For many years, most healthcare providers and nutrition researchers have been telling Americans that HDL-cholesterol (HDL-C) is “good cholesterol" because it helps protect arteries from developing atherosclerosis and eventually coronary heart disease (CAD). However, more recent scientific evidence is refuting the simplistic conclusion that more HDL-C is always good.
This is not to say that people with higher HDL-C are not at lower risk of having heart attacks, but rather that it now appears that improving the functionality of HDL particles may be more important than simply increasing the HDL-C levels pre se. Research indicates that drugs that increased HDL-C levels have not been effective at reducing heart attacks and other cardiovascular disease (CVD) events. In fact, these CTEP-inhibitor drugs (i.e. torcetrapib, dalcetrapib, evacetrapib) markedly increase HDL-C levels, lower LDL-C levels, and yet still have been shown to increase CVD events (1). So while higher HDL-C levels are generally associated with less CVD, it is now clear that a higher HDL-C is not necessarily beneficial.
Some diet and lifestyle changes that increase HDL-C levels do reduce CVD events such as quitting smoking, exercising, and getting rid of excess body weight (and keeping it off). However, there are no clinical trials that prove increasing HDL-C levels by replacing dietary carbohydrate with fat actually helps reduce the risk of CAD or slows the growth of atherosclerotic plaques. Nevertheless, for years it has been assumed that everything that increases HDL-C reduces CVD. This is unfortunate because for years the drop in HDL-C levels often seen when people adopt very-low-fat (VLF) diets has been used as the rationale for discouraging people from adopting vegan or near vegan VLF diets for treating and preventing CAD despite all the evidence indicating that CAD can actually be stopped and even reversed with near vegan and vegan VLF diets. Such diets have long been advocated by Morrison, Pritikin, Ornish, McDougal, Esselstyn, and others. One of the main reasons expert panels keep discouraging the use of VLF diets for patients at risk of CAD is this observation that such VLF diets frequently do result (at least initially) in the reduction of supposedly “good” HDL-C levels in most people. This reduction in "good" HDL-C, they have assumed, must be bad for arteries. As a result of this unproven assumption, the AHA, NCEP, ACC, and most recently the new 2015-2020 US Dietary Guidelines have been actively discouraging the use of VLF diets simply because they often do lower "good" HDL-C levels which they assume cannot be good for preventing or reducing CAD. This unproven assumption has long trumped published research showing that VLF vegan or near vegan diets can reverse atherosclerosis and/or reduce the risk of CVD events even in people with advanced CAD despite the fact that such diets often do result in reduced HDL-C (2).
However, if higher blood HDL-C levels do not necessarily lead to less atherosclerosis and a reduced risk of CAD, this may explain why VLF diets can be effective for preventing heart disease even if they do lower HDL-C levels. Perhaps VLF diets are improving the ability of HDL particles to remove cholesterol from the artery wall and bring it back to the liver. This process is known as reverse cholesterol transport (RCT). A new study examined HDL-C levels and CVD risk and showed that some people have a genetic mutation that results in their livers making fewer scavenger receptor B1s (SR-B1s). Because these SR-B1s are largely responsible for removing cholesterol from HDL particles in the blood (and likely remove dysfunctional HDLs from circulation too), it appears that things that result in fewer SR-B1s will slow the removal of HDL-C from the blood, resulting in higher HDL-C levels. However, increased HDL-C might not be as protective against CAD as once believed by most cardiologists. The thinking about HDL and how it functions to affect RCT has been evolving. Recently the concept that more HDL-C levels does not directly protect against atherslcerosis and CAD has been supported by yet another line of research. This study's senior author, Daniel J. Rader, MD, said that “Our results indicate that some causes of raised HDL-C actually increase risk for heart disease. This is the first demonstration of a genetic mutation that raises HDL-C but increases risk of heart disease."
What Dr. Rader and his colleagues did was sequence the lipid-modifying regions of the genomes of 328 people who had markedly elevated HDL-C levels and compared them to those of a control group with much lower HDL-C levels in order to identify genetic mutations that were causing the high HDL-C levels. One of the genes they focused on was coded for SR-B1, which is the major liver receptor needed for removing cholesterol from HDL particles in the blood. They identified, for the first time, one person without any functional SR-B1s. This person had an extremely high HDL-C level of about 150 mg/dL. This subject had two copies of a defective gene that caused them to make SR-B1 that simply did not work. This mutation is called P376L, which the team showed caused a breakdown in the functioning of the liver's SR-B1 receptors. Among the many approaches they took, the researchers generated induced pluripotent stem cells (iPSCs) from the SR-B1 deficient person and used them to create liver cells. They then showed these new liver cells had a profound reduction in their ability to take up cholesterol from HDL particles. “This mutation prevents the SR-B1 receptor from getting to the cell surface where it functions to bind and take up HDL,” Dr. Rader explained. “This disruption in the receptor’s ability to do its job is due to mistakes in its folding and processing during protein synthesis.”
