Cholesterol metabolism in gallstone disease .Preliminary evidence from the analysis of circulating markers of sterol homeostasis

Little is known on the molecular mechanisms underlying cholesterol cholelithiasis even if previous evidence has suggested that reduced production of bile acids might play a role. AIM of the present study was to analyze the hepatic expression of a number of genes involved in bile acid metabolism in human cholelithiasis. METHODS. Surgical liver biopsies were obtained in 11 patients with untreated cholesterol cholelithiasis and 9 gallstone-free subjects; mRNA levels of CYP7A1 and related nuclear receptors and coactivators were assayed by real-time quantitative RT-PCR. RESULTS. No differences were detected the expression of any of the genes studied, with the exception of PPAR-gamma coactivator 1 (PGC-1), a transcriptional coactivator of CYP7A1 involved in insulin sensitivity and energy balance, which was significantly (p < 0.01) less expressed in gallstone subjects. Expression of PGC-1 was linearly correlated with the bile acid receptor FXR in the population of gallstone patients (r = 0.87 on a log scale, p < 0.01). CONCLUSIONS. PGC-1 appears to play a role in the prevention of cholesterol gallstone disease in humans; the finding might suggest a link with insulin resistance conditions. This effect might take place via interaction with the bile acid receptor FXR, whose protective role in cholelithiasis has been suggested by recent evidence in animal models. PGC-1 and related genes might therefore represent molecular targets for the prevention and/or treatment of gallstone disease.