Regulation of lecithin:cholesterol acyltransferase by TGF-beta and interleukin-6.

ABSTRACT

The human hepatoma derived HepG2 cells were treated with transforming growth factor-beta (TGF-beta) or interleukin-6 (IL-6) +/- dexamethasone. The effects of treatment on lecithincholesterol acyltransferase (LCAT) catalytic activity and mRNA level as well as on the apolipoprotein A-I (apo A-I) mRNA level were determined. Both the LCAT activity in medium from treated HepG2 cells and the LCAT mRNA level were decreased by TGF-beta. There was no significant effect of IL-6 +/- dexamethasone, neither on the LCAT activity nor on LCAT mRNA levels. Treatment with dexamethasone alone resulted in a decreased LCAT activity in spite of a slight increase in LCAT mRNA level. The apo A-I mRNA level was reduced after treatment with TGF-beta and increased after treatment with IL-6 +/- dexamethasone and dexamethasone alone. To analyze if the effects on mRNA levels were caused by transcriptional or post-transcriptional mechanisms, run-on experiments on isolated nuclei from treated HepG2 cells and mRNA degradation experiments were performed. The transcription rate of the LCAT gene was not affected by TGF-beta, but was increased (50-100%) after treatment with IL-6 +/- dexamethasone and dexamethasone alone. The transcription rate of the apo A-I gene was reduced (20%) by TGF-beta and increased (30-60%) by IL-6 +/- dexamethasone and dexamethasone alone. Both dexamethasone and TGF-beta increased the rate of LCAT mRNA degradation. These results show that the reduced LCAT mRNA level after treatment with TGF-beta was caused by post-transcriptional mechanisms.