Preliminary Study On The Relationship Between Retinol Binding Protein 4 And Cholesterol Gallstone Formation

[Background] RBP4 is specific transporter responsible for transferring retinol from liver to target tissue. Recent studies show that elevated levels of RBP4 is closely associated with a variety of abnormal glycolipid metabolism diseases such as insulin resistance, obesity, diabetes mellitus, and metabolic syndrome, but the relationship between RBP4 and cholesterol gallstones remains unclear. In this study, we investigated the relationship between RBP4 and cholesterol gallstone formation.[Methods] 1. Twenty-four male C57/B6 mice were randomly divided into a normal control group (group C, n=8), a gallstone group (group G, n=8), and a medication group (group M, n=8). Group C was fed a normal diet. Cholesterol gallstones were induced in mice of groups G and M by feeding them a lithogenic diet. Mice in group M were intragastrically administered pioglitazone 8 mg/kg.d. After 10 weeks, the incidence of gallstone formation was observed, and the metabolism indices were calculated. Serum RBP4 levels were measured by ELISA. RBP4 expression in liver and adipose tissue was detected by western blotting. The transcription of RBP4 mRNA, PPARy mRNA in the liver was measured using real-time PCR. To observe morphologic changes of liver by HE stained paraffin sections.2. Metabolism indices, including serum RBP, fasting glucose (FG), total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) of 110 cholesterol gallstone patients and 73 healthy controls were collected for further analysis.[Results] 1. The incidences of gallstone formation were 0/8 (group C),7/8 (group G), and 2/8 (group M). Group G had significantly higher body weight, adipose mass, FG, serum RBP4, TC, TG, and HDL than group C. In group M, pioglitazone decreased body weight, adipose mass, levels of serum RBP4, FG, TC, and TG, and it increased levels of HDL. Mice with gallstones (group G) had elevated levels of RBP4 and RBP-4 mRNA in liver and adipose tissue, and this increase was effectively prevented by pioglitazone in group M. Pioglitazone could prevent decreased transcription of PPARymRNA in liver result from the lithogenic diet. No hepatic steatosis was observed in group C. Compared with mild hepatic steatosis in group M, mice in group G showed different degrees of severe hepatic steatosis.2. Patients with gallstones had elevated levels of serum RBP, FG, TC, TG, ALT, and AST, and had decreased HDL levels compared with healthy controls. Levels of serum RBP were positively correlated with TC, TG, LDL, and FG, and were negatively correlated with HDL in gallstone patients. Elevated serum RBP was associated with increased risk for cholesterol gallstone formation (OR=2.29,95% CI=1.58-5.41, p<0.01).[Conclusion] Elevated RBP4 is associated with the morbidity of cholesterol gallstones and metabolic syndrome. RBP4 may play an important role in the course of cholesterol gallstone formation. Pioglitazone could downregulate RBP4 expression in liver and adipose tissue, improve glycolipid metabolism and prevent mice from diet-induced cholesterol gallstone.