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. Author manuscript; available in PMC: 2019 Jan 1.
Published in final edited form as: Pharmacol Ther. 2017 Jul 16;181:1–12. doi: 10.1016/j.pharmthera.2017.07.010

Figure 2. LXRs are master regulators of reverse cholesterol transport.

Figure 2

The in vivo pathways for disposal of excess cellular – in this case, macrophage – cholesterol from the organism, so called ‘reverse cholesterol transport,’ are depicted. Proteins in green font are encoded by LXR target genes, and are thus upregulated by LXR agonists (note, however, that cytochrome P450 family 7 subfamily A member 1 [CYP7A1] is an LXR target in mice and not humans, and cholesteryl ester transfer protein [CETP] is expressed in humans but not mice). ATP Binding Cassette (ABC)A1 in enterocytes and hepatocytes generates plasma high density lipoprotein (HDL) by lipidation of plasma apolipoprotein (apo)A-I. HDL in turn induces cholesterol efflux from macrophages via cooperative interactions with ABCA1 and ABCG1. HDL-associated cholesterol can then either be cleared via hepatocyte scavenger receptor (SR)-BI, or transferred to apoB100-containing lipoproteins via CETP in exchange for triglyceride (TG). Finally, apoB100-lipoprotein cholesterol is cleared from the plasma either by hepatocyte low density lipoprotein receptor (LDLR), or by trans-enterocyte transfer into the gut lumen, the so-called ‘trans-intestinal cholesterol excretion’ (TICE) pathway. Hepatic cholesterol that is not used to assemble very LDL (VLDL) mnplasma particles can be excreted into the biliary system (and from there into the gut lumen), either via ABCG5/8-dependent transport as free cholesterol, or as bile acids, after conversion by CYP7A1. In enterocytes, LXR upregulates ABCA1 (driving HDL production) and ABCG5/8 (promoting cholesterol efflux into gut lumen), and downregulates Niemann Pick C1 like 1 (NPC1L1) protein (reducing uptake of luminal cholesterol). Taken together, enterocyte LXR increases plasma HDL, reduces cholesterol absorption, and promotes cholesterol excretion. Hepatic LXR increases plasma HDL and promotes biliary cholesterol excretion. Hepatic LXR also induces the lipogenic genes sterol response element binding protein (SREBP)-1c, fatty acid synthase (FAS), and stearoyl coA-desaturase (SCD)1, as well as inducible degrader of the LDLR (IDOL). In rodent models, treatment with LXR agonists drives fecal excretion of macrophage-derived cholesterol (ie, RCT). HL, hepatic lipase; IDL, intermediate density lipoprotein; LPL, lipoprotein lipase.