de Aguiar Vallim et al miR-144 Regulates ABCA1/HDL After FXR Activation

High plasma concentrations of low-density lipoprotein are a known risk factor for the development of cardiovascu-lar disease.1 Conversely, high plasma levels of high-density lipoprotein (HDL) are considered to be cardioprotective.2 The putative protective mechanisms include the anti-inflammatory properties of HDL and its role in reverse cholesterol transport, a process involving transport of cholesterol from atheroscle-rotic lesions back to the liver for subsequent excretion in bile.3 The importance of ATP binding cassette transporter A1 (ABCA1) in HDL synthesis was first realized when inactivat-ing mutations in the ABCA1 gene were shown to be causative for Tangier disease. Patients with Tangier disease have very low HDL levels (<5 % of normal levels).4 Although ABCA1 is expressed in numerous cell types, tissue-specific deletion studies in mice demonstrated that hepatic, intestinal, and adi-pose tissue ABCA1 contribute 70 % to 80%, 15 % to 20%, and 15%, respectively, of the total plasma HDL.5,6 Although bone marrow transplantation studies in mice have identified a criti-cal role for ABCA1 in mediating cholesterol efflux from mac-rophages to lipid-poor apoproteins,7 there is no evidence that macrophage ABCA1 affects plasma HDL. In This Issue, see p 1521 Editorial, see p 1529 ABCA1 mRNA and protein levels are highly regulated by both transcriptional and posttranscriptional mechanisms. Activation of the liver X receptor (Nr1h3) results in increased transcription of the ABCA1 gene and increased levels of functional protein.8,9 More recent studies demonstrated that ABCA1 is also regulated posttranscriptionally by 2 microRNAs, miR-33a and miR-33b, derived from intronic regions of the sterol-response element-binding protein genes