Statin effects of low-carb diets
A recent study published in the online journal Lipids in Health and Disease demonstrates that low-carbohydrate diets act in much the same way statin drugs do to reduce cholesterol.
Before we delve into what this study shows, let’s take a moment and discuss the synthesis of cholesterol in the body.
Although every cell can make cholesterol, most is made in the liver and small intestine. The fact that every cell can make cholesterol should at least imply that cholesterol is a pretty important molecule, which indeed it is. Most of the cholesterol in the body is made in the cells, but about 15 percent of it comes from the diet.
When a cell needs cholesterol it has two places from which to get it: it can make it and/or it can get it from the blood. Usually it does both. If the cell makes cholesterol it goes through the multi-step process shown above. If the cell wants to get cholesterol from the blood, it synthesizes little protein structures called LDL receptors that it sends to the surface of the cell. Once on the surface of the cell these receptors bind to LDL-cholesterol in the blood and transport it into the interior where the cholesterol is released for use by the cell.
As in all synthesis pathways there is a single reaction in the long chain of reactions that is the rate-limiting one, the reaction that determines the overall output of the pathway. In the case of cholesterol synthesis this reaction is the step shown in the diagram below in which hydroxymethylglutaryl-CoA (HMG-CoA) is converted to mevanolate, catalyzed by the enzyme HMG-CoA reductase.
Scientists have known for years that the enzyme HMG-CoA reductase is the rate-limiting enzyme in the 
entire cholesterol synthesis cascade. They figured that if they could design a drug that would interfere with this enzyme, they would have a drug that would lower cholesterol. The class of drugs ultimately developed to perform this task are the statins. Statins are a type of drug called HMG-CoA reductase inhibitors.
When statins (or anything else) inhibit HMG-CoA reductase, the cells can’t make the cholesterol they need to function properly so they resort to the other method and synthesize many LDL receptors that are dispatched to the surface to harvest LDL-cholesterol from the bloodstream. The LDL-cholesterol extracted from the blood means there is less in the blood and levels measured are lower, which is why statins reduce LDL-cholesterol levels.
Now that we’ve had the briefest of primers on cholesterol synthesis, let’s look at this enlightening study. It would seem that if people eat a lot of cholesterol – as they usually do on low-carb diets – that cholesterol levels would go up. But it has been shown that in people following low-carb diets this doesn’t really happen. Why is this the case? That’s what the researchers who did this study wanted to find out.
Subjects were randomized into two groups, both of which consumed low-carb diets (10-15% energy from carbs, 30-35% from protein and 55-60% from fat) for 12 weeks. The groups differed in that one group was given an extra 640 mg per day of cholesterol in the form of eggs while the other group was given an egg substitute containing no cholesterol.
At the end of the intervention, there were no changes in plasma total of LDL cholesterol (LDL-C) compared to baseline or differences in plasma total of LDL-C between groups.
Mononuclear cells were taken from the blood of these subject, then RNA was extracted from these cells. The researchers then used the polymerase chain reaction to determine the amount of messenger RNA (mRNA) for both HMG-CoA reductase and the LDL-receptor protein. (If you need to brush up on mRNA and protein synthesis, take a look at the video in this post from about a year ago.) In short, mRNA correlates with the amount of a specific protein being synthesized – if mRNA is high, then a lot of this protein is being made.
When researchers measured the mRNA they discovered that in those subjects consuming the extra cholesterol there was a significant decrease in the amount of HMG-CoA reductase mRNA ( which means a decrease in the amount of HMG-CoA reductase being made) and a decrease in the amount of LDL-receptor mRNA. The subjects consuming the lesser amounts of cholesterol had the opposite findings – they made more HMG-CoA reductase and more LDL receptors.
What does this all mean? It means that a low-carbohydrate diet allows the body to regulate cellular cholesterol levels over a wide range of dietary cholesterol levels by changing the cellular synthesis and uptake. And it does all this by acting in much the same way that statins do, but without all the side effects.
Another interesting finding in this study is that the group who ate the extra cholesterol had a 21% increase in HDL-cholesterol levels while the group consuming the lower amount of cholesterol had no HDL-cholestrol increase over baseline.
The take-home message from this study is that you don’t really have to worry about the extra cholesterol you might be getting in your low-carb diet. Your body will deal with it nicely. And if you want to go up on the cholesterol by, say, eating a few more eggs, not only will your body compensate, but it will throw in some extra HDL in the bargain.
In short, don’t worry about your cholesterol on a low-carb diet.
So low-carb breaks the cholesterol-synthesis chain, and it does it at the same place as statins.
Then does low-carb potentially have some of the same side effects as do statins? In particular, if they both equally shut down synthesis of mevanolate, then aren’t they both equally shutting down production of CoQ10 (ubiquitin)? If not, why not?
I’ve been low-carbing for 4+ years. Should I then be taking a CoQ10 supplement?
David
Hi David–
No, it doesn’t have the same effect that statins do. Statins reduce the level of the enzyme all the time, whereas the insulin and glucagon in the diet do it whenever appropriate.
