The findings could lead to more tailored treatments for cardiovascular disease.
Scientists at the National Institutes of Health (NIH) have achieved a critical milestone in understanding the mechanisms behind the accumulation of “bad” cholesterol, or low-density lipoprotein cholesterol (LDL-C), in the body. For the first time, researchers have demonstrated how the primary structural protein in LDL interacts with its receptor, initiating the process of LDL clearance from the bloodstream. They also identified the consequences of disruptions in this process.
Published in Nature, the findings enhance our knowledge of how LDL contributes to heart disease—the leading cause of death worldwide—and may pave the way for more tailored LDL-lowering therapies, such as personalized statin treatments, to improve their effectiveness.
The Link Between LDL and Cardiovascular Disease
“LDL is one of the main drivers of cardiovascular disease which kills one person every 33 seconds, so if you want to understand your enemy, you want to know what it looks like,” said Alan Remaley, M.D., Ph.D., co-senior author on the study who runs the Lipoprotein Metabolism Laboratory at NIH’s National Heart, Lung, and Blood Institute.
Until now scientists have been unable to visualize the structure of LDL, specifically what happens when it links up with its receptor, a protein known as LDLR. Typically, when LDL binds to LDLR, the process of clearing LDL from the blood begins. But genetic mutations can prevent that work, causing LDL to build up in the blood and get deposited into the arteries as plaque, which can lead to atherosclerosis, a precursor for heart disease.
In the new study, the researchers were able to use high-end technology to get a view of what’s happening at a critical stage of that process and see LDL in a new light.
“LDL is enormous and varies in size, making it very complex,” explained Joseph Marcotrigiano, Ph.D., chief of the Structural Virology Section in the Laboratory of Infectious Diseases at NIH’s National Institute of Allergy and Infectious Diseases and co-senior author on the study. “No one’s ever gotten to the resolution we have. We could see so much detail and start to tease apart how it works in the body.”
Advanced Techniques Uncover New Insights
Using advanced imaging technique called cryo-electron microscopy, the researchers were able to see the entirety of the structural protein of LDL when it is bound to LDLR. Then, with artificial intelligence-driven protein prediction software, they were able to model the structure and locate the known genetic mutations that result in increased LDL. The developers of the software, who were not involved in the study, were recently awarded the 2024 Nobel Prize in Chemistry.
The researchers found that many of the mutations that mapped to the location where LDL and LDLR connected, were associated with an inherited condition called familial hypercholesterolemia (FH). FH is marked by defects in how the body uptakes LDL into its cells, and people with it have extremely high levels of LDL and can have heart attacks at a very young age. They found that FH-associated variants tended to cluster in particular regions on LDL.
The study findings could open new avenues to develop targeted therapies aimed at correcting these kinds of dysfunctional interactions caused by mutations. But, as importantly, the researchers said, they could also help people who do not have genetic mutations, but who have high cholesterol and are on statins, which lower LDL by increasing LDLR in cells. By knowing precisely where and how LDLR binds to LDL, the researchers say they may now be able to target those connection points to design new drugs for lowering LDL from the blood.
Reference: “Structure of apolipoprotein B100 bound to the low-density lipoprotein receptor” by Mart Reimund, Altaira D. Dearborn, Giorgio Graziano, Haotian Lei, Anthony M. Ciancone, Ashish Kumar, Ronald Holewinski, Edward B. Neufeld, Francis J. O’Reilly, Alan T. Remaley and Joseph Marcotrigiano, 11 December 2024, Nature.
DOI: 10.1038/s41586-024-08223-0
This work was supported by the Intramural Research Programs of the National Heart, Lung, and Blood Institute, the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, and the High-Value Datasets program from the NIH Office of Data Science Strategy.
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37 Comments
Very promissing.
This gives me hope! I was diagnosed with Familiar Hypercholesterolemia in 2020 when two stents went into the Widow Maker! Dr. said it’s a miracle I didn’t have a heart attack. I can’t take statins, was referred to a Cardiologist/Lipodoligst at UCHICAGO MEDICINE. He put me on Praluent. Everything has been great until this year. I recently had a 75% blockage in the Right Carotid Artery and mini strokes. Waiting to see a Neurologist. I’ve done everything right! Eating, walking…etc. He’s top in his field with (FH) but he also was honest and told me there’s no cure and he can only help me live with it. This new research finding is a blessing for so many people dying from Cholesterol. People like myself see hope, not skepticism! Advanced Science is discovered all the time. Let’s be grateful. I am!
