Sci. Aging Knowl. Environ., 13 August 2003
Making Mischief in Macrophages
Fat-slicing enzyme spurs atherosclerosis in a novel way
Key Words: lecithin cholesterol acyltransferase atherogenic lipolysis
The enzyme hepatic lipase has been as evasive as a mobster who keeps ducking prosecution. Many researchers have suspected that it helps trigger atherosclerosis, but they couldn't make the case. A new study finally provides evidence to indict the enzyme, suggesting that it incites fatty accumulation in arteries by conspiring with immune cells.
Produced primarily in the liver, hepatic lipase snips triglycerides and other lipids, reducing the fat load toted by HDL and LDL, the "good" and "bad" forms of cholesterol. Hiking the activity of hepatic lipase in the liver cuts the amount of HDL, and some studies suggest that a rise in hepatic lipase also increases the density of LDL, boosting LDL's artery-plugging potential. However, studies of hepatic lipase's impact on atherosclerosis have produced conflicting results. Some found increased hepatic lipase activity in atherosclerosis patients; others detected reduced activity. The new study suggests that hepatic lipase's effects on blood cholesterol might be a red herring. A clue to the protein's role in atherosclerosis came last year, when a team from the National Heart, Lung, and Blood Institute (NHLBI) in Bethesda, Maryland, showed that immune cells called macrophages make hepatic lipase. The discovery was provocative because macrophages help instigate atherosclerosis. These cells squeeze into arterial walls and absorb lipids, helping build a lesion. The NHLBI team wondered whether hepatic lipase within macrophages might spur artery clogging.
To find out, Nong and colleagues studied mice engineered to lack hepatic lipase, a lipid-grabbing protein called apolipoprotein E (apoE), or both. The arteries of mice that don't make apoE clog rapidly. The team irradiated the mice to kill their bloodmaking cells, then infused bone marrow from animals lacking combinations of the proteins. When mice missing apoE and hepatic lipase received marrow from mice lacking only apoE, they developed large arterial lesions, presumably because the transplanted cells brought working versions of hepatic lipase. The plaques were less than one-third as big in rodents that received marrow from mice without either protein. "The results show that [hepatic lipase production] in macrophages is a contributor to atherosclerosis," says co-author Lita Freeman, a molecular biologist at NHLBI. Transplants did not alter the amounts of LDL or other lipids in the blood, indicating that hepatic lipase in macrophages can spur atherosclerosis without changing these measures. Other experiments indicated that hepatic lipase prompts macrophages to gobble up oxidized forms of LDL, which pile up in fatty lesions.
"This is a major step in investigating the role of macrophage hepatic lipase," says biochemist John Hill of the University of British Columbia in Vancouver, Canada. The work suggests that hepatic lipase's deeds in the macrophages, not its influence on the amount of fats in the blood, are what drive atherosclerosis. It indicates "that changes independent of lipid levels are important," says Hill. The work provides a clue about how hepatic lipase might work, but many questions remain, he says, such as what spurs the enzyme's production in immune cells. Although scientists have amassed enough evidence to file charges, they need to uncover more before they can be sure of a conviction.
August 13, 2003
Science of Aging Knowledge Environment. ISSN 1539-6150