Biliary Lipid Secretion in NPC1-deficient Mice

S. Zanlungo, L. Amigo, H. Mendoza, F. Morera, J. F. Miquel, A. Rigotti, F. Nervi.:

Presentado a: Congreso anual de la American Gastroenterological Association. 20 al 26 de Mayo, 2000. San Diego, California, Estados Unidos.

The liver plays a critical role in lipoprotein cholesterol metabolism and is a key organ for cholesterol removal from the body. Although most of the cholesterol secreted in bile is normally derived from plasma lipoproteins, it is not certain the relative contribution from any particular hepatic lipoprotein metabolic pathway for biliary lipid secretion. The receptor-mediated endocytic pathway is one of the major mechanisms for uptake of lipoprotein cholesterol in the liver. Since NPC1 is a key component in the hepatic delivery of lipoprotein cholesterol through the endocytic pathway, it may play a critical role in controlling bile secretion of plasma lipoprotein-derived cholesterol.

Aim: To analyze the relevance of the NPC1-related endocytic pathway for lipoproteins in the liver in regulating biliary lipid secretion in vivo.

Methods: BALB/cnpcnih NPC1-deficient mice (1 month old) were fed for 2 weeks with chow diet or with a high cholesterol diet (2%w/w) and hepatic cholesterol content, bile flow and biliary lipid secretion were measured.

Results: As excepted the liver from NPC1-deficient mice showed a higher content of unesterified cholesterol in comparison with control mice in chow diet (11.8 mg/liver vs. 2.4 mg/liver), and this difference was even greater after feeding a high cholesterol-diet (37.9 mg/liver vs. 3.1 mg/liver). With regard to biliary lipid secretion, chow diet-fed NPC1-deficient mice exhibited a 1.7-fold increase in cholesterol secretion compared with control mice. During the high cholesterol-diet feeding period, control mice increased cholesterol secretion 3-fold, whereas affected mice did not. Surprisingly, affected mice increased bile salt secretion 1.9-fold compared with control mice after a high cholesterol-diet feeding.

Conclusion: These results show that NPC1 expression is an important factor for the regulation of biliary lipid secretion in mice during feeding either a cholesterol-poor chow diet or a cholesterol-rich diet. Further studies are required to elucidate the cholesterol source, metabolic pathways, and cellular mechanisms involved in the NPC1-dependent changes observed in lipid secretion into the bile.