Everybody talks about cholesterol (as in cholesterol-free), butnobody really understands how this steroid alcohol goes about itsdirty work in the body, or what it's good for.
This is not for lack of trying; myriads of cell biologists keep finding,and publishing, new insights into cholesterol's guilty secrets.
A paper in this month's Journal of Cell Biology opens another smalldoor of knowledge onto how cholesterol molecules enter a singlecell, and maintain their steady state therein. Its arcane title:"Caveolin moves from caveolae to the golgi apparatus in response tocholesterol oxidation."
When cell biologist Richard Anderson and his co-authors at theUniversity of Texas SW Medical Center in Dallas discovered thisintracellular transport route, they were "trying to do something else,"Anderson told BioWorld Today.
"We thought if we messed up the cholesterol in the caveolae, thenwe would block its ability to internalize." Caveolae, he explained,"are a type of cell membrane organelle that internalizes smallmolecules, such as vitamins and ions."
He continued, "Prior to this finding, the dogma of how moleculesentered cells across the plasma membrane was that they first wentthrough a pathway that ended up reaching the lysosome and theGolgi apparatus," which packages newly synthesized proteins ontheir way to their action stations.
"But," he observed, "there was never a traffic pattern that wentdirectly from the plasma membrane to the endoplasmic reticulum(ER) _ the protein-manufacturing site where the ribosomes do theirthing." Anderson's lab had been studying caveolae "for six or sevenyears, but we hadn't a clue that it might directly communicate withthe ER, until this study came along."
Experimental Oxidative Trickery
The study's "experimental trick," he said, "the way we discoveredthe pathway, was by putting on the cell an enzyme that damages thecholesterol and the membrane." Responding to that insult, amolecule called caveolin _ function unknown _ which residesalmost exclusively in the caveolae, "moves out along this route to theER. Its traffic pattern directly correlates with trying to get rid of thatoxidized cholesterol."
Once it does so, the caveolin shuttles back to its normal location inthe caveolar compartment of the plasma membrane. "Somehow thispathway is important for normal cholesterol homeostasis," Andersonsaid. "It's a missing link, you might say, because now we think wehave identified how the cholesterol is moving."
This new insight, the Dallas scientist suggested, "has immediateimportance for understanding cholesterol metabolism. There's atleast one disease," he suggested, "Niemann-Pick disease type C, [ahorrendous genetic lipid-storage disorder a.k.a. sphingomyelinlipidosis] that ought to be looked at from this perspective."
Eventually, "this finding might be a focus for diabetes research,trying to understand how fatty acids get into cells," he said. As foratherosclerosis, cholesterol's current hottest button, "it's verydifficult to know at this point." Anderson noted that there are twotypes of cholesterol: metabolic and structural. The former, "perhapswhen oxidized, can stimulate the formation of lesions in the blood-vessel wall, leading to atherosclerosis and heart disease."
But this popular fixation, he underscored, "completely ignores thefact that cholesterol is a vital sterol. We can't live without it." To thebig question in cell biology: What is its function? "there has beenvery little clue. We knew we need it to make steroid hormones, suchas progesterone, estrogen and testosterone. Now we know it alsoseems to act as keeper of the caveolar keys that admit the sterol tothe cell."
Cholesterol: Replenishing, Removing
Since submitting their paper to the Journal of Cell Biology lastsummer, the Dallas group has explored the question of whether thetraffic pattern from caveolar membrane to ER, and back via theGolgi apparatus, occurs only when they damage the cholesterol withoxidase. Rather, it proved to be a normal trafficking pattern "that wejust happen to see," Anderson said, "because of this experimentaloxidase trick that we applied. And our bet is," he observed, "that thispattern is required to keep the cholesterol replenished in the caveolarcompartment of the membrane.
"This compartment is constantly opening and closing, as a functionof the cell's life cycle, so it may be that it just has to keep pumpingthe cholesterol in." He added that "Cholesterol oxidation is occurringall the time in our bodies, damaging it so it has to be removed."
A paper reporting this latest study "is just about ready to send off,"Anderson said.
The Golgi apparatus "must have some machinery for helping get ridof these damaged cholesterol molecules," Anderson noted, "and wedon't understand that at all."
He described the implications of the two-way pathway discovery as"staggering," and suggested that "many opportunistic molecules,such as toxins and viruses, may well hijack caveolae to reach theendoplasmic reticulum."
Replying to the obvious question whether his discovery of the newpathway might hold potential for pharmaceutical intervention inremoving "bad" cholesterol, Anderson allowed, "I couldn't evenbegin to tell you." But he did add, "Researchers need to look at thispathway from the point of view of how a cell gets rid of its excesscholesterol, and how it regulates its sterol genes. Maybe out of thatkind of analysis somebody might discover that you can manipulatethis pathway favorably for the cell." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.