Abstract
Background:
The role of apoAIV in the diurnal regulation of plasma lipids is unknown.
Results:
Plasma lipids, lipid absorption, and MTP, FoxO1, and FoxA2 levels are lower at night and at mealtime in apoAIV
−/−
mice.
Conclusion:
ApoAIV increases intestinal lipid absorption by modulating the expression of MTP involving FoxA2 and FoxO1.
Significance:
Inhibition of intestinal apoAIV expression might reduce plasma lipids.
We have shown previously that Clock, microsomal triglyceride transfer protein (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. Plasma triglyceride in apoAIV
−/−
mice showed diurnal variations similar to apoAIV
+/+
mice; however, the 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 and FoxO1 transcription factors and their binding to the identified
cis
elements in the MTP promoter at night. Knockdown of FoxA2 and FoxO1 abolished apoAIV-mediated MTP induction. Similarly, knockdown of apoAIV in differentiated Caco-2 cells reduced MTP, FoxA2, and FoxO1 mRNA levels, cellular MTP activity, and media apoB. Moreover, FoxA2 and FoxO1 expression showed diurnal variations, and their expression was significantly lower in apoAIV
−/−
mice. These data indicate that apoAIV modulates diurnal changes in lipid absorption by regulating forkhead transcription factors and MTP and that inhibition of apoAIV expression might reduce plasma lipids.