LXR Driven Induction of HDL-Cholesterol is Independent of Intestinal Cholesterol Absorption and ABCA1 Protein Expression

• Published in: Lipids 2014-01, Vol.49 (1), p.71-83
• Main Authors: Kannisto, Kristina, Gåfvels, Mats, Jiang, Zhao-Yan, Slätis, Katharina, Hu, Xiaoli, Jorns, Carl, Steffensen, Knut R., Eggertsen, Gösta
• Format: Article
• Language: English
• Subjects: ABCA1; ABCG5; Absorption; Animals; Anticholesteremic Agents - pharmacology; ApoAI; Apolipoprotein A-I - blood; Apolipoprotein A-I - metabolism; ATP Binding Cassette Transporter 1 - genetics; ATP Binding Cassette Transporter 1 - metabolism; ATP Binding Cassette Transporter, Sub-Family G, Member 5; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; Azetidines - pharmacology; Basic Medicine; Benzoates - pharmacology; Benzylamines - pharmacology; Biomedical and Life Sciences; Blotting, Western; Cell Line, Tumor; Cells, Cultured; Cholesterol; Cholesterol - blood; Cholesterol - metabolism; Cholesterol, HDL - blood; Cholesterol, HDL - metabolism; Combined treatment; Ezetimibe; Farmakologi och toxikologi; Feces - chemistry; Gene Expression - drug effects; GW3965; HDL; Hepatocytes - drug effects; Hepatocytes - metabolism; Intestinal Absorption - drug effects; Intestinal cholesterol absorption; Intestines - drug effects; Intestines - metabolism; Life Sciences; Lipidology; Lipoproteins - genetics; Lipoproteins - metabolism; Liver - drug effects; Liver - metabolism; Liver X Receptors; LXR; Läkemedelskemi; Male; Medical and Health Sciences; Medical Biochemistry; Medicin och hälsovetenskap; Medicinal Chemistry; Medicinska och farmaceutiska grundvetenskaper; Membrane Transport Proteins - genetics; Membrane Transport Proteins - metabolism; Mice; Mice, Inbred C57BL; Microbial Genetics and Genomics; Neurochemistry; NPC1L1; Nutrition; Original Article; Orphan Nuclear Receptors - agonists; Orphan Nuclear Receptors - metabolism; Pharmacology and Toxicology; Reverse Transcriptase Polymerase Chain Reaction; Synergistic effect
• ISSN: 0024-4201; 1558-9307; 1558-9307
• DOI: 10.1007/s11745-013-3853-8

We investigated whether: (1) liver X receptor (LXR)-driven induction of high-density lipoprotein cholesterol (HDL-C) and other LXR-mediated effects on cholesterol metabolism depend on intestinal cholesterol absorption; and (2) combined treatment with the LXR agonist GW3965 and the cholesterol absorption inhibitor ezetimibe results in synergistic effects on cholesterol metabolism that could be beneficial for treatment of atherosclerosis. Mice were fed 0.2 % cholesterol and treated with GW3965+ezetimibe, GW3965 or ezetimibe. GW3965+ezetimibe treatment elevated serum HDL-C and Apolipoprotein (Apo) AI, effectively reduced the intestinal cholesterol absorption and increased the excretion of faecal neutral sterols. No changes in intestinal ATP-binding cassette (ABC) A1 or ABCG5 protein expression were observed, despite increased mRNA expression, while hepatic ABCA1 was slightly reduced. The combined treatment caused a pronounced down-regulation of intestinal Niemann–Pick C1-like 1 (NPC1L1) and reduced hepatic and intestinal cholesterol levels. GW3965 did not affect the intestinal cholesterol absorption, but increased serum HDL-C and ApoAI levels. GW3965 also increased Apoa1 mRNA levels in primary mouse hepatocytes and HEPA1-6 cells. Ezetimibe reduced the intestinal cholesterol absorption, ABCA1 and ABCG5, but did not affect the serum HDL-C or ApoAI levels. Thus, the LXR-driven induction of HDL-C and ApoAI was independent of the intestinal cholesterol absorption and increased expression of intestinal or hepatic ABCA1 was not required. Inhibited influx of cholesterol via NPC1L1 and/or low levels of intracellular cholesterol prevented post-transcriptional expression of intestinal ABCA1 and ABCG5, despite increased mRNA levels. Combined LXR activation and blocked intestinal cholesterol absorption induced effective faecal elimination of cholesterol.