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Human CYP7A1 deficiency: progress and enigmas
Anne Beigneux,1 Alan F. Hofmann,2 and Stephen G. Young1
1Gladstone Institute of Cardiovascular Disease, Cardiovascular Research Institute, and Department of Medicine, University of California, San Francisco, San Francisco, California, USA2 Department of Medicine, University of California, San Diego, La Jolla, California, USA
Address correspondence to: Stephen G. Young, Gladstone Institute of Cardiovascular Disease, 365 Vermont Street, San Francisco, California 94103, USA. Phone: (415) 826-7500; Fax: (415) 285-5632; E-mail: syoung@gladstone.ucsf.edu.
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1Gladstone Institute of Cardiovascular Disease, Cardiovascular Research Institute, and Department of Medicine, University of California, San Francisco, San Francisco, California, USA2 Department of Medicine, University of California, San Diego, La Jolla, California, USA
Address correspondence to: Stephen G. Young, Gladstone Institute of Cardiovascular Disease, 365 Vermont Street, San Francisco, California 94103, USA. Phone: (415) 826-7500; Fax: (415) 285-5632; E-mail: syoung@gladstone.ucsf.edu.
Find articles by Hofmann, A. in: JCI | PubMed | Google Scholar
1Gladstone Institute of Cardiovascular Disease, Cardiovascular Research Institute, and Department of Medicine, University of California, San Francisco, San Francisco, California, USA2 Department of Medicine, University of California, San Diego, La Jolla, California, USA
Address correspondence to: Stephen G. Young, Gladstone Institute of Cardiovascular Disease, 365 Vermont Street, San Francisco, California 94103, USA. Phone: (415) 826-7500; Fax: (415) 285-5632; E-mail: syoung@gladstone.ucsf.edu.
Find articles by Young, S. in: JCI | PubMed | Google Scholar
Published July 1, 2002 - More info
J Clin Invest. 2002;110(1):29–31. https://doi.org/10.1172/JCI16076.
© 2002 The American Society for Clinical Investigation
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.
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Qualitative and quantitative effects on bile acids
Pullinger et al. (3) report a 94% reduction in bile acids excretion in one of their homozygotes. In a healthy person, cholic acid synthesis exceeds synthesis of chenodeoxycholic acid by a factor of two. In their patient, fecal bile acid analysis showed that the major bile acid formed was chenodeoxycholic acid. The fact that CYP7A1 deficiency did not abolish bile acid formation is not surprising, since there are several pathways, differing in their initial steps, for conversion of cholesterol into bile acids (Figure 1) (12, 13). The classical neutral pathway involves CYP7A1, which directly converts cholesterol into 7α-hydroxycholesterol (Figure 1a). In the alternate acidic pathway, cholesterol is first converted by sterol hydroxylases into oxysterols, the major one being 27-hydroxycholesterol. These oxysterols then undergo 7α-hydroxylation by an oxysterol 7α-hydroxylase, either CYP7B1 or CYP39A1 (Figure 1b). Subsequent enzymatic steps lead to the preferential conversion of 7α-hydroxycholesterol into cholic acid and the preferential conversion of 7α-hydroxy-oxysterols into chenodeoxycholic acid.
Figure 1(a) The classical pathway for bile acid synthesis begins with CYP7A1, which converts cholesterol into 7α-hydroxycholesterol. This pathway mainly produces cholic acid in humans. (b) Alternate pathways for bile acid synthesis. Cholesterol is first converted into oxysterols by one of three different enzymes: sterol 27-hydroxylase (CYP27), expressed in multiple tissues including liver; cholesterol 25-hydroxylase, present at low levels in multiple tissues including heart, lung, and kidney; and cholesterol 24-hydroxylase (CYP46), expressed predominantly in the brain. Oxysterols are transported through the bloodstream to the liver, where they are 7α-hydroxylated by oxysterol 7α-hydroxylase (CYP7B1) in the case of 25- and 27-hydroxycholesterol and by CYP39A1 in the case of 24-hydroxycholesterol. Alternate pathways preferentially produce chenodeoxycholic acid in humans.
The shift in primary bile acid synthesis toward chenodeoxycholic acid is entirely consistent with decreased CYP7A1 activity and compensation by the acidic pathway. Of note, a low bile acid synthetic rate and preferential formation of chenodeoxycholic acid were observed previously in two hypercholesterolemic patients whose bile acid synthesis profile was characterized by Einarsson et al. (14) a quarter century ago. We wonder whether those patients might have had CYP7A1 mutations.
The 94% reduction in fecal bile acid excretion (equivalent at steady state to hepatic bile acid synthesis) was observed in a single 24-hour stool collection in a single subject. A longer stool collection would seem essential for quantifying accurately the decreased rate of bile acid synthesis. Future studies should be directed at clarifying this issue as well as determining the rate of bile acid secretion, which can be measured by duodenal intubation and isotopic tracer studies. Better characterization of bile acid biosynthesis in human CYP7A1-deficient patients is particularly important given a distinct lack of evidence for cholesterol or vitamin malabsorption in those individuals. Given that adequate intraluminal concentrations of bile acids are essential for the absorption of cholesterol and fat-soluble vitamins, it seems possible that increased intestinal reclamation of bile acids in CYP7A1-deficient patients may have compensated for their decrease in bile acid biosynthesis. In the guinea pig, low concentrations of bile acids within the lumen of the intestine upregulate the ileal bile acid transport system (15).
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