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Why high-protein diets may lead to atherosclerosis

Fat, carbohydrate and protein are three macronutrients that give us the energy we need to live, macros being a very convenient way to define the major thrust of the diet wars of the past 40 years, but too much of a good thing is not always ideal.

F Perry Wilson in Medscape, Wilson writes:

From the late 1980s low-fat craze (“fat makes you fat”) to the 1990s and 2000s shift away from carbohydrates in general and sugar in particular, we arrive now to what seems like a fascination with protein.

High-protein diets like the paleo and Zone diets are gaining in popularity. And though the increasingly popular keto diet is really anti-carb more than pro-protein, any diet that limits one macro will inherently increase the concentrations of the others.

It makes some sense that high-protein diets would be good for you. Good things inside your body (such as muscles) are made of protein – but the data don’t necessarily support the contention that high-protein is really very healthy.

Animal studies show fairly consistently that higher protein diets are associated with more atherosclerosis. And some, but by no means all, epidemiologic studies in humans also show a link between protein intake and heart disease.

So are we in trouble? Is there no good macronutrient?

A recent paper suggests that some of the observed problems with protein might boil down to just one amino acid: leucine.

The study was published in Nature Metabolism: Identification of a leucine-mediated threshold effect governing macrophage mTOR signalling and cardiovascular risk, led by Xiangyu Zhang and colleagues at the University of Pittsburgh.

To understand the study, you have to understand their central hypothesis. The ingestion of protein leads to an increase in amino acid in the blood, and somehow one or more of those amino acids stimulate monocytes – inflammatory cells – to activate.

The inflammation causes atherosclerosis and, eventually cardiovascular disease. Let’s walk through how they test this paradigm out.

The centrepiece of the paper is two highly controlled, although very brief, human studies. After a 12-hour fast, 14 people drank either a low-protein shake or a high-protein shake.

Later on, they did the opposite, so they served as their own controls. The shakes were matched in calories, and after the individuals drank it, their blood was sampled over the next few hours.

A parallel experiment had a similar design, except here the individuals ate a solid meal with differing protein content more in the normal ranges of human diets: 15% vs 22% protein intake.

Did ingesting protein increase the amount of amino acids in the blood? Well, of course it did. Compared with lower protein meals, higher-protein meals lead to more amino acids. I guess this proves at least that digestion works.

Much more interesting is the investigators’ analysis of monocyte activation. They have several biochemical readouts but all of the results are similar – roughly 20% higher activation in the high-protein state. Similar but less extreme results were seen in their solid food study.

This is good proof of concept and supports the central hypothesis. Now the researchers had to find which amino acid or acids could be the culprit. They reasoned that whatever the culprit amino acid is, it must be elevated relative to controls in both experiments, which narrowed it down to seven.

The usual suspects rounded up, they exposed monocytes in cell culture to them. Now, the dose here is clearly supraphysiologic. These monocytes are positively being flooded with amino acids, but the experiment was successful in showing which ones stimulated them most. Top of the list? Leucine.

Leucine is one of three branched-chain amino acids and is an essential amino acid. We have no biologic pathways to create it; we can only take it in from the protein we eat. And lots of foods we eat contain leucine (Swiss cheese, pork, beef peanuts, raw green peas).

I mean, any food that is high in protein is going to be somewhat high in leucine but, in general, animal proteins are higher in leucine than are plant-based proteins.

Crazy doses of leucine stimulate monocytes, but what about normal doses? The researchers exposed monocytes to the same concentration of leucine observed in the blood of participants in the feeding studies – so, a reasonable range of concentrations.

The findings, and I’m not even touching the mouse studies, which had similar findings, taken together, paint an intriguing explanation for what I might call the “protein paradox”: if high-fat, high-carb and high-protein diets are bad, are we supposed to just not eat?

Of course, maybe the answer is that a balanced diet is optimal. But all this talk about macros ignores the fact that these studies controlled total calorie intake completely; they matched calories and varied the proportion of calories from each macro.

That might not be how the real world works. If a certain diet is high in protein, but it leads you to consume fewer calories than you otherwise would have, then the benefit of taking in fewer calories may easily outweigh any hypothetical harm from the extra leucine.

But if you’re still worried about protein, remember that leucine lives predominantly in animal proteins. That means if you want to continue to favour protein as your macro of interest, the best place to get it may be from plant sources.

Study details

Identification of a leucine-mediated threshold effect governing macrophage mTOR signalling and cardiovascular risk

Xiangyu Zhang, Divya Kapoor, Babak Razani, et al.

Published in Nature Metabolism on 19 February 2024


High protein intake is common in western societies and is often promoted as part of a healthy lifestyle; however, amino-acid-mediated mammalian target of rapamycin (mTOR) signalling in macrophages has been implicated in the pathogenesis of ischaemic cardiovascular disease. In a series of clinical studies on male and female participants (NCT03946774 and NCT03994367) that involved graded amounts of protein ingestion together with detailed plasma amino acid analysis and human monocyte/macrophage experiments, we identify leucine as the key activator of mTOR signalling in macrophages. We describe a threshold effect of high protein intake and circulating leucine on monocytes/macrophages wherein only protein in excess of ∼25 g per meal induces mTOR activation and functional effects. By designing specific diets modified in protein and leucine content representative of the intake in the general population, we confirm this threshold effect in mouse models and find ingestion of protein in excess of ∼22% of dietary energy requirements drives atherosclerosis in male mice. These data demonstrate a mechanistic basis for the adverse impact of excessive dietary protein on cardiovascular risk.

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and public health and director of Yale's Clinical and Translational Research Accelerator.


Nature Metabolism article – Identification of a leucine-mediated threshold effect governing macrophage mTOR signalling and cardiovascular risk (Open access)


Medscape article – Why High-Protein Diets May Lead to Atherosclerosis (Open access)


See more from MedicalBrief archives:


Long-term kidney damage a risk for those on high protein diets


Atherosclerosis in more than 40% of Swedish adults with no known heart disease – SCAPIS


Most popular diets deliver weight loss and lower BP, but benefits last only a year


Boosting protein intake may be key to healthier eating, weight loss – US study


Lower protein diet may lessen risk for cardiovascular disease






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