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Studies of human mutations have paved the way toward understanding elevated plasma cholesterol levels, both by exposing the mechanisms of lipid transport and by focusing hypotheses for further studies (1, 2). In this issue, Pullinger et al. (3) studied a kindred with hypercholesterolemia and identified a mutation in CYP7A1, which encodes cholesterol 7α-hydroxylase, the first and rate-limiting step in the classical bile acid synthetic pathway (4). As has been the case before, this new mutation has simultaneously shed light on mechanisms of lipid metabolism and raised a welter of issues for future investigation.  The study by Pullinger et al. (3) must have been supremely gratifying for the authors: They started with an imaginative hypothesis about hypercholesterolemia — one rooted in simple clinical findings — and, after some serious screening efforts, hit pay dirt. They hypothesized that CYP7A1 deficiency would reduce the conversion of cholesterol to bile acids, resulting in elevated liver cholesterol levels, downregulated LDL receptors, and hypercholesterolemia. They further hypothesized that the increased hepatic cholesterol levels would render these patients resistant to the hypocholesterolemic effect of statins and that CYP7A1 deficiency would cause premature gallstone disease, a result of reduced bile acid secretion rates. By screening appropriate patients from their lipid clinic, they identified two brothers, both with premature gallstone disease and statin-resistant hypercholesterolemia, who were homozygous for a frameshift mutation in CYP7A1 that abolished enzyme activity. A third homozygote also had hypercholesterolemia, and six heterozygotes had higher cholesterol levels than unaffected family members, leading the authors to conclude that CYP7A1 deficiency in humans causes hypercholesterolemia. This conclusion is consistent with population studies that have shown an association between plasma cholesterol levels and polymorphisms at the CYP7A1 locus (5, 6).  While the guiding hypothesis of Pullinger et al. (3) is attractive, we believe that a cautionary note should be sounded about the hyperlipidemic phenotype. Because the authors identified a hyperlipidemic kindred within a tertiary care lipid clinic, the possibility of ascertainment bias must be considered, particularly since their kindred was not particularly large and since the conclusions were based on a limited number of lipid measurements. More kindreds with CYP7A1 mutations will be needed if the phenotype is to be defined conclusively.  Assuming that the hypercholesterolemic phenotype is upheld by future studies, it will be crucial to explore mechanisms. Their hypothesis holds that CYP7A1-deficient subjects have elevated liver cholesterol levels leading to reduced LDL receptor activity and retarded removal of LDL from the bloodstream. This hypothesis must be tested. The VLDL and LDL turnover rates in CYP7A1-deficient subjects should be measured and compared with those in both normal controls and subjects with the heterozygous form of familial hypercholesterolemia.

Human CYP7A1 deficiency: progress and enigmas