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

• Published in: Journal of lipid research Vol. 52; no. 2; pp. 289 - 298
• Main Authors: Henkel, Anne S., Anderson, Kristy A., Dewey, Amanda M., Kavesh, Mark H., Green, Richard M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2011; American Society for Biochemistry and Molecular Biology; The American Society for Biochemistry and Molecular Biology; Elsevier
• Subjects: Animals; bile acids; Bile Acids and Salts - metabolism; Cholesterol - metabolism; Cholesterol 7-alpha-Hydroxylase - biosynthesis; Cholesterol, Dietary - administration & dosage; Extracellular Signal-Regulated MAP Kinases - metabolism; Fibroblast Growth Factors - biosynthesis; Hep G2 Cells; hepatic inflammation; Humans; Interleukin-1beta - biosynthesis; JNK Mitogen-Activated Protein Kinases - metabolism; Liver - drug effects; Liver - metabolism; Male; Mice; Mitogen-Activated Protein Kinases - metabolism; tumor necrosis factor α; Tumor Necrosis Factor-alpha - metabolism; hepatic inflammation; bile acids; tumor necrosis factor α
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.M012781

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.