Abstract 2: Circadian Regulation of Intestinal Lipid Absorption by ApoAIV Involves Forkhead Transcription Factors A2/O1 and MTP

Abstract

Clock, MTP and nocturnin are involved in the circadian regulation of intestinal lipid absorption. Here, we clarified the role of apolipoprotein AIV (apoAIV) in the diurnal regulation of plasma lipids and intestinal lipid absorption in mice. Total plasma triglyceride/cholesterol in ApoAIV -/- mice showed diurnal variations similar to ApoAIV +/+ mice; however, increases in plasma triglyceride at night were significantly lower in these mice. ApoAIV -/- mice absorbed fewer lipids at night and showed blunted response to daytime feeding. To explain reasons for these lower responses, we measured MTP expression; intestinal MTP was low at night and its induction after food entrainment was less in ApoAIV -/- mice. Conversely, apoAIV overexpression increased MTP mRNA in hepatoma cells indicating transcriptional regulation. Mechanistic studies revealed that sequences between -204/-775 bp in the MTP promoter respond to apoAIV and that apoAIV enhances expression of FoxA2/FoxO1 transcription factors and their binding to the identified cis -elements in the MTP promoter at night. Knockdown of FoxA2/FoxO1 abolished apoAIV mediated MTP induction. Moreover, FoxA2/FoxO1 expression showed diurnal variations and their expressions were significantly lower in ApoAIV -/- mice. These data indicate that apoAIV modulates diurnal regulation of lipid absorption by regulating forkhead transcription factors and MTP, and that inhibition of apoAIV expression might reduce plasma lipids.