A chronic high-cholesterol diet paradoxically suppresses hepatic CYP7A1 expression in FVB/NJ mice

Anne S. Henkel, Kristy A. Anderson, Amanda M. Dewey, Mark H. Kavesh, Richard M. Green

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Cholesterol 7α-hydroxylase (CYP7A1) encodes for the rate-limiting step in the conversion of cholesterol to bile acids in the liver. In response to acute cholesterol feeding, mice upregulate CYP7A1 via stimulation of the liver X receptor (LXR) α. However, the effect of a chronic high-cholesterol diet on hepatic CYP7A1 expression in mice is unknown. We demonstrate that chronic cholesterol feeding (0.2% or 1.25% w/w cholesterol for 12 weeks) in FVB/NJ mice results in a >60% suppression of hepatic CYP7A1 expression associated with a >2-fold increase in hepatic cholesterol content. In contrast, acute cholesterol feeding induces a >3-fold upregulation of hepatic CYP7A1 expression. We show that chronic, but not acute, cholesterol feeding increases the expression of hepatic inflammatory cytokines, tumor necrosis factor (TNF)α, and interleukin (IL)-1β, which are known to suppress hepatic CYP7A1 expression. Chronic cholesterol feeding also results in activation of the mitogen activated protein (MAP) kinases, c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK). Furthermore, we demonstrate in vitro that suppression of CYP7A1 by TNFα and IL-1β is dependent on JNK and ERK signaling. We conclude that chronic high-cholesterol feeding suppresses CYP7A1 expression in mice. We propose that chronic cholesterol feeding induces inflammatory cytokine activation and liver damage, which leads to suppression of CYP7A1 via activation of JNK and ERK signaling pathways.

Original languageEnglish (US)
Pages (from-to)289-298
Number of pages10
JournalJournal of lipid research
Volume52
Issue number2
DOIs
StatePublished - Feb 2011

Keywords

  • Bile acids
  • Hepatic inflammation
  • Tumor necrosis factor α

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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