TY - JOUR
T1 - Proteasome inhibition protects against diet-induced gallstone formation through modulation of cholesterol and bile acid homeostasis
AU - Lee, Eun Ji
AU - Kim, Min Hee
AU - Kim, Ye Ryung
AU - Park, Joo Won
AU - Park, Woo Jae
N1 - Funding Information:
this study was supported by the Gachon university research fund of 2013 (grant no. 2013-m050).
PY - 2018/3
Y1 - 2018/3
N2 - Gallstone disease is one of the most prevalent and costly gastrointestinal disorders worldwide. Gallstones are formed in the biliary system by cholesterol secretions in bile, which result from excess cholesterol, a deficiency in bile salts or a combination of the two. The present study examined the effects of proteasome inhibition on gallstone formation using the proteasome inhibitors bortezomib (BT) and carfilzomib (CF ). C57BL/6J mice were fed a lithogenic diet to generate gallstones and injected with BT or CF for 12 weeks. After 12 weeks of the lithogenic diet, 8 out of the 10 mice in the control group had developed gallstones, whereas none of the mice who received proteasome inhibitors had developed gallstones. Notably, the expression of genes associated with cholesterol synthesis (sterol regulatory element-binding protein-2 and 3-hydroxy-3-methylglutaryl-C oA reductase), cholesterol secretion [AT P-binding cassette subfamily G member 5 (ABCG5) and ABCG8] and bile acid synthesis [cytochrome P450 family 7 subfamily A member 1 (Cyp7a1), Cyp7b1, Cyp27a1 and Cyp8b1] was reduced in the livers of mice injected with BT or CF. Cyp7a1 encodes cholesterol 7α-hydroxylase, the rate-limiting enzyme in the synthesis of bile acid from cholesterol. The present study therefore measured the expression levels of transcription factors that are known to inhibit Cyp7a1 expression, namely farnesoid X receptor (FXR), pregnane X receptor (PXR) and small heterodimer partner (SHP). Although FXR, PXR and SHP expression was predicted to increase in the presence of proteasome inhibitors, the expression levels were actually reduced; thus, it was concluded that they were not involved in the proteasome inhibition-induced regulation of Cyp7a1. Further investigation of the mitogen-activated protein kinase and protein kinase A (PKA) signaling pathways in human hepatoma cells revealed that proteasome inhibition-induced c-J un N- terminal kinase (JN K) phosphorylation reduced CYP7A1 and CYP27A1 expression. In addition, reduced PKA phosphorylation as a result of proteasome inhibition regulated ABCG5 and ABCG8 expression. In conclusion, these findings suggest that proteasome inhibition regulates cholesterol and biliary metabolism via the JN K and PKA pathways, and is a promising therapeutic strategy to prevent gallstone disease.
AB - Gallstone disease is one of the most prevalent and costly gastrointestinal disorders worldwide. Gallstones are formed in the biliary system by cholesterol secretions in bile, which result from excess cholesterol, a deficiency in bile salts or a combination of the two. The present study examined the effects of proteasome inhibition on gallstone formation using the proteasome inhibitors bortezomib (BT) and carfilzomib (CF ). C57BL/6J mice were fed a lithogenic diet to generate gallstones and injected with BT or CF for 12 weeks. After 12 weeks of the lithogenic diet, 8 out of the 10 mice in the control group had developed gallstones, whereas none of the mice who received proteasome inhibitors had developed gallstones. Notably, the expression of genes associated with cholesterol synthesis (sterol regulatory element-binding protein-2 and 3-hydroxy-3-methylglutaryl-C oA reductase), cholesterol secretion [AT P-binding cassette subfamily G member 5 (ABCG5) and ABCG8] and bile acid synthesis [cytochrome P450 family 7 subfamily A member 1 (Cyp7a1), Cyp7b1, Cyp27a1 and Cyp8b1] was reduced in the livers of mice injected with BT or CF. Cyp7a1 encodes cholesterol 7α-hydroxylase, the rate-limiting enzyme in the synthesis of bile acid from cholesterol. The present study therefore measured the expression levels of transcription factors that are known to inhibit Cyp7a1 expression, namely farnesoid X receptor (FXR), pregnane X receptor (PXR) and small heterodimer partner (SHP). Although FXR, PXR and SHP expression was predicted to increase in the presence of proteasome inhibitors, the expression levels were actually reduced; thus, it was concluded that they were not involved in the proteasome inhibition-induced regulation of Cyp7a1. Further investigation of the mitogen-activated protein kinase and protein kinase A (PKA) signaling pathways in human hepatoma cells revealed that proteasome inhibition-induced c-J un N- terminal kinase (JN K) phosphorylation reduced CYP7A1 and CYP27A1 expression. In addition, reduced PKA phosphorylation as a result of proteasome inhibition regulated ABCG5 and ABCG8 expression. In conclusion, these findings suggest that proteasome inhibition regulates cholesterol and biliary metabolism via the JN K and PKA pathways, and is a promising therapeutic strategy to prevent gallstone disease.
KW - Bile acid synthesis
KW - Cholesterol secretion
KW - Cholesterol synthesis
KW - Gallstone disease
KW - Lithogenic diet
KW - Proteasome inhibition
UR - http://www.scopus.com/inward/record.url?scp=85040972659&partnerID=8YFLogxK
U2 - 10.3892/ijmm.2017.3326
DO - 10.3892/ijmm.2017.3326
M3 - Article
C2 - 29286073
AN - SCOPUS:85040972659
SN - 1107-3756
VL - 41
SP - 1715
EP - 1723
JO - International Journal of Molecular Medicine
JF - International Journal of Molecular Medicine
IS - 3
ER -