**4.1 Relation of plasma LDL cholesterol and dietary intake of cholesterol**

Plasma LDL cholesterol value changes depending on oral intake of cholesterol. One meta-analysis of 17 studies reported that a 100 mg increment in dietary cholesterol from eggs elevated plasma total cholesterol by 2.2 mg/dl [124]. On the contrary, many studies have brought into question the apparent association between dietary cholesterol consumption and blood cholesterol [38]. Plasma cholesterol undergoes a highly degree of regulation to balance absorption in the intestine and synthesis in the liver [125]. Low dietary cholesterol intake is compensated for by an increase in absorption. These mechanisms explain the inter-individual variability in absorption (20–80%) in humans. Thus, there are responders and nonresponders to intake of cholesterol in terms of plasma cholesterol levels. Interestingly, repeated cholesterol loading has changed some nonresponders to responders [126, 127]. The presence of two types of cholesterol response may reflect just day-to-day variation of cholesterol absorption from the gut in a single person rather than a true difference between responders and nonresponders. In responders, both LDL and HDL cholesterol increased with no change in ratio of LDL to HDL. A gene of ABCG5/8 regulates absorption of dietary cholesterol and sterol from gut [128]. People carrying polymorphisms of ABCG5/8 have a higher absorption rate of cholesterol. In these subjects, the effects of manipulation of intake of cholesterol in food on plasma LDL cholesterol levels have been very significant.

The possible link between dietary cholesterol and CHD risk is potentially distorted by confounding factors from other features in the diet, especially SFA [129]. A previous recommendation of less than 300 mg of dietary cholesterol has been removed from the 2013 AHA/ACC Guideline on Lifestyle Management to Reduce Cardiovascular Risk [38], stating that there is insufficient evidence to determine whether lowering dietary cholesterol reduces LDL-C. The same action was taken in the 2015 Dietary Guidelines of USDA [40] and the 2015 Japanese dietary intake standards by Ministry of Health, Labor and Welfare [33]. By contrast, other guidelines still restrict the dietary cholesterol intake, for instance, 200 mg/day in JAS [35] and AACE [130] guidelines, or 300 mg/day in ESC/EAS [39], ADA [36], and JDS [34] guidelines. These guidelines engender the risk of potentially increasing intake of SFA by abandoning the recommendation for dietary cholesterol intake. However, all of these, in common, stress risk evaluation of atherothrombotic diseases and execution of comprehensive management to reduce the risk. Even the guideline from JAS, which limits dietary cholesterol intake at 200 mg/day, states very clearly that only restricting dietary cholesterol intake is hardly efficacious in reducing plasma LDL cholesterol, and rather more attention should be paid to reducing SFA in food.
