Fatty acyl-CoAs inhibit retinoic acid-induced apoptosis in Hep3B cells

Abstract

Retinoic acid (RA) induces apoptosis in Hep3B human hepatoma cells. 9- Cis-RA (c-RA) had a similar effect as all- trans-RA (t-RA) in inducing cell death in Hep3B cells. RA-induced Hep3B-cell death was associated with inhibited expression of the hepatocyte nuclear factor 4 (HNF-4) gene. Palmitoyl-CoA ((C16:0)-CoA), the reported HNF-4 ligand, prevented RA-induced apoptosis. The effect of (C16:0)-CoA was specific, since palmitic acid and co-enzyme A had no effect in preventing RA-induced apoptosis. Bovine serum albumin (BSA) also prevented RA-induced apoptosis. However, in contrast to BSA, which induced cell growth, (C16:0)-CoA alone had no effect on cell growth. Investigating the possible role of HNF-4 in apoptosis, the reported HNF-4 antagonist (C18:0)-CoA was employed, and it also prevented RA-induced apoptosis. By transient transfection, overexpression of HNF-4 did not prevent RA-induced apoptosis. The induction and prevention of apoptosis caused by RA and (C16:0)-CoA were associated, respectively with the induction and inhibition of the expression of transforming growth factor β (TGFβ), which is known to play a role in apoptosis. Furthermore, RA and (C16:0)-CoA can regulate AP-1, which is a key regulator of the TGFβ gene. Our data indicate that fatty acyl-CoAs can prevent RA-induced apoptosis and that TGFβ, rather than HNF-4, may play a role in these regulatory processes. Our data also suggest that (C16:0)-CoA and (C18:0)-CoA are not the agonist and antagonist for HNF4, respectively in the Hep3B cell system.