Increased activity of hepatic microsomal triglyceride transfer protein and bile acid synthesis in gallstone disease

A strong interrelationship exists between the regulation of bile acid (BA) metabolism and hepatic very low density lipoprotein (VLDL) production. We have recently shown that BA synthesis is increased in gallstone disease. We investigated the activity of hepatic microsomal triglyceride transfer protein (MTTP) as a surrogate of VLDL production, BA synthesis, and mRNA expression levels of proteins that regulate fatty acid (FA) metabolism in the liver of gallstone (GS) patients compared with GS-free patients. Twenty-seven volunteers subjected to elective surgery; 9 were GS-free and 18 with GS agreed to have a liver biopsy. We quantified by a fluorescence assay the activity of MTTP and by quantitative reverse-transcription PCR (RT-PCR) the mRNA content of hepatic MTTP and genes that regulate hepatic sterol and FA metabolism. Plasma was assayed for lathosterol and 7alpha-hydroxy-4-cholesten-3-one. Liver histology was normal in GS and GS-free patients. Serum VLDL triglycerides and apoB were significantly increased in GS. Hepatic triglycerides tripled in GS (P<0.001) compared with GS-free. MTTP activity increased 70% (P<0.001). Serum lathosterol and hepatic cholesterol concentrations, and mRNA expressions of MTTP, CD36, and FABP1 were similar in GS-free and GS patients. Hepatic mRNA expression of hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR) and 3-hydroxyl-3-methyl-glutaryl-CoA synthase (HMGS) were significantly decreased--40% and 27%, respectively--in GS. Serum 7alpha-hydroxy-4-cholesten-3-one was 75% higher, and mRNA expression of CYP7A1 was increased sevenfold (P<0.001) in GS.

Hepatic MTTP activity and BA synthesis are increased in GS. Results suggest that hepatic VLDL production and trafficking of BA are increased in gallstone patients.