Received for publication April 23, 2007.
Revised July 12, 2007.
Accepted for publication July 12, 2007.

Physiological differences between human and rat primary hepatocytes in response to LXR activation by GW3965

Abstract

The liver is central for 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, GW3965, results in reduced output of bile acids and VLDL-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.

Key words: Insulin, Comparative genome analyses, Regulation of gene expression, Regulation - transcriptional, Cholesterol metabolism/lipoproteins