Proteasome inhibition protects against diet-induced gallstone formation through modulation of cholesterol and bile acid homeostasis

Eun Ji Lee, Min Hee Kim, Ye Ryung Kim, Joo Won Park, Woo Jae Park

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1715-1723
Number of pages9
JournalInternational Journal of Molecular Medicine
Volume41
Issue number3
DOIs
StatePublished - Mar 2018

Keywords

  • Bile acid synthesis
  • Cholesterol secretion
  • Cholesterol synthesis
  • Gallstone disease
  • Lithogenic diet
  • Proteasome inhibition

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