Low plasma levels of HDL-cholesterol (HDL-C) have been consistently associated with increased risk of atherosclerotic cardiovascular diseases. It is therefore considered to be an anti-atherogenic lipoprotein 1. The development of novel therapies to enhance the atheroprotective properties of HDL may further reduce the residual risk. Reverse cholesterol transport (RCT) is believed to be a primary atheroprotective property of HDL and its major protein, apolipoprotein A-I (apoA-I) 2. HDL and apoA-I have been shown to promote efflux of excess cholesterol from macrophage-derived foam cells via the cholesterol transporters, ATP-binding cassette transporter A1 (Abca1), Abcg1 and scavenger receptor class B, type I (Sr-bI), and then transport it back to the liver for excretion into the bile and eventually into feces 3. Several steps of RCT are transcriptionally regulated by liver X receptors (nuclear receptors, Lxrs) in macrophages, the liver, and intestine. Lxrs are activated by oxysterols as natural ligands and induce Lxr-target genes such as ATP-binding cassette transporters (Abc) A1 (Abca1), Abcg1, Abcg5, Abcg8, and cholesterol 7α hydroxylase (Cyp7a1). Pharmacological activation of Lxrs using their agonists reportedly inhibits the development of atherosclerosis via activation of RCT in animal models [4], [5], [6], [7]. Lxrβ is expressed ubiquitously whereas, Lxrα is predominantly expressed in tissues, such as liver, intestine and macrophage tissues, which play important roles in cholesterol homeostasis. In whole-body Lxrα/β double-knockout (Lxrα/β-/-) mice (DKO), reduced HDL cholesterol (HDL-C) levels, attenuated RCT, and enhanced atherosclerosis were observed [8], [9]. Further, accumulating evidence suggests beneficial effects of tissue-specific Lxr expression on atherogenesis since macrophage or liver-specific Lxr deletion resulted in accelerated development of atherosclerosis in mice [6], [9], [10], [11].

Macrophage Lxrs reportedly contribute to anti-atherogenesis by reducing RCT 12, although physiological roles of liver Lxrs in RCT remain unclear. Hepatic Lxrα deletion abolished Lxr agonist-induced promotion of RCT; however, there was no difference in RCT between Lxrα knockout and wild type mice under physiological conditions (without Lxr agonist administration) [11], [12]. It remains uncertain how hepatic Lxrβ contributes to RCT in vivo.

In order to extend our knowledge of the effects of hepatic Lxrs on RCT, we induced hepatic overexpression of sulfotransferase family cytosolic 2B member 1 (Sult2b1) in mice to inhibit hepatic Lxr pathways. Sult2b1 facilitates the generation of sulfated cholesterol by adding a sulfate group to cholesterol side chains, resulting in reduced oxysterol production, which, in turn, inhibits Lxrα/β signaling 13. Here we demonstrate that hepatic Lxr inhibition by Sult2b1 overexpression reduced circulating HDL levels and attenuated RCT but only under a high cholesterol (HC) diet.