Effects of Fatty Acids and Ketone Bodies on Cytochromes P450 2B, 4A, and 2E1 Expression in Primary Cultured Rat Hepatocytes

• Published in: Archives of biochemistry and biophysics Vol. 337; no. 2; pp. 217 - 224
• Main Authors: Zangar, Richard C., Novak, Raymond F.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.01.1997
• Subjects: 3-Hydroxybutyric Acid; Acetoacetates - pharmacology; ACIDE GRAS; ACIDOS GRASOS; Animals; Carnitine - analogs & derivatives; Carnitine - pharmacology; Cells, Cultured; CETONAS; CETONE; CYP2B; CYP2E1; CYP4A; Cytochrome P-450 CYP2B1 - biosynthesis; Cytochrome P-450 CYP2B1 - genetics; Cytochrome P-450 CYP2E1 - biosynthesis; Cytochrome P-450 CYP2E1 - genetics; Cytochrome P-450 CYP4A; Cytochrome P-450 Enzyme System - biosynthesis; Cytochrome P-450 Enzyme System - genetics; cytochrome P450; Decanoic Acids - pharmacology; Enzyme Inhibitors - pharmacology; fatty acids; Fatty Acids - biosynthesis; Fatty Acids - pharmacology; Fatty Acids, Unsaturated - pharmacology; Glycerol - pharmacology; Hydroxybutyrates - pharmacology; ketone bodies; Ketone Bodies - pharmacology; Liver - cytology; Liver - enzymology; Mixed Function Oxygenases - biosynthesis; Mixed Function Oxygenases - genetics; Palmitates - pharmacology; peroxisome proliferator; Pyruvic Acid - pharmacology; RAT; RATA; Rats; RNA, Messenger - genetics; RNA, Messenger - metabolism; Triazoles - pharmacology; peroxisome proliferator; CYP2B; fatty acids; ketone bodies; CYP2E1; cytochrome P450; CYP4A
• ISSN: 0003-9861; 1096-0384
• DOI: 10.1006/abbi.1996.9785

CYP2B, CYP4A, and CYP2E1 mRNA levels are elevated in response to pathophysiological conditions, such as diabetes, high-fat diet, and fasting, in which lipids and ketone bodies are increased. In order to avoid confounding hormonal effects, we utilized primary rat hepatocytes to examine whether ketone bodies or fatty acids altered CYP2B, CYP4A, or CYP2E1 expression. Ketone bodies increased CYP2B mRNA and protein levels, but failed to alter CYP4A or CYP2E1 expression. Straight-chain saturated fatty acids, C8 to C16, increased levels of CYP2B and CYP4A mRNA, but not CYP2E1 mRNA. Treatment with octanoylcarnitine, a mitochondrial β-oxidation inhibitor, in combination with hexadecanoate increased CYP2B and CYP4A expression ∼1.4-fold over that observed with hexadecanoate alone, suggesting that mitochondrial conversion of fatty acids to ketone bodies was not required for enhanced CYP2B expression and that mitochondrial β-oxidation decreased intracellular fatty 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 the conversion of monocarboxylic to dicarboxylic acids and thereby decreasing peroxisomal β-oxidation and increasing intracellular fatty acid levels. Addition of glycerol, which suppresses fatty acid synthesis by inhibiting conversion of lactate to pyruvate, decreased basal expression of CYP2B and CYP4A but did not alter CYP2E1 expression. Pyruvate, but not lactate, completely prevented the glycerol-mediated decrease in CYP2B expression. These results provide evidence that intracellular levels of fatty acids and ketone bodies regulate the expression of CYP2B but not CYP2E1.