It should be noted that our study, using Cyp7a1-tg mice as a model, does not necessarily contradict results from other bile-acid–treated experimental models because we have shown that increasing de novo bile acid synthesis did not result in bile acid accumulation in the liver, likely as a result of efficient bile acid secretion. Finally, this study identified that a novel miR-33a-mediated repression of CYP7A1, as a result of SREBP2 induction, could be part of the feedback loop to reduce bile acid synthesis. H 89 order The recent discovery of coexpression of SREBP2 and miR-33a, as well as down-regulation of ABCA1 by miR-33a, provided the first evidence that miR-33a down-regulates

cellular cholesterol efflux to HDL in response to decreased cellular cholesterol levels to maintain hepatic lipid homeostasis.[9] Our study provides further evidence that miR-33a inhibition of CYP7A1 and bile acid synthesis may also contribute to maintaining cholesterol homeostasis. Cholesterol/oxysterols might also repress miR-33a levels to increase CYP7A1 expression as well as cholesterol efflux transporters.[9] Figure 6 shows a proposed mechanism for the regulation of cholesterol homeostasis by a CYP7A1/SREBP2/miR-33a axis, based on this study, and the selleck screening library well-recognized mechanism for maintaining cholesterol homeostasis and pool by intracellular cholesterol or oxysterol levels.[8]

Increased CYP7A1 enzyme activity results in increased cholesterol catabolism and decreased intracellular cholesterol, which leads to proteolytic

activation of SREBP2 and subsequent stimulation of de novo cholesterol synthesis and LDLR-mediated cholesterol uptake to reduce serum cholesterol. Simultaneously, SREBP2 activation of its own gene transcription coinduces miR-33a, which down-regulates cholesterol efflux transporters and bile acid synthesis. These changes result in increased intrahepatic cholesterol, which subsequently represses SREBP2 and miR-33a expression. This mechanism integrates bile acids and cholesterol metabolism to control lipid homeostasis at both transcriptional and posttranscriptional levels. Thus, CYP7A1 may play a central role in sensing intracellular cholesterol Histone demethylase levels by converting excess hepatic cholesterol to bile acids, thus activating SREBP2 and miR-33a, which inhibits CYP7A1 translation as a rapid feedback mechanism. Inducing CYP7A1 activity by targeting miR-33a may be a potential therapeutic approach to improve metabolic homeostasis. This study suggests that the cardioprotective effects of miR-33a antagonism can be attributed not only to stimulating HDL biogenesis, but also bile acid synthesis, the final step in macrophage-to-feces reverse cholesterol transport. In this study, we also showed that mRNA of CYP8B1, NTCP, and BSEP were repressed upon miR-33a overexpression in mice, indicating that miR-33a antagonism also stimulates enterohepatic bile acid circulation.