Involvement of Angiotensin II in Intestinal Cholesterol Absorption

Niemann-Pick C1-like 1 (NPC1L1) protein is identified as a key molecule of cholesterol absorption into the intestine. Although there is a controversy about the association between sitosterol levels and cardiovascular disease (CVD), cholesterol absorption may contribute to the increased risk for CVD because increased levels of sitosterol, a marker of cholesterol absorption, are associated with future cardiovascular events in high-risk patients. However, which anthropometric and metabolic variables could regulate serum levels of sitosterol in humans and whether serum sitosterol levels might reflect transport function of NPC1L1 are largely unknown. In this study, we first investigated the independent determinants of serum sitosterol levels in apparently healthy patients not taking lipid-lowering agents. We next examined the effects of angiotensin II on NPC1L1 gene and protein expression in differentiated Caco-2 cells. Seventy apparently health patients not taking lipid-lowering agents (28 men and 42 women, mean age 73.7+/-10.1 years old) underwent a complete history and physical examination, determination of blood chemistries, including serum levels of sitosterol. Univariate regression analysis showed that serum levels of sitosterol were associated with low-density-lipoprotein (LDL)-cholesterol (r=0.284, p=0.021) and use of the renin-angiotensin system (RAS) inhibitors (r=-0.289, p=0.018). By the use of multiple stepwise regression analyses, use of RAS inhibitors (p=0.025) was remained significant independently. Further, angiotensin II was found to up-regulate NPC1L1 mRNA and protein levels in Caco-2 cells, which were completely blocked by an angiotensin II type 1 receptor blocker or an anti-oxidant, N-acetylcysteine. The present study suggests the possible involvement of RAS in NPC1L1 expression in vitro and cholesterol absorption in humans.