Relevance Of NPC1, SREBP2Expression In Lithogenic Bile Of Cholesterol Stone

Objective: To investigate the relevance of liver NPC1, SREBP2,LDLR, HMGCR expression in biliary lipid and lithogenic bile of cholesterolstone. Methods: Gallbladder stones of35gallstone patients was measured toinvestigate its cholesterol fraction, which≥70%was divided as cholesterolstone(CS) group(30patients).15non-gallstone patients with benign diseases ascontrol. The gallbladder bile, preoperative fasting venous blood and liver tissueof each patient were collected. The contents of total cholesterol(TC), total bileacid(TBA), triglyceride(TG), low density lipoprotein(LDL), high densitylipoprotein(HDL) and apolipoprotein B(ApoB) in plasma and contents of TC,TBA, phospholipid (PL) in bile were measured, and the cholesterol saturationindex(CSI) was calculated. Reverse-transcription polymerase chainreactin(RT-PCR) was used to test the mRNA expression of NPC1, SREBP2,LDLR and HMGCR in liver tissue. Results:(1)There were30gallbladderstones whos cholesterol fraction≥70%, accounting for85.71%of all thegallstone patients.(2)Serum TC(t=3.646, P=0.001), TBA(t=2.037, P=0.048),ApoB(t=2.132, P=0.039）and LDL(t=2.549，P=0.014) level in CS group weresignificantly increased compared with control. Serum TG level increased andHDL level decreased in CS group but differences were not significant.(3)TClevel of gallbladder bile(t=2.708, P=0.010)and CSI(t=3.581, P=0.001) increased in CS group compared with control and the TBA level(t=-3.282，P=0.004)decreased.(4)The liver mRNA expression of NPC1(t=2.734， P=0.009),LDLR(t=2.533，P=0.015) and HMCGR(t=4.084，P=0.000) were significantlyincreased in CS group. There was no significant difference in SREBP2expression level between the two groups.(5)There were positive correlationsbetween mRNA expression of HMGCR and bile TC(r=0.447，P=0.002) as wellas CSI(r=0.424，P=0.004). Conclusions: The increased expression of NPC1may result in increased bile cholesterol Secretion. When the body lose controlof SREBP2regulation pathway, activity of SREBP2can not be depressed byincreased cellular cholesterol level, LDLR and HMGCR expression level areupregulated, which promote cellular uptake of plasma cholesterol andcholesterol synthetise, resulting in overload of bile cholesterol. It may play arole in cholesterol stone formation. The liver expression level of HMGCRpositively related with bile TC level and CSI, its upregulation may be a keypoint of bile cholesterol supersaturation and lithogenic bile formation.