EFFECTS OF FATTY-ACIDS AND KETONE-BODIES ON CYTOCHROMES P450 2B, 4A, AND 2E1 EXPRESSION IN PRIMARY CULTURED RAT HEPATOCYTES

CYP2B, CYP4A, and CYP2E1 mRNA levels are elevated in response to patho physiological conditions, such as diabetes, high-fat diet, and fasting , in which lipids and ketone bodies are increased. In order to avoid c onfounding hormonal effects, we utilized primary rat hepatocytes to ex amine whether ketone bodies or fatty acids altered CYP2B, CYP4A, or CY P2E1 expression. Ketone bodies increased CYP2B mRNA and protein levels , but failed to alter CYP4A or CYP2E1 expression. Straight-chain satur ated fatty acids, C8 to C16, increased levels of CYP2B and CYP4A mRNA, but not CYP2E1 mRNA. Treatment with octanoylcarnitine, a mitochondria l beta-oxidation inhibitor, in combination with hexadecanoate increase d CYP2B and CYP4A expression similar to 1.4-fold over that observed wi th hexadecanoate alone, suggesting that mitochondrial conversion of fa tty acids to ketone bodies was not required for enhanced CYP2B express ion and that mitochondrial beta-oxidation decreased intracellular fatt y acid levels and thereby lowered CYP2B expression. Undecynoic acid or aminobenzotriazole treatment increased CYP2B mRNA levels, consistent with these compounds inhibiting the initial CYP4A-catalyzed step in th e conversion of monocarboxylic to dicarboxylic acids and thereby decre asing peroxisomal beta-oxidation and increasing intracellular fatty ac id levels. Addition of glycerol, which suppresses fatty acid synthesis by inhibiting conversion of lactate to pyruvate, decreased basal expr ession of CYP2B and CYP4A but did not alter CYP2E1 expression. Pyruvat e, but not lactate, completely prevented the glycerol-mediated decreas e in CYP2B expression. These results provide evidence that intracellul ar levels of fatty acids and ketone bodies regulate the expression of CYP2B but not CYP2E1. (C) 1997 Academic Press.