by Tim Bonfield

Many people know that HDL cholesterol is supposed to be the “good” cholesterol.

While low density lipoproteins (LDL) – the “bad” cholesterol – collect in cardiac artery walls, high-density lipoproteins (HDL) help to transport them away. Thus, if people want to avoid heart attacks and strokes, they should boost their HDL cholesterol levels while reducing their LDL cholesterol levels.

If only preventing heart disease could be so straightforward.

Amy Sanghavi Shah, MD, MS.

Not-so-good cholesterol? New research, led by Dr. Amy Sanghavi Shah and colleagues, shows that high-density lipoproteins (HDL) play a more complex role in heart disease risk for teens with Type 2 diabetes than previously thought. The size of HDL particles may dramatically alter their effectiveness, and the smallest sizes appear to offer the weakest benefits.

In the clinic at Cincinnati Children’s, Amy Sanghavi Shah, MD, MS, works closely with obese teens who have developed Type 2 diabetes and have already begun to show early signs of heart disease risk. In the laboratory, she works to find better ways to reduce those risks. In the process, she has learned that the relationship between heart disease and HDL is much more complicated than previously believed.

“It’s not just the HDL cholesterol number,” Shah says. “Cardiovascular risk also appears to be influenced by the types of HDL a person has.”


Scientists have known for many years that HDL is not just cholesterol. These complex particles have a core packed with triglycerides and cholesteryl esters surrounded by a coating of phospholipids and apolipoproteins. In fact, cholesterol comprises less than 20 percent of an HDL particle.

Less well known, until recently, has been that HDL particles can vary significantly in size and composition. Run a blood sample through a standard lipid panel and the results will reveal simple levels of HDL and LDL cholesterol and triglycerides. Put that same sample through a gel filtration column and the results will reveal one or more of 10 subspecies of HDL.

“These different-sized particles appear to have differing actions,” Shah says. “The larger ones that are richer in phospholipids may have a beneficial effect, while the smaller ones are more cholesterol rich and appear more likely to have negative effects.”

But why do some people have larger HDL particles floating in their blood while others have smaller ones? Are these size differences a possible cause of increased heart disease risk, or a symptom of the disease process? That is what Shah and colleagues hope to find out.

“There’s a lot more to know inside the world of HDL,” she says.


In addition to size differences, Shah and colleagues are using the latest in proteomics technology to learn more about the apolipoproteins on these HDL particles.

This line of research built upon work from scientists at the University of Washington who found that HDL particles carry some 90 different proteins. Shah and colleagues applied similar mass spectrometry technology to HDL subspecies collected from teens with Type 2 diabetes, with results published in July 2013 in the journal Diabetes.

“We found proteins that confirm HDL has a role in lipid transport and identified proteins that point to roles in antioxidation, immunity and glucose metabolism,” Shah says.

The complicated roles played by HDL may help explain why a number of other studies have produced head-shaking findings:

  • Several large clinical trials of HDL cholesterol-boosting drugs have shown disappointing results at reducing heart disease risk.
  • People with Type 2 diabetes have shown residual cardiac risk even when LDL has been reduced to the lowest possible levels.
  • Even people born with unusually high, natural HDL cholesterol levels (a small percentage of the population) do not consistently escape heart disease risk.


So if controlling HDL levels has such inconsistent effects on heart disease risk, should people bother with cholesterol testing? Well, yes.

Shah predicts cholesterol testing will become much more sophisticated as understanding of HDL particles grows, so staying in the testing habit has value. If nothing else, the findings of simple cholesterol testing serve to remind people of the undisputed need to battle obesity and preventing Type 2 diabetes by eating well and getting plenty of regular exercise.

In the meantime, the search has begun to identify and understand the most beneficial subspecies of HDL.

“We need to understand what these different subspecies are doing,” Shah says. “Eventually, we hope new therapies may be developed that can help boost the right kinds of HDL.”

Having one foot in the lab and another in the clinic gives Shah a special perspective on the urgency of the work ahead.

Only now are the children who started developing Type 2 diabetes as part of the obesity wave that struck America in the 1990s beginning to reach their 30s. Few of these people are suffering heart attacks – yet – but some already are experiencing kidney complications, neuropathies and other problems that normally strike diabetics later in life.

“It took a long time for these children to get to where they are today,” Shah says. “Reversing the process may take even longer.”