Abstract 621: Reduced Dietary Cholesterol Availability in Infancy Programs Cholesterol Absorption in Adult Mice

Abstract

Epidemiological research showed that feeding breast milk, which is rich in cholesterol, translates into reduced cardiovascular risk in adulthood compared to feeding formula, which is cholesterol free. The mechanisms underlying these observations are unclear. Therefore, the present study aimed to investigate the impact of reduced dietary cholesterol availability during the suckling period on cholesterol metabolism in adult life in mice. To achieve reduced dietary cholesterol exposure from breast milk LDLR knockout offspring were given the cholesterol absorption inhibitor ezetimibe for 3 weeks during the suckling period. Ezetimibe was added to the food of nursing dams and reached the offspring’s intestine via excretion into breast milk. Low cholesterol exposure (LC) mice were compared to normal cholesterol (NC) controls with respect to all relevant parameters of cholesterol metabolism including biliary and fecal cholesterol excretion, intestinal absorption and endogenous synthesis using stable isotope kinetics. At 24 weeks intestinal cholesterol absorption was decreased in LC mice (-30%, p<0.001) due to decreased Npc1l1 expression, the main intestinal cholesterol uptake transporter (-50%, p<0.05). Methylation analysis of the NPC1L1 promoter revealed substantial differences between jejunum and colon (p<0.001), but not between LC and NC. Plasma cholesterol levels were not different between NC and LC due to increased endogenous synthesis in the LC group (p<0.05). Food intake, biliary and fecal cholesterol excretion did not differ between groups. In summary, our results demonstrate that early life reduction of dietary cholesterol exposure programs the murine intestine in adulthood towards decreased cholesterol absorption via reduced Npc1l1 expression. These results support a key role of the intestine as sensor and integrator of cholesterol metabolism with high relevance for cardio-metabolic disease.