggests that the poor protection of AI/AII- HDL is the result of apoA-II protein impairing the cholesterol collecting ability seen in AI-HDL. However, future research with the same types of transgenic mice used in this study should further clarify this issue of exactly how HDL acts to protect individuals against heart disease. In the meantime, the LBL researchers say that doctors now have an additional reason to identify which form of HDL their patients have. There is also now even more impetus to develop means of boosting AI-HDL levels.