• Potential conflict of interest: Nothing to report.

We thank Dr. Bertolotti and colleagues for their interest in our recent article showing increased synthesis of bile acids (BA) and concentration of triglycerides and activity of microsomal transfer protein (MTTP) in the liver of gallstone patients.1 We agree that gallstone disease, as a multifactorial condition, could be induced by different pathophysiological mechanisms. Therefore, a number of different metabolic abnormalities could be associated to the pathogenic process.2 Our study does not prove but does support the hypothesis that hepatic very-low-density lipoprotein (VLDL) production is increased in gallstone disease. The finding of increased synthesis of BA in our gallstone patients confirm the results previously found in Swedish gallstone patients3 and in our population-based survey among Chilean Hispanics and Mapuche Indians with and without gallstones.4 These observations allowed us to speculate that some gallstone patients from both European and Amerindian origin could have a primary defect in the intestine, with impaired BA absorption and increased fecal loss BA, consistent with a decreased BA pool found in gallstone patients.2 Thus, an important driving force stimulating BA synthesis and hepatic VLDL production in cholesterol cholelithiasis should simply be a reduced level of BA in the enterohepatic circulation as a primary pathophysiological mechanism. As suggested by Bertolotti et al., an important issue therefore would be to assess whether our gallstone patients present a primary defect in the intestine characterized by impaired absorption and increased fecal loss of BA, as found among North American Indians5 and Argentineans.6 This would help to definitively establish a relationship linking intestinal BA uptake, hepatic VLDL production, and gallstone disease.

Hepatic nuclear receptors function as lipid sensors that activate metabolic pathways intended to maintain homeostatic balance by controlling the expression of key genes involved in lipid production, transport, and elimination.7 Farnesoid X receptor (FXR), the BA nuclear receptor, is a natural candidate to be involved as a molecular linker between BA and VLDL production. Interestingly, Hirokane et al.8 showed that in HepG2 cells chenodeoxycholic acid, a ligand for FXR, decreased the messenger RNA levels for mttp indirectly by increasing the expression of the factor small heterodimer partner (SHP), which suppresses the expression of the hepatocyte nuclear factor-4, a transcription activation factor in the mttp promoter. These results indicate that FXR, a key transcription factor that regulates cyp7A1,7 is closely involved in mttp gene expression regulation and provide evidence for a molecular interaction between BA and VLDL metabolism. As suggested by Bertolotti et al., an important issue therefore would be to assess whether gallstone subjects from this population present changes in FXR expression, or activity. Our preliminary data on a small number of patients (9 gallstone-free patients and 10 patients with cholesterol gallstones) did not show a significant change in the hepatic messenger RNA levels of FXR and SHP. However, it can not be ruled out that changes in FXR activity, or different unknown mediators and/or transcription factors, could underlay the interrelationships between BA synthesis, VLDL metabolism, and gallstone disease in humans.

Silvana Zanlungo*, Juan Francisco Miquel*, Flavio Nervi*, * Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.