INDUCTION OF PEROXISOMAL FATTY-ACID BETA-OXIDATION AND LIVER FATTY ACID-BINDING PROTEIN BY PEROXISOME PROLIFERATORS - MEDIATION VIA THE CYTOCHROME P-450IVA1 OMEGA-HYDROXYLASE PATHWAY
Rm. Kaikaus et al., INDUCTION OF PEROXISOMAL FATTY-ACID BETA-OXIDATION AND LIVER FATTY ACID-BINDING PROTEIN BY PEROXISOME PROLIFERATORS - MEDIATION VIA THE CYTOCHROME P-450IVA1 OMEGA-HYDROXYLASE PATHWAY, The Journal of biological chemistry, 268(13), 1993, pp. 9593-9603
Both the enzymes of peroxisomal fatty acid beta-oxidation and the live
r fatty acid-binding protein (L-FABP) are induced in the liver by pero
xisome proliferators, such as clofibrate (CF), as well as high fat die
ts. One proposed mechanism for this induction is that it represents an
adaptive response to altered intracellular fatty acid fluxes, mediate
d by dicarboxylic fatty acids formed via the cytochrome P-450IVA1 omeg
a-oxidation pathway. The studies presented in this paper were designed
to investigate the role of the products of P-450IVA1 omega-oxidation
in the regulation of peroxisomal beta-oxidation and L-FABP. In primary
hepatocyte cultures exposed to CF, the increase in P-450IVA1 activity
preceded the induction of peroxisomal beta-oxidation and L-FABP. The
CF-mediated increases in peroxisomal beta-oxidation and L-FABP, but no
t P-450IVA1, could be significantly inhibited pretranslationally by co
ncurrent exposure of cultured hepatocytes to inactivators of cytochrom
es P-450, such as 1-aminobenzotriazole and 10-undecynoic acid. Hexadec
anedioic acid, a 16-carbon dicarboxylic fatty acid, that is poorly met
abolized in hepatocytes, induced peroxisomal beta-oxidation and L-FABP
, but not P-450IVA1, via a pretranslational mechanism that was not inh
ibited by 1-aminobenzotriazole. Long-chain monocarboxylic acids were w
ithout such inducing effect. In further studies, non-beta-oxidizable d
icarboxylic acid analogs were found to display greater potency as indu
cers of peroxisomal beta-oxidation when compared to hexadecanedioic ac
id. The inducing effects of the dicarboxylic acid analogs were also in
dependent of the P-450 omega-oxidation pathway. The results of these s
tudies suggest that the regulation of peroxisomal beta-oxidation enzym
es and L-FABP is mediated, to a significant extent, by poorly metaboli
zed long-chain dicarboxylic acids formed via the P-450IVA1 pathway.