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Physiological Differences between Human and Rat Primary Hepatocytes in Response to Liver X Receptor Activation by 3-[3-[N-(2-Chloro-3-trifluoromethylbenzyl)-(2,2-diphenylethyl)amino]propyloxy]phenylacetic Acid Hydrochloride (GW3965)

Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden (P.K., P.P., K.R.S., J.-Å.G., A.M.); Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania (E.E., S.S.); Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden (P.P.); and Department of Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden (L.-M.N.)

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.

Address correspondence to: Dr. Knut R. Steffensen, Dept of Biosciences and Nutrition, Karolinska Institutet, Novum, S-141 57 Huddinge, Sweden. E-mail: knut.steffensen{at}biosci.ki.se