Abstract
The liver is central to the maintenance of glucose and lipid homeostasis, and liver X receptors (LXRs) are key regulators of expression of the genes involved. So far, effects of activation of LXR in human hepatocytes have not been well characterized. Here we show that treatment of primary human hepatocytes with the synthetic LXR ligand 3-[3-[N-(2-chloro-3-trifluoromethylbenzyl)-(2,2-diphenylethyl)amino]propyloxy]phenylacetic acid hydrochloride (GW3965) results in reduced output of bile acids and very low density lipoprotein triglycerides and induced expression of adipose differentiation-related protein accompanied by increased lipid storage. Genome wide-expression profiling identified novel human LXR target genes in the glycolytic and lipogenic pathways and indicated that LXR activation reduced hepatic insulin sensitivity. Comparative experiments showed significant differences in the response to GW3965 between human and rat hepatocytes, raising the question as to how well rodent models reflect the human situation. In summary, the risk of hepatic steatosis upon pharmaceutical targeting of LXR may be a particularly serious consequence in humans.
Footnotes
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This work was supported by grants from the Swedish Science Council, the Swedish Hearth-Lung-Foundation, KaroBio AB, Swedish Medical Association, and the Norwegian Research Council (to K.R.S.), and in part by the National Institutes of Health/DK92310 (to S.S.).
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P.K. and E.E. contributed equally to this work
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Conflict of interest statement: J.-Å.G. is a consultant, shareholder, and grant receiver of KaroBio AB, Sweden. S.S. is a consultant of Lonza Walkersville (Walkersville, MD). The other authors have nothing to declare.
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Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
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doi:10.1124/mol.107.037358.
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ABBREVIATIONS: LXR, liver X receptor (gene symbols: LXRα, NR1H3 and LXRβ, NR1H2); GO, Gene Ontology; SLR, signal log ratio; ADFP, adipose differentiation-related protein; ChREBP, carbohydrate response element binding protein (gene symbol MLXIPL); qPCR, quantitative polymerase chain reaction; VLDL, very low density lipoprotein; TG, triglyceride; GCK, glucokinase; PKLR, liver pyruvate kinase; PEPCK, phosphoenolpyruvate carboxy kinase (gene symbol PCK1); GLUT2, glucose transporter 2 (gene symbol SLC2A2); SREBP, sterol response element binding protein; FASN, fatty acid synthase; SCD, stearoyl CoA desaturase; DGAT, diacylglycerol transferase; ABC, ATP-binding cassette; LDLR, low density lipoprotein receptor; CPT, carnityl palmitoyl transferase; GW3965, 3-[3-[N-(2-chloro-3-trifluoromethylbenzyl)-(2,2-diphenylethyl)amino]propyloxy]phenylacetic acid hydrochloride; T0901317, N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2,-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide.
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↵ The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
- Received April 23, 2007.
- Accepted July 12, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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