Effect of eicosapentaenoic acid on cholesterol gallstone formation in C57BL/6J mice

Abstract

Abstract. The present study investigated the preventive effect of ω-3 fatty acids against cholesterol gallstone (CG) formation. CG formation was induced in C57BL/6J mice using a lithogenic diet (LD). The mice were divided into four treatment groups: i) LD, ii) LD plus eicosapentaenoic acid (EPA), iii) LD plus docosahexaenoic acid (DHA) and iv) LD plus EPA plus DHA. Subsequent to feeding the mice the LD for four weeks, EPA and/or DHA (70 mg/kg/day) were orally administered for eight weeks. The mice in the EPA treatment groups exhibited significantly less gallstone formation than those in the LD group. By contrast, DHA treatment only slightly suppressed gallstone formation. The expression of mucin 2, 5AC, 5B and 6 was significantly decreased in the gallbladders of mice in the EPA groups (70-90%) and the LD plus DHA group (30-50%), compared with that in the mice in the LD group. In addition, the mRNA expression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase was significantly decreased in the livers of mice in the EPA treatment group compared with that in the livers of mice in the LD group. In conclusion, EPA was found to have a dominant anti-lithogenic effect in C57BL/6J mice. IntroductionEicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are essential fatty acids belonging to the group of ω-3 fatty acids, which are primarily found in coldwater fish. These polyunsaturated fatty acids (PUFAs) have an important role in the functions of the body and are converted into hormone-like substances known as prostaglandins and leukotrienes (1). EPA has been shown to provide health benefits in patients with coronary heart disease, high blood pressure, mental health conditions, such as schizophrenia, and inflammatory disorders, including rheumatoid arthritis (2-6). DHA is a key component of brain tissue and the retina of the eye (7,8). Low levels of DHA cause reduced serotonin levels in the brain, which may result in depression, attention deficit hyperactivity disorder, cognitive decline and Alzheimer's disease (9-11).It is well established that the key factors associated with cholesterol gallstone (CG) formation are biliary cholesterol hypersaturation and gallbladder mucin hypersecretion. The hypersaturation of cholesterol in the bile may result from a high-cholesterol diet or hepatic cholesterol overproduction. The elevation of biliary cholesterol concentration leads to the hypersecretion of mucin and the aggregation of cholesterol crystals (12,13). Several mucin (MUC) genes, including MUC2, MUC5AC, MUC5B and MUC6, are expressed in the gallbladder mucosa (14). The upregulation of these MUC genes leads to increased mucin concentrations, which increase bile viscosity and lead to the formation of a gel matrix that can entrap cholesterol crystals in the gallbladder (15-16).The only established medical treatment for CG is ursodeoxycholic acid (UDCA). However, a number of studies have demonstrated that the therapeutic efficacy exhibited by UDCA lacks consistency and is not entirely satisfactory (17-19). Despite numerous...

Prevention of Cholesterol Gallstone Formation by Lactobacillus acidophilus ATCC 43121 and Lactobacillus fermentum MF27 in Lithogenic Diet-Induced Mice

“…It is well known that polyunsaturated fatty acids (PUFAs), especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), play a critical role in regulating biological functions of the human body, and could positively affect on the serum biochemical indices ( Cho et al, 2015 ; Sugiyama et al, 2008 ). These cholesterol-lowering effects in the serum may occur through modulating cholesterol metabolism in the liver ( Sugiyama et al., 2008 ), and are associated with decreased activity of HMG CoA R , which is involved in cholesterol synthesis, in the liver ( Ramaprasad et al, 2006 ).…”

“…UDCA as a conservative treatment has demonstrated antilithiatic effect, which is associated with expression of MUC2, MUC5AC, and MUC5B, and reduced mucin secretion, as seen in the gallbladder bile (Jüngst et al, 2012; Kim et al, 2012 ). Cho et al (2015) reported that PUFAs, including DHA and EPA, have the antilithogenic effects, as they led to reduced expression of MUC2, MUC5AC, and MUC5B genes in C57BL/6J mice. In the current study, L. acidophilus ATCC 43121 and L. fermentum MF27 were found to inhibit the expression of MUC5AC and MUC5B , although no significant effect was observed on the expression of MUC1 and MUC2 compared to the LD group.…”

Diet and gallstone

“…It was found that a medical combination of ω-3 PUFAs (EPA and DHA) originating from fish oil had a preventive effect against cholesterol gallstone formation in C57BL/6 J mice [52]. Dietary fish oil supplementation decreases hypertriglyceridemia and reduces cholesterol crystal nucleation along with decreased gallstone formation in prairie dogs [53,54].…”

Associations of fatty acids with the risk of biliary tract calculus and inflammation: a Mendelian randomization study

“…The proportion of omega-6 PUFAs compared to omega-3 PUFAs is positively associated with cholelithiasis, and total omega-3 PUFA and docosahexaenoic acid (DHA) levels are both negatively associated with cholelithiasis [ 10 ]. In a C57BL/6J mouse lithogenic diet model, eicosapentaenoic acid (EPA) and DHA had the ability to inhibit gallstone formation [ 11 ]. Cholelithiasis is a general term for diseases in which stones occur in any part of the biliary system (including the gallbladder and bile ducts) with or without inflammation.…”