Can’t take cholesterol statins loose all power to lift anything. Had to get help even getting out of bed. Problems opening refrigerator door. 6 different pills.
I read that statins can cause muscle loss in many folks. It seems it’s time you find a new doctor, preferably a cardiologist.
The same with me, now I use praluent or repatha, it’s expensive and lucky my insurance covers part of it. It’s an injection 2x a month, my lipid profiles are perfect now. Look into it.
Praluent made me really sick, and so foggy I couldn’t drive..
Then I found pravastatin a mild statin (tried 3-4 others with bad effects,,) which has been fine and working very well!
I am 78 taking stations. Not sure the effects if any. I still work. Haven’t had any of the problems I have read about. Been taking them for over 20 years. Health is so unsolvable too many unknowns too much CHEMISTRY. Follow your body responses
I have over the past few years had reaction to statins ….
I have suffered with weekness in legs cramp.etc etc. I stopped taking them and showed quick improvements . After blood tests which showed return of colestral I was prescribed different statins this resulted in return to side effects .
I had my biannual phone call from cardiologist after telling him my story he has prescribed a medication which is not a statin . He says it should solve my problems and that it helps stimulating healthy colestral
The jury is out so can’t inform you of results yet
Cardiologist recommended my statins. At least mine did and informed me there was no known substitute.
I was same until tried pravastatin
No side effects! 10 mg lowered my cholesterol a lot. Give it a try if u haven’t………
Me as well. Exercise and diet and good fish oil are my only options.
Very interesting and seems promising. Have anyone ever taken into account an individual’s genetic make up? I’ve had elevated cholesterol even when I was in top condition, basically training for tri-athlons. Ht. 66″, Wt. 165lb, body fat 10% pre-1995. Tried statins a couple of times and got every side effect, except death!
I’m very slim exercise eat healthy and I had high cholesterol since I was in my early 40s and now I’m prediabetic so not sure what else I can do it’s so frustrating
Please ask your Dr for bloodwork including your LPa tested. You may have familial hyperlipidemia that runs in some families. What’s your family heart health look like? A lipidologist will test you for the gene that causes the liver to pump out thick cholesterol . He will put you on Praluent or Repatha injections to treat LPa if you have it. Your bad LDL cholesterol # will drop significantly in a month. Good luck! 👍
Look into studies by Dave Feldman that identify a potential called Lean Mass Hyper Responder or LMHR.
I was in so much pain on Statins I had to come off them. Had x rays and everything Took myself off statins after 1 day no more pain and none since
Stop eating carbs and depend on saturated and monosaturated fats for better energt there not unhealthy
Watch some videos on ken berry on YouTube and then stop following suit in the epidemic of obesity, diabetes ,cancer and hearth disease make a change we have been “fed a lie” another video to watch
I read genetics plays a big role. It’s worth finding out your Lipoprotein A level in your blood. Disclaimer: I’m not a doctor.
I did and I’m on Repatha injections. My LDL LPa dropped drastically in one month! Two heart attacks and 3 stents and I have a great cardiologist now who found the problem immediately!
Genetic makeup is absolutely critical. Familial hypercholesterolemia is a genetic condition that causes high cholesterol. People with this genetic factor are at much higher risk of cardiovascular disease. I Consider getting a coronary artery calcium scan. No needless, no drink, no prep, and I didn’t even take my shoes off for the test. I had no symptoms, no family history of early events, good cholesterol numbers and BP, never smoked, and climbed on a stair machine for an hour 3X per week. Got the surprise of my life! Now under the care of a good cardiologist who has my LDL below 50 mg/dl with a non-statin called Ezetimibe. No side effects from it.
You lost me at statin. A hard pass.
This stuff is hard, but not knowing the basics of human physiology is like driving on a long desert highway not knowing how to change tires.
You might try a non-statin like Ezetimibe. Works for me without the side effects the high dose stations had. It’s not one of the new high priced drugs for lowering CVD risk either
Look for a cardiologist that is a board certified lipidologist. They have a better grasp of the situation. I am now working toward my 76th birthday. I had a tribple bypass at age 57. My mother passed at 53, her older brother at 53, her younger brother at 46. My youngest son died at age 30. My grandmother passed in her early 60’s. The lipidologist has a larger quiver of tools and knows how to use them. Travel if you have to.