Cheers–
MRE
Is there a study that shows a correlation between LC and changes in cholesterol levels? From what I’ve heard anecdotally on the LC websites, it seems that at least the gross levels of total cholesterol and LDL don’t tend to respond uniformly. At least not like triglycerides which seem to really decrease dramatically in the majority of people. I’ve heard of many instances where ratios seemed to improve even though total cholesterol remained elevated or even increased a bit. Just wondering if there is any consensus yet on what blood lipid effects you might expect. I’m sure it is going to depend on body fat and rate of fat loss. You would think it was common sense that when fat stores are being broken down and mobilized, there might be some transient increase. Though it would seem that triglyceride catabolism more than keeps up with this as those levels decrease early in the process of doing LC.
There are numerous studies showing decreases in total and LDL-cholesterol levels with low-carb diets. But the data in most of these studies shows that there is not a uniform response in these numbers across all subjects whereas a lowering of triglycerides is a uniform finding. What does seem to be a uniform finding is that even when LDL-cholesterol levels don’t decrease (or even increase) the particle size either doesn’t change or gets larger. With low-fat diets the opposite holds. Uniformly LDL falls to some extent, but particle size always gets smaller.
Cheers–
MRE
dr. mike! just catching up with all your posts – keep these statin posts coming!
building off another comment above, re: “rebound effect” when going off statins. are there any (good) studies you can point me to effects of quitting statins abruptly? more importantly, any studies linking this “rebound effect” and actual mortality (i.e., not just higher total cholesterol)?
finally, if someone is following LC – goes off statins – what is your expectation for the length of this rebound? could this be as short as 10 days (as you mentioned above – re: improvement time for lipids)?
Hi ec–
I don’t really know the answer to your question. Usually when I took patients off statins I didn’t recheck their bloodwork for six weeks, and by then the rebound effect was pretty much over. I would imagine the effect lasts for a week to 10 days, but I don’t know for sure.
Best–
MRE
I’m a bit confused as to why BOTH the LDL receptors and HMG-CoA were down-regulated in the EGG group. I would have imagined an uptick in LDL-R concomitant with less being made inside the cell. Do cells just need less receptors to garner the same amount of cholesterol in this case? Any insight is greatly appreciated.
Because the cells have plenty of cholesterol available to them so they don’t have to make more or go out and drag it in. If the cells are deficient, they can get it two ways: they can make it and/or they can go out and pull it in with LDL receptors. If the cells contain plenty they don’t need to do either, and so they don’t activate the machinery to do so.
Cheers–
MRE
Would you kindly explain why BOTH the LDL receptors and HMG-CoA were down-regulated in the EGG (higher cholesterol) group. I’m guessing the cell’s needs remain constant…so do they just require less receptors to garner the same amount of cholesterol? Your insight is greatly appreciated, as always.
You’re correct. Because the cells have plenty of cholesterol available to them so they don’t have to make more or go out and drag it in. If the cells are deficient, they can get it two ways: they can make it and/or they can go out and pull it in with LDL receptors. If the cells contain plenty they don’t need to do either, and so they don’t activate the machinery to do so.
Cheers–
MRE
True or false: Most cholesterol under normal conditions is manufactured in extrahepatic tissues.
True
False
Explanation:
Most cholesterol under normal conditions is manufactured in extrahepatic tissues, and the principal and essential task is to move cholesterol to the liver for excretion as bile acids and unaltered cholesterol. The liver is the only organ that can excrete the cholesterol in these forms and in quantities necessary to maintain balance between excretion and the combined effects of dietary absorption and synthesis. It is believed that virtually all cells can synthesize sufficient cholesterol to meet the basic needs for normal function.
Okay, I’m confused. My LDL recently was 151, and my (Internal Med) doc wants to put me on a statin. I said no.
I spoke to a cardiologist the other day, asking about the difference between the fluffy and dense LDL sizes, and why a statin? Her response was that the statin helps repair the endothelium, thus preventing the particles from adhering to the arterial walls, regardless of whether they’re dense or fluffy.
Can you comment on this? I’m now concerned as to whether the statin might help, after all.
Also, she suggested I talk with an endocrinologist in regards to Metformin and increasing insulin sensitivity, which might have some success in helping Metabolic Syndrome pre-diabetics lose weight. Thoughts?
First, you’ve got to understand that randomized, placebo-controlled studies (the only kind that really count) have shown no benefit in terms of longevity for women taking statins. Period. End of story. It didn’t matter if the women were young or old or if they had already been diagnosed with heart disease or not, statins didn’t make them live longer.
Statins may or may not “repair endothelium,” but it doesn’t matter because the data show that the drugs don’t make women live longer, which is the real issue. I suspect that the idea that these drugs repair the endothelium is an ad hoc hypothesis to somehow counter the idea that the drugs don’t work in terms of increasing longevity.
There is some evidence that Metformin does increase insulin sensitivity and that, consequently, it can help with weight loss. Metformin is one of the very few drugs that I use in my practice, but I try dietary changes first.