These studies led us to postulate that the saturation of the micellar compartment with endogenous cholesterol reduces the capacity of dietary cholesterol to move from the oil to the micellar compartment within the intestinal lumen. Moreover, these studies suggest that cholesterol excretion may have an important role in the regulation of dietary cholesterol absorption and emphasize the need of studies that will clarify the regulation, at the molecular levels, of cholesterol excretion into the bile. We are currently addressing this regulation by studying the differential effect of dietary cholesterol on liver and intestinal gene expression at the transcriptional and protein levels. To identify novel genes whose expression is regulated by dietary cholesterol, we use cDNA microarrays to simultaneously assay over 9000 genes. Some of these genes are known to be cholesterol-regulated, but others are novel and subject to active investigation.
Similar approaches are underway to study gene expression in the intestine.
We also performed careful dietary studies using the facilities of the Rockefeller Hospital GCRC and examined the relationships between dietary cholesterol absorption and plasma lipoproteins responsiveness. In these studies we found that on a fixed diet there is a marked interindividual variability in cholesterol absorption rates. However, unlike our findings in the mouse, individual subjects differed markedly in their response to dietary cholesterol with some individuals suppressed, some maintained and others even increased the percentage of dietary cholesterol absorption. These results suggest that genetic factors may account for the interindividual large variability in dietary cholesterol absorption and plasma LDL levels and that variability in the regulation of cholesterol responsive genes may account for the variability in cholesterol absorption and plasma LDL cholesterol responsiveness to dietary cholesterol. To get insight into the nature of these genes we are studying the effect of cholesterol feeding on plasma cholesterol response in humans sib-pairs and in different inbred strains of mice.