The Effects of Steroid Hormones on Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase (LCHAD) Enzyme Expression in LCHAD Deficient Cells and Induction of Long-Chain Fatty Acid Binding Proteins on Long-Chain Fatty Acid-Induced Hepatotoxicity

Abstract

Background: Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency has been implicated in the pathogenesis of acute fatty liver of pregnancy (AFLP) and the Hemolysis Elevated Liver Enzyme, Low Platelet (HELLP) syndrome. Yet not all pregnant women with LCHAD deficiency develop these conditions and whether induction of long-chain fatty acid binding proteins (L-FABP) might be of therapeutic value remains to be determined. Objectives: To document: (1) the effects of pregnancy associated steroid hormones on LCHAD expression and (2) induction of L-FABP on long-chain fatty acid (LCFA)-induced hepatotoxicity. Methods: LCHAD deficient B2325 cells were exposed to various concentrations of β-estradiol and/or progesterone in vitro and LCHAD mRNA and protein expression documented by RT-PCR and Western Blot analysis for 24-72 hours thereafter. In addition, Huh-7 hepatocytes exposed to toxic concentrations of LCFA (a mixture of oleic and palmitic acid) for 24 hours were treated with L-FABP inducers clofibrate or simvastatin (6.25-100 mM) for a subsequent 48 hours prior to documenting cell toxicity. Results: Neither β-estradiol, progesterone or a combination thereof consistently decreased LCHAD mRNA or protein expression. Moreover, hepatocyte survival was not altered by either clofibrate or simvastatin. Conclusions: Increases in steroid hormones associated with pregnancy are unlikely to contribute to LCFA-induced hepatotoxicity in LCHAD deficient women. Induction of L-FABP does not hold promise as a therapeutic strategy for pregnant women with AFLP or HELLP.