Going back to the other sequenced genomes, the researchers were then able to show that people who carried only one copy for making defective SR-B1 P376L also have significantly higher HDL-C levels in their blood. From this, Dr. Rader thought based on their knowledge of how SR-B1 function from previous studies in mice, that having this SR-B1 P376L mutation may result in much higher HDL-C levels, but might paradoxically also increase the risk of CAD and CVD events despite the much higher HDL-C levels in their blood. Working with other researchers around the world, this University of Pennsylvania team was able to show exactly what they had surmised was the case. It turned out that people who have this mutated gene for making SR-B1 clear HDL-C more slowly from the blood. This is similar to what happens to people who inherit a mutated gene for making LDL-receptors. Having only half the normal LDL-receptors results in LDL-C being removed more slowly from the blood resulting in much higher than normal LDL-C levels (3). Dr. Rader's group showed that having half the normal SR-B1s resulted in much higher HDL-C levels in the blood and yet people with this mutated gene for making dysfuntional SR-B1s had an average 80% increased risk of developing serious coronary heart disease. Dr. Rader noted that this P376L mutation in the gene for making SR-B1s appears to be specific to people of Ashkenazi Jewish descent. He suggested that testing for it in this ethnic group might be particularly important. “The work demonstrates that the protective effects of HDL are more dependent upon how it functions than merely how much of it is present,” Rader concluded. “We still have a lot to learn about the relationship between HDL function and heart disease risk” (4).
How Does Dr. Rader's Research Relate to Dietary Fat and Increased HDL-C?
Unfortunately for the proponents of eating more fat and less carbohydrate to raise HDL-C levels in the blood, this increase appears to happen in large part by reducing the number of SR-B1s. Fewer SR-B1s reduces the ability of HDL particles to get cholesterol from the artery wall back to the liver for disposal, thus impairing RCT and so promoting CAD (5). Dr. Rader's new study demonstrated that higher HDL-C levels that result from making fewer functional SR-B1s results in higher HDL-C levels and yet also more CAD. So it appears that higher fat diets impair the clearance of cholesterol from the circulating HDL particles. Since SR-B1s also appear responsible for the removal of dysfunctional HDL particles from the circulation, this may also contribute to more CAD. Why? These dysfunctional HDLs are believed to result from denaturization of the HDL's apoA-1 protein. This structural change in the shape of apo-A1 renders it incapable of picking up cholesterol in the artery wall and also reducing the ability of the HDL particles to reduce inflammation in the artery wall (6, 7). Research at the Pritikin Longevity Center showed that just a couple weeks of a VLF diet composed largely of whole grains, fruits, and vegetables significantly reduced the amount of pro-inflammatory HDL particles and increased the amount of anti-inflammatory HDLs (8). Thus the long-held assumption that the best diet for preventing and reversing atherosclerotic heart disease is high in unsaturated fat is increasingly dubious.
Bottom Line: Fewer SR-B1s actually are bad for one's arterial health because fewer SR-B1s slow the removal of cholesterol from HDL particles and likely also the removal of dysfunctional HDL particles. When these changes occur in response to consuming a diet higher in fat and lower in carbohydrate, they may raise HDL-C levels and may also impair the body's ability to affect RCT and prevent CAD from progressing, thus increasing the risk of heart attacks and other CVD events. So while higher fat diets may result in higher HDL-C levels in the blood, it is now appears this increase is in large part due to slowing the clearance of defective HDL particles with denatured apoA-1s from the blood and also in part to slowing down the removal of cholesterol from the functional HDLs. Removal of cholesterol from functional HDLs allows them to return to the artery wall and effect more rapid RCT. So high fat diets appear to impair RCT largely by increasing dysfunctional HDL particles in the artery wall that have lost their ability to remove excess cholesterol deposited in the artery wall (by LDLs and other atherogenic apoB-containing lipoproteins) and bring that excess cholesterol back to the liver (the primary way RCT occurs). By interfering with RCT and increasing dysfunctional HDLs that promote inflammation (rather than suppress it) diets higher in "good" fats may actually be promoting more atherosclerosis compared to VLF diets composed largely of whole fruits, grains, and vegetables, despite the fact that the higher fat diets tend to increase HDL-C levels in the blood. Of course, increasing HDL-C levels by impairing RCT is now clearly bad for one's arteries and likely will increase CVD events.
By James J. Kenney, PhD, FACN
- Kenney JJ. Very low fat diets for the prevention and treatment of hypercholesterolemia. Clin Appl Nutr 1992;2(1):81-93; RJ Ornish D, Scherwitz LW, Billings JH, et al. Intensive lifestyle changes for the reversal of coronary heart disease. J Am Med Assoc 1998;280:2001-7.
- P. A. Zalloua et al. Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease. Science, 2016; 351 (6278): 1166 DOI: 10.1126/science.aad3517
- Brinton EA, et. al. A low-fat diet decreases high density lipoprotein (HDL) cholesterol levels by decreasing HDL apolipoprotein transport rates. J Clin Invest. 1990 Jan;85(1):144-51
- Huang Y, et. al. An abundance of dysfunctional apo A1 in human atheroma. Nature Medicine 2014:DOI: Volume: 20;Pages:193–201. Year published:doi:10.1038/nm.3459, or http://www.medscape.com/viewarticle/819773
- Briel M, et. al. Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: systematic review and meta-regression analysis. BMJ 2009;338:b92 doi:10.1136/bmj.b92
- Roberts, CK, et al. Effect of a short-term diet and exercise intervention on inflammatory/anti-inflammatory properties of HDL in overweight/obese men with cardiovascular risk factors. Appl Physiol. 2006;101:1727-32
Stephanie Ronco has been editing for Food and Health Communications since 2011. She graduated from Colorado College magna cum laude with distinction in Comparative Literature. She was elected a member of Phi Beta Kappa in 2008.