If You’re Physically Active, Don’t Drink to That

We Want the Lumberjacks to be OK

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I am a drug dealer, legal drugs, but still drugs. I use statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors to decrease lower density lipoprotein cholesterol (LDL-C). I love drugs as previously confessed in a peer-reviewed publication. (1). I guess I shouldn’t be so proud because when I tried to find my publication on Google, I was listed with some other folks you might not want to “invite to dinner”.

So, why the drugs? Because fixing hyperlipidemia with diet is tough. It requires dozens of decisions per day of “to eat or not to eat”. And even minor dietary transgressions, such as ingesting small amounts of saturated fat, can sabotage the effort.

Here’s why a little cheating hurts. LDL-C levels are regulated by the LDL-C receptors on the liver cells, the “hepatocytes”. These receptors grab the LDL-C particle, transport it into the liver, release it and go back to the surface of the liver to pick up more LDL. If you have a lot of LDL receptors on your hepatocytes, you have low LDL levels. Your genetics have a lot to do with the number and activity of the LDL receptors. About 1 in 250 people inherit only one of the LDL receptor-producing genes so have “genetic” or “familial” hyperlipidemia. About 1 in 250,000 people inherit no LDL receptor genes and have really high cholesterol levels. These later folks are very difficult to treat with drugs because they make no LDL-C receptors.

Drugs used to treat high cholesterol levels trick the liver into making or keeping more LDL receptors. Statins block the production of cholesterol in the liver. This depletes the liver cells of cholesterol, so the hepatocytes say, “I need more cholesterol. I need to make more LDL receptors so I can get more cholesterol.” The cholesterol-lowering drug, ezetimibe, blocks cholesterol absorption in the gut. Since less cholesterol is absorbed, there is less cholesterol returning to the liver so the hepatocytes repeat the mantra, “I need more cholesterol. I need to make more LDL receptors”. Another type of cholesterol-lowering drug, the bile sequestrant resins, blocks the reabsorption of bile. The liver makes bile from cholesterol and secretes the bile into the gut. But the bile is not wasted. Bile is reabsorbed in the gut and returned to the liver. Bile sequestrant drugs, like colesevelam, bind the bile in the intestine so that it cannot be reabsorbed. The sequestrants carry the bile out the “poop chute”. (“Poop chute” is the preferred medical term – that’s an attempted joke.) So, less bile comes back to the liver, and the liver has to use its cholesterol stores. This depletes the liver of cholesterol so the liver repeats the mantra, “I need more cholesterol. I need to make more LDL receptors”.

You get the picture? It should also be clear why people who totally lack the genes to make LDL receptors are so hard to treat.. The drugs cannot trick the liver into making more receptors if the person does not have the genes to make the receptors.

The PCSK9 inhibitors work differently but also affect the LDL receptor. I tell students that the LDL receptor is “green” because it’s recycled. After the LDL receptor migrates into the liver and drops off its cholesterol, it’s recycled to the liver surface to do the deed again. But if the PCSK9 protein binds with the combined LDL receptor/particle on the surface of the liver, PCSK9 does not allow the receptor to release the LDL particle in the liver and come back to the liver surface. The receptor is destroyed in the liver, and LDL cholesterol levels rise. PCSK9 inhibitors bind with the PCSK9 molecule before the molecule can grab the LDL receptor/particle complex.

Diet, specifically saturated fat, also affects the LDL receptors. Saturated fat generally comes from the milk and meat of animals and some topical nuts like macadamia and palm nuts. Saturated fat is usually firm or hard at room temperature. Unfortunately, saturated fat, even a little, decreases LDL receptor activity. So if a patient avoids saturated fat most of the day, but makes a transgression and eats some hamburger, that transgression reduces LDL receptor activity and the day’s effort is lost. Not totally lost, but a lot is lost. So it is hard to get really low cholesterol levels by diet alone.

I agree that it’s ideal to lower your LDL by diet and to avoid drugs. But medicine is not a morality play, and your arteries don’t really care how you lower your LDL as long as you do it. You can lower your LDL a lot if you pick parents with better LDL receptor genes, but it’s a little late for that. You can become a vegan and eat no animal products. But if you cannot do the vegan route, you can follow the next best diet and become a vegetarian. If you cannot do that, you can become a pescatarian or, a vegetarian who eats anything from the sea except the cow that fell in. But all of this diet stuff is hard and requires lots of discipline. And a little transgression undermines a lot of the effect. Plus patients have other stuff to worry about, like paying my bill, so I use drugs.

But there is a diet/lifestyle change that clinicians often overlook that can make a big dent in the LDL-C level especially for patients who are very active at work or do a lot of vigorous physical activity. That change is to cut down on alcohol intake.

Most clinicians know that alcohol increases triglyceride levels. It does this because alcohol is converted in the liver to free fatty acids (FFAs) and FFAs are combined with glycerol to make triglycerides. Thus the origin of the name “triglyceride”. One glycerol and three FFA molecules make a “triglyceride”. The triglycerides are packaged inside the very low density lipoprotein (VLDL) particle and shipped out of the liver into the bloodstream. They are called VLDL because they contain a lot of triglyceride or fat so they float easily. The triglycerides are packaged this way because fat and water don’t mix. The VLDL particles are constructed so that fat can survive in the water world of your blood stream and not clog up the pipes. In the bloodstream the FFA's are removed from the VLDL particle by a key enzyme, lipoprotein lipase (LPL). Without the fat to help the VLDL particle float, it converts from “very low dense” to just “low dense” or LDL.

Here us the key issue. We demonstrated over 30 years ago, that active people, like endurance athletes, have increased LPL activity, and that exercise acutely increases LPL. I wrote an editorial entitled “What do muscle have to do with lipoproteins?”(3) because muscle doesn’t synthesize or directly catabolize lipoproteins so what’s the connection? The mechanism for the increase in LPL goes like this: Endurance exercise consumes fat for energy. This reduces intramuscular fat. The muscle then increases LPL to replace the fat, and in the process, converts VLDL into LDL.

Now, let’s be careful here. I have never seen a study proving that alcohol is especially effective at increasing LDL in active people. This is an observation from my clinical experience, and my 11 years of directing a National Institutes of Health (NIH) grant entitled, “Exercise in Active Men: The Role of Exercise and Diet” (NIH/R01-HL028467-08). But the theory makes sense because drugs that increase LPL activity, such as fenofibrate, also increase LDL levels, especially in people with high triglycerides.

So even though I fix lipid levels primarily by drugs, I do routinely recommend low saturated fat diets, but I also strongly recommend restricting alcohol intake, especially in very active people like endurance athletes and manual laborers like lumberjacks. Getting rid of the alcohol, gets rid of the increased VLDL production, which gets rid of the conversion of the VLDL to LDL cholesterol. If you’re an endurance athlete or a lumberjack, I want you to be “OK.” (By the way, if you haven’t seen the Monty Python skit, “I’m a lumberjack and I’m OK”, it’s worth a look.)

The Rules:

1. Use drugs to really lower LDL-C.

2. But give alcohol restriction a trial especially in physically active patients

References:

1. Thompson PD. Editorial commentary: Confessions of a drug dealer. Trends Cardiovasc Med. 2018 Nov;28(8):532-533. PMID: 30301517

2. Thompson PD. What do muscles have to do with lipoproteins? Circulation. 1990 Apr;81(4):1428-30. PMID: 2317921

.#cholesterol #alcohol #lipids #atherosclerosis #lumberjacks #heartdiseaseprevention