Nafenopin-induced peroxisome proliferation in vitamin A deficient rats.
Induction of peroxisome proliferator responsive genes is thought to be mediated through binding of a peroxisome proliferator-activated receptor (PPAR) to specific peroxisome proliferator response elements in the upstream region of these genes. Binding of PPAR to the acyl-CoA oxidase promoter requires heterodimerization with the retinoid X receptor (RXR), and subsequent transactivation is strongest when ligands for both PPAR and RXR are present. Therefore, we hypothesized that depletion of ligand for the retinoid receptor would limit the induction of peroxisome proliferation in rats. Hepatic retinol content was reduced by more than 90% by feeding weanling rats a vitamin A deficient (VAD) diet for approximately 3 months. Nafenopin treatment for 7 days induced peroxisomal beta-oxidation 18-fold in VAD rats compared with 16-fold in rats fed a vitamin A sufficient (VAS) diet. Nafenopin induced microsomal laurate hydroxylase and mitochondrial beta-oxidation to comparable rates of specific activity in both VAD and VAS rats. However, the activities in VAD controls were significantly lower than in VAS controls, so the magnitude of the nafenopin-induced increases was greater in the VAD rats. Relative liver weights were increased nearly 2-fold in both VAS and VAD rats treated with nafenopin. Ultrastructural examination of the livers demonstrated that nafenopin increased the number and size of peroxisomes in both VAD and VAS rats. These data demonstrate that rats with severely depleted vitamin A stores remained responsive to the peroxisome proliferator nafenopin. Whether critical retinoid pools that supply RXR ligand (9-cis-retinoic acid) are spared in the vitamin A deficient rats remains to be determined.
Lawrence
J W
JW
Lilly Research Laboratory, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Foxworthy
P S
PS
Perry
D N
DN
Jensen
C B
CB
Giera
D D
DD
Meador
V P
VP
Eacho
P I
PI
D000818:Animals; D008055:Lipids / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008830:Microbodies / Q000187:drug effects* / Q000378:metabolism; D009255:Nafenopin / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D014802:Vitamin A Deficiency / Q000378:metabolism*
D008055:Lipids; D009255:Nafenopin