When we have a physical examination and find that our cholesterol level is elevated, doctors or nutritionists will tell us to "eat less meat, don't eat egg yolks, and don't eat animal offal." These familiar and simple phrases reflect a crude understanding, namely: hypercholesterolemia is caused by eating! So by not eating high-cholesterol foods, we can prevent or reduce hypercholesterolemia.
But the truth is not that simple, because the cholesterol circulating in our body also follows the 80/20 rule, that is, 80% of the circulating cholesterol is produced by the human body (to be precise, 80% in the liver and 15% in the small intestine), and only 20% of the circulating cholesterol comes from the diet [1].
Therefore, even Ancel Keys, an American biochemist and a pioneer in opposing saturated fat and cholesterol, had to say with emotion [2]: "In order to control serum cholesterol levels, dietary cholesterol should not be completely ignored, but focusing solely on this factor will have little effect."
"Little effect" is a more appropriate statement, because according to the serum cholesterol response prediction equation developed by Professor Ancel Keys, when dietary cholesterol is reduced from 250 mg of cholesterol per 1000 calories to 0 g of cholesterol (that is, there is no cholesterol in the diet), the serum cholesterol level is expected to decrease by only 24 mg/dL, while the normal total blood cholesterol level is 200 mg/dL; when dietary cholesterol is reduced by 50%, the serum cholesterol level is expected to decrease by only 7 mg/dL [2]. Therefore, controlling dietary cholesterol alone can indeed be said to have "little effect."
The reality in the real world is even more complicated, because people at high risk of hypercholesterolemia, such as those with metabolic dysfunction-associated fatty liver disease (MAFLD), insulin resistance, obesity, and metabolic syndrome, all show the phenomenon of "low cholesterol absorption rate" [3] [4]. In other words, the dietary cholesterol absorption rate of these high-risk people is lower than that of ordinary people. However, their endogenous cholesterol is much higher than that of ordinary people under the stimulation of liver selective insulin resistance, which is the main reason for their hypercholesterolemia. Therefore, restricting dietary cholesterol intake in these people will not only fail to lower blood cholesterol levels, but may increase blood cholesterol.
Because in cholesterol homeostasis, the less dietary cholesterol intake, the more endogenous cholesterol is synthesized. Conversely, the more dietary cholesterol intake, the less endogenous cholesterol is synthesized. For example, in early experiments with humans and baboons, when 800-1000 mg of dietary cholesterol was consumed per day, liver cholesterol biosynthesis was completely inhibited [5]. A more extreme example is an 88-year-old man who compulsively eats 20-30 eggs a day, equivalent to consuming 3600-5400 mg of cholesterol per day. However, for many years, his cholesterol level has been ≤200 mg/dL[6], which is a completely normal serum cholesterol level. Studies have shown that this elderly man only absorbs a small part of the dietary cholesterol he consumes, about 18%. In addition, compared with the control group, his average rate of bile acid synthesis is twice that of the control group, indicating that more cholesterol is metabolized.
For more information on cholesterol homeostasis, please see: Why is my cholesterol rising? 13,000 words detailed explanation of the whole process of cholesterol increase.
Therefore, in the vast majority of humans with normal cholesterol homeostasis mechanisms, dietary cholesterol intake is insufficient to have a significant effect on serum cholesterol, because the body will balance the increase in cholesterol intake by reducing cholesterol absorption and/or endogenous cholesterol synthesis[7]. In humans with imbalanced cholesterol homeostasis mechanisms, endogenous cholesterol synthesis does not decrease with increased dietary cholesterol intake, but may increase with decreased dietary cholesterol intake.
However, people who have already developed ASVCD (atherosclerotic cardiovascular disease) are different. This group of people is characterized by increased endogenous cholesterol synthesis [9] [10], and increased dietary cholesterol absorption, especially when receiving statin treatment [8]. However, in contrast, the metabolism of cholesterol into bile acid in this group of people is reduced, and the amount of cholesterol and bile acid excreted through feces is much lower than that of ordinary people (on average one-third lower) [11-13]. It is as if there is a cholesterol black hole in their body that is greedily absorbing cholesterol. This cholesterol black hole is composed of chemically modified LDL and inflammatory cells (mainly macrophages).
Therefore, people who have already developed ASVCD should pay attention to controlling dietary cholesterol, but simply controlling dietary cholesterol is far from enough; because compared with dietary cholesterol, dietary carbohydrates and saturated fatty acids have a greater impact, but the two have different effects. Dietary carbohydrates will promote the increase of small and dense LDL and triglyceride levels, while reducing HDL cholesterol [14-15]; the result is to promote the development of atherosclerosis.
Saturated fat promotes the increase of large and fluffy LDL and HDL cholesterol levels [16]. The increase of HDL cholesterol levels helps the reverse cholesterol transport of ASCVD patients, thereby alleviating symptoms, which is beneficial to ASCVD patients. Although large and fluffy LDL can also be absorbed by atherosclerotic lesions, it has more unique advantages than small and medium-sized LDL:
1. Due to its larger size and stronger buoyancy, it is less likely to pass through the arterial endothelium and less likely to deposit in atherosclerotic lesions [17]. This is easy to understand, right?
2. Large and fluffy LDL has more space to carry other substances, such as antioxidants. Therefore, it has stronger antioxidant capacity, is less likely to be oxidized by lesions, and has stronger self-protection ability [18]. Oxidative modification leading to LDL denaturation is a prerequisite for LDL to cause atherosclerotic plaques. In other words, large and fluffy LDL is less likely to promote the development of atherosclerosis because of its stronger antioxidant modification ability.
