Dietary Cholesterol Feeding Suppresses Human Cholesterol Synthesis Measured by Deuterium Incorporation and Urinary Mevalonic Acid Levels

Abstract

The objective of this study was to measure the response of cholesterol biosynthesis in subjects to three different amounts of dietary cholesterol: 50 (low), 350 (medium), and 650 (high) mg cholesterol per 2800 kcal. Individuals with low (n = 7), normal (n = 12), and elevated (n = 11) plasma cholesterol concentrations consumed in random order solid-food test diets (15%, 55%, and 30% of energy as protein, carbohydrate, and fat, respectively) at each dietary cholesterol level. The three diets were consumed for 4 weeks each, and each dietary phase was separated by a 4-week washout period. During the final week of each diet, 0.7 g D2O was given per kilogram of body water and deuterium incorporation into the erythrocyte cholesterol pool was measured for 24 hours. Urinary mevalonate levels were also determined in samples obtained during two consecutive 24-hour periods. Both techniques provided measurements of whole-body cholesterol biosynthesis. In all subjects the cholesterol synthesis rate as measured by deuterium incorporation was significantly lower (P < .05) after the transition from low- to medium- and low- to high-cholesterol diets. Urinary mevalonate excretion decreased after the change from the medium- to high- (P < .05) and low- to high- (P < .01) cholesterol diets. Although correspondence between the two methods was poor, they both indicated some suppression of cholesterol synthesis by dietary cholesterol. The response of cholesterogenesis to different amounts of dietary cholesterol was related to the rate of synthesis under depressed conditions of the low-cholesterol diet. These findings indicate modest downregulation of synthesis in response to dietary cholesterol in humans, independent of plasma cholesterol levels.

Feedback inhibition of the cholesterol biosynthetic pathway in patients with Smith-Lemli-Opitz syndrome as demonstrated by urinary mevalonate excretion

“…Dietary cholesterol has been shown to regulate HMGCoA reductase activity by feedback inhibition (43)(44). Egg yolk supplemented high cholesterol diets not only increased plasma cholesterol levels but also decreased urinary mevalonate excretion in our experiments.…”

Low-density lipoprotein profile changes during the neonatal period

“…A possible mechanism was reported that early cholesterol exposure suppressed endogenous cholesterol synthesis even in later life. 25 The present study suggested that infants with younger gestational age did not have enough cholesterol exposure in neonatal period, when they were given formula milk. Additional longitudinal studies are necessary to determine whether the effect of gestational age on LDL profile persists into adulthood or changes with age, as observed in TC concentrations in breast-fed adults.…”

Effect of ursodeoxycholic acid on cholesterol absorption and metabolism in humans

“…Although we did not directly measure hepatic LDL receptor and HMGCoA reductase mRNA levels, previous studies have demonstrated an excellent correlation between the hepatic and monocyte values (51). Since one would anticipate that there would be a reciprocal relationship between FSR/HMG-CoA reductase mRNA levels and cholesterol absorption (52)(53)(54), it is reassuring to see that without changes in absorption, these other measurements did not change, thereby serving as an internal validation for each other. Interestingly, the absence of change in plasma cholesterol concentration might not be unexpected in normolipemic subjects, because the greatest UDCA-dependent reductions in plasma cholesterol concentrations occurred in patients with the highest plasma cholesterol concentrations (55,56).…”