Molecular Mechanisms for Protection of Hepatocytes against Bile Salt Cytotoxicity

Abstract

Biliary lipids consist mainly of bile salts, phospholipids and cholesterol, which form mixed micelles and vesicles. Bile salts play various physiological roles but have damaging effects on cell membranes due to their detergent properties. The cytotoxicity of bile salts on hepatocytes leads to liver injuries and is largely determined by the bile salt species, the concentrations of bile salts, phospholipids and cholesterol, and the lipid composition of cell membranes. In bile, monomers and simple micelles of bile salts coexist with mixed micelles and vesicles in dynamic equilibrium, and contribute to the cytotoxicity on hepatocytes. The ATPbinding cassette (ABC) transporter family members, ABCB11, ABCB4 and ABCG5/ABCG8, mediate the biliary secretion of bile salts, phospholipids and cholesterol, respectively. Mutations in ABCB4 result in severe cholestatic diseases, and the biliary phospholipids are necessary for the attenuation of bile salt cytotoxicity. On the other hand, cholesterol reverses the cytoprotective effects of phospholipids against bile salts. In addition, phosphatidylethanolamine N-methyltransferase increases the cell resistance to bile salts by changing the phospholipid composition and structures of the apical membranes. In this review, we focus on the molecular mechanisms for the protection of hepatocytes against bile salt cytotoxicity. Further understanding of these mechanisms will help to develop new therapeutic strategies for cholestatic liver diseases.

Attenuation of the Hepatoprotective Effects of Ileal Apical Sodium Dependent Bile Acid Transporter (ASBT) Inhibition in Choline-Deficient L-Amino Acid-Defined (CDAA) Diet-Fed Mice

“…It was previously shown that treatment of high fat diet-fed mice with the ASBTi for 16 weeks shifted the hepatic bile acid composition shifted toward a more hydrophobic and thus potentially cytotoxic profile (10). In vitro studies have shown that PC protects hepatocytes from bile acid-induced cytotoxicity (48,49). Although not injurious when hepatic PC synthesis is intact, the ASBTi-induced shift to a more hydrophobic bile acid pool may be injurious under PC-deficient conditions.…”

Protocols for Enzymatic Fluorometric Assays to Quantify Phospholipid Classes

“…Bile salts damage cell membranes due to their detergent properties. The biliary phospholipids are necessary to protect hepatocytes from bile salt cytotoxicity [8,40]. The cytotoxicity of bile salts is attenuated by the formation of mixed micelles with phospholipids.…”

“…The cytotoxicity of bile salts is attenuated by the formation of mixed micelles with phospholipids. PC is the predominant (>95%) biliary phospholipid, whereas only small amounts of PE, PS, and SM are present in bile [8,41]. The phospholipid secretion from hepatocytes into bile is mediated by the transporter ABCB4 [41][42][43][44].…”

“…The phospholipid secretion from hepatocytes into bile is mediated by the transporter ABCB4 [41][42][43][44]. ABCB4 gene mutations cause a wide spectrum of liver diseases, including progressive familial intrahepatic cholestasis type 3, intrahepatic cholestasis of pregnancy, low phospholipid-associated cholelithiasis, primary biliary cirrhosis, and cholangiocarcinoma [8,41].…”

“…It has been previously reported that abnormalities in phospholipid metabolism and transport are closely associated with disorders, including dyslipidemia, atherosclerosis, cholestasis, drug-induced liver injury, neurological diseases, autoimmune diseases, respiratory diseases, cardiac and skeletal myopathies, and cancers [1][2][3][4][5][6][7][8][9][10]. Therefore, phospholipid classes have potential as biomarkers for these diseases, and it is highly desired to develop high-sensitive and high-throughput methods for analyzing phospholipid classes.…”