3. Large and fluffy LDL particles have a higher affinity for LDL receptors [19]. This is very important because it means two things: A. Large and fluffy LDL particles are more easily recycled and removed by the liver, thereby reducing the total amount of LDL in the blood circulation. B. Large and fluffy LDL particles are more easily captured by other cells that need cholesterol to perform physiological functions. Remember what we said earlier about the increase in endogenous cholesterol synthesis in ASCVD patients? One reason is that most of the LDL particles in their blood circulation are small and dense particles, which makes it impossible for the liver and other cells that need cholesterol to capture them, thus creating the illusion of lack of cholesterol. If the LDL particles in their blood circulation are mainly large and fluffy, the cells that need cholesterol to perform physiological functions are supplied with cholesterol, then their endogenous cholesterol synthesis will be reduced. This is also easy to understand, right?
In summary, the effect of dietary saturated fat on cholesterol in the body is at least neutral.
Finally, what determines the size of LDL? The answer is that it is determined by the levels of triglycerides and glucose (blood sugar) in the blood [20]. The higher the levels of triglycerides and blood sugar in the blood, the smaller the volume of LDL. This is because the LDL in the blood circulation is actually a downgraded version of VLDL after unloading triglycerides (see Why is my cholesterol rising? 13,000 words to explain the whole process of cholesterol increase). Therefore, when the liver synthesizes VLDL, the more triglycerides it puts into it, the less other substances it has. As a result, when VLDL unloads triglycerides and turns into LDL, its volume will inevitably become smaller, becoming small and dense LDL instead of large and fluffy LDL. This small and dense LDL will be chemically modified by the body environment and denatured, promoting the development of atherosclerosis.
So what determines the levels of triglycerides and blood sugar in the blood? The answer is dietary carbohydrates (starch, glucose, and especially fructose) [25], and ethanol (if you drink alcohol frequently). Studies have shown [21] that during periods of excessive carbohydrate intake, plasma triglycerides increase 10-fold, while VLDL increases from 20% to 70%, an increase of 3.5 times. These newly synthesized triglycerides are synthesized in the liver through acetyl coenzyme A converted from carbohydrates. Therefore, the more carbohydrates you eat, the more triglycerides you synthesize, the higher your blood sugar, and the higher the number of small, dense LDL.
This is why many studies believe that carbohydrates (especially refined carbohydrates) are the culprit for promoting atherosclerosis [14-15], and reducing carbohydrates (rather than saturated fat) is more effective in reducing small, dense LDL, improving blood lipid status and atherosclerosis [22], especially in female patients with cardiovascular disease.
A large prospective study by the University Medical Center Utrecht in the Netherlands [23] showed that the risk of cardiovascular disease in the highest quartile of dietary glycemic load (representing total carbohydrate intake) was 47% higher than that in the lowest quartile. Similar results were observed for dietary glycemic index (representing the absorption rate of carbohydrates), with a 33% higher risk of cardiovascular disease. The study concluded that in women who consume a moderate glycemic load diet, high dietary glycemic load and glycemic index increase the risk of cardiovascular disease, especially for overweight women.
The American Nurses' Health Study [24] is the largest female cardiovascular health study to date. Based on their 10-year follow-up of 75,521 women aged 38-63, the results showed that dietary glycemic load (representing total carbohydrate intake) is directly related to the risk of coronary heart disease, and the risk of coronary heart disease is 98% higher in the highest quintile of glycemic load than in the lowest quintile. They emphasized that classifying carbohydrates by glycemic index, rather than traditional simple or complex classification, can better predict the risk of coronary heart disease. This means that the higher the glycemic index (representing the absorption rate of carbohydrates), the more harmful the carbohydrates are to coronary heart disease. This is especially true for women who are above average in weight (i.e. BMI ≥ 23).
So the fatter a person is and the more carbohydrates they eat, the higher their risk of cardiovascular disease.
Therefore, if a person has high cholesterol and is also suffering from arterial stenosis or even diagnosed with coronary heart disease, please remember to reduce dietary carbohydrates. No matter how kindly others advise you to eat two more bowls of rice, you should ignore it!
On the contrary, dietary cholesterol may not be that important. Why? The Minnesota Coronary Artery Survey is the largest closed study to date, involving 4,393 men and 4,664 women. The study was conducted in six psychiatric hospitals and a nursing home in Minnesota. The diet was completely controlled by the researchers. They designed two diets, one high-cholesterol diet (39% fat control diet (18% saturated fat, 5% polyunsaturated fat, 16% monounsaturated fat, 446 mg dietary cholesterol per day)), and the other low-cholesterol diet (38% fat treatment diet (9% saturated fat, 15% polyunsaturated fat, 14% monounsaturated fat, 166 mg dietary cholesterol per day)). The longest-term 1,568 subjects adopted these two diets for an average of 384 days, with a total time of more than 2 years.
At the beginning of the study, the average serum cholesterol level was 207 mg/dl. After the study, the treatment group (low cholesterol group) dropped to 175 mg/dl, and the control group (high cholesterol group) dropped to 203 mg/dl. However, for the entire study population, no difference was observed between the treatment group (low cholesterol group) and the control group (high cholesterol group) in terms of cardiovascular events, cardiovascular death, or total mortality.
As early as 1965, Ancel Keys lamented that "in order to control serum levels, dietary cholesterol should not be completely ignored, but focusing solely on this factor will have little effect [2]". However, due to various factors (mostly interest factors), it was not until 2015 that the US Department of Agriculture issued the US Dietary Guidelines to remove the restrictions on dietary cholesterol [26]. Prior to this, for decades, their dietary cholesterol restrictions had been below 300 mg/day. The reason they lifted the dietary cholesterol restrictions was that "there is no obvious relationship between dietary cholesterol intake and serum cholesterol". Isn't this an obvious fact since ancient times?
Reference
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