Extremely misleading and does not concur with the lasted research, this very much looks like another advertisement for big phama and the statin industry. In the 60 thousand person 20 year gold standard research study people with low LDL had a higher mortality rate. This article is misleading and is most likely paid for by the statin industry
Hi Andy could you share your thoughts / latest research. Thanks.
You are 100% right but they’re harder to find. The few you can see interviewed on YouTube like Dr. William Cromwell are light years ahead of the YouTube guru doctors selling supplements and books.
Wow- just heard the complete opposite of this whole idea, that high LDL doesn’t predict early death or heart attack based on recent studies finding that stations are massively overprescribed, and 40% of people taking them don’t need them. This is pro Big Pharma so probably funded by them.
The statin studies that I trust show negligible benefit in a large population. The obvious explanation for this is that we don’t measure when we have overcorrected the problem that statins treat (elevated LDL), or corrected any problems that statins cause (e.g. CoQ10 depletion, NAD+ deficits and resulting metabolic damage). I think lipid theory has also become self-perpetuating despite increasing evidence that the inflammatory hypothesis of heart disease is the stronger paradigm. If inflammation causes heart disease, it explains people like me, who have familial hypercholesteremia and no signs of atherosclerosis. I will always read these studies with a combination of interest and skepticism because I believe oxidative stress and inflammation are more important mechanisms to be paying attention to.
yes, but not recent studies. we’ve known for a long time that high bad cholesterol is not actually a predictor for future heart disease and that statins don’t work. follow the money, find the buried and misquoted/misinterpreted studies to find the truth.
Seat belts also have a negligible benefit in a large population, but you hopefully wouldn’t stop wearing your seatbelt. In 2022, seat belts saved an estimated 15,000 lives in the United States out of the hundreds of millions of people who rode in cars. The more you ride in cars, the more your total risk over time increases. Seat belts themselves carry a risk if you don’t have a seat belt cutter handy and are trapped by them in an accident. The statin the studies only run for a few years but cardiovascular risk builds over multiple decades. Check out resources who are not selling supplements or books. Nutrition Made Simple on YouTube is an excellent one.
Fully agree with inflammation as root cause. LMHR phenotype study totally discredits high LDR causal hypothesis. This is another example of drug pushing by pharma with all the wrong incentives … profit before people.
No it doesn’t. Checkout Nicholas Norwitz on YouTube. He is a LMHR researcher. Yes, the LMHR phenotype absolutely contradicts the conventional LDL cholesterol hypothesis. However, he and another well-known researcher, Dave Feldman, state that it does not invalidate it. It only illustrates that the conventional hypothesis is incomplete because it does not appear to apply to this phenotype.
I’m healthy so I thought! No have a heart stent and on blood thinners and stain.I feel like my life is over !
When one gets into these so called blood tests , it’s the very beginning for your downfall, because they will surely find something which is irrelevant and put on medications that where never required at the first place and follow the side effects of drugs . This is how the transition from a heathy person turns into a patient. Your body will give you the signal if something is wrong these so called blood tests are as true as a coin toss.
Unbelievable how this ideologically driven “scientists” still wanting to keep alive this absolute rubbish hypothesis. Millions and millions of healthy men and women with “high” cholesterol died every year +90 years old. They cannot even explain children atherosclerosis or animal atherosclerosis with this theory
LDLR is G protein coupled receptor. The binding of LDL allows two photon super exchange interaction to propagate over receptor. The 2p SEI achieves the gate opening.
All G proteins have conserved tryptophan at their active site. When G protein is twisted the free electrons in trp indole group are forced from p orbital to f orbital. When twist releases the electrons emit opposite spin photons which interact with chiral Carbon sp3 inside wavelength. The photon is invisible because it interacts inside wavelength. The photon can be observed by Ag reduction.
Because momentum is conserved, both momentums spinorates ,kicking each other forward, (propagates, but electrons are spinors) using other trp sp3 bonds as Andersson´s location as long they meet delocalized electron. In this case the delocalized electron is in LDL gate. Two photon super exchange interaction is the mechanism how G proteins work.
If correct ligand does not bind to receptor the SEI can´t open the gate.