To conclude, the last several years have seen a resurgence of interest in the biosynthesis of bile acids This focus has come about due to the central roles that these molecules play in cholesterol and fat metabolism and due to recent advances in their chemistry, biochemistry, and molecular biology The application of probes generated by these methodologies has begun to generate novel insight into bile acid metabolism, regulation, and genetics The next several years should be equally exciting

Bile acid biosynthesis

The intracellular nuclear receptor farnesoid X receptor and the transmembrane G protein-coupled receptor TGR5 respond to bile acids by activating transcriptional networks and/or signalling cascades. These cascades affect the expression of a great number of target genes relevant for bile acid, cholesterol, lipid and carbohydrate metabolism, as well as genes involved in inflammation, fibrosis and carcinogenesis. Pregnane X receptor, vitamin D receptor and constitutive androstane receptor are additional nuclear receptors that respond to bile acids, albeit to a more restricted set of species of bile acids. Recognition of dedicated bile acid receptors prompted the development of semi-synthetic bile acid analogues and nonsteroidal compounds that target these receptors. These agents hold promise to become a new class of drugs for the treatment of chronic liver disease, hepatocellular cancer and extrahepatic inflammatory and metabolic diseases. This Review discusses the relevant bile acid receptors, the new drugs that target bile acid signalling and their possible applications.

Bile acid receptors as targets for drug development

Mutations in the bile acid biosynthetic enzyme sterol 27-hydroxylase underlie cerebrotendinous xanthomatosis.

Conditions Associated with Pigment Stones The demographic characteristics of persons at high risk for pigment gallstones differ from those in whom cholesterol stones are likely to develop, as noted

Risk factors for the development of cholelithiasis in man (first of two parts).

To assess the risk factors for symptomatic gallstones, 88,837 women in the Nurses' Health Study cohort (age range, 34 to 59 years) were followed for four years after completing a detailed questionnaire about food and alcohol intake in 1980. A total of 433 cholecystectomies and 179 cases of newly symptomatic, unremoved gallstones, diagnosed by ultrasonographic examination or x-ray films, were reported during the four-year follow-up. The age-adjusted relative risk for very obese women, who had a Quetelet index of relative weight (weight in kilograms divided by the square of the height in meters) of more than 32 kg per square meter, was 6.0 (95 percent confidence interval, 4.0 to 9.0), as compared with women whose relative weight was less than 20 kg per square meter. For slightly overweight women (relative weight, 24 to 24.9 kg per square meter), the relative risk was 1.7 (95 percent confidence interval, 1.1 to 2.7). Overall, we observed a roughly linear relation between relative weight and the risk of gallstones. Among the 59,306 women whose relative weight was less than 25 kg per square meter, a high energy intake (greater than 8200 J per day), as compared with a low energy intake (less than 4730 J per day), was associated with an increased incidence of symptomatic gallstones (relative risk, 2.1; 95 percent confidence interval, 1.4 to 3.3), and an alcohol intake of at least 5 g per day was associated with a decreased incidence as compared with abstention (relative risk, 0.6; 95 percent confidence interval, 0.4 to 0.8). Parity did not appear to be an important risk factor after an adjustment was made for relative weight. These data support a strong association between obesity and symptomatic gallstones and suggest that even moderate overweight may increase the risk.

G. Nicolau

Papers

Hepatic cholesterol metabolism in patients with gallstones.

Chenodeoxycholic acid inhibits increased cholesterol and cholestanol synthesis in patients with cerebrotendinous Xanthomatosis