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Induction of liver apolipoprotein A-IV mRNA in porphyric mice
Abstract:
We have isolated cDNA clones for mRNAs that are induced by porphyria from a mouse liver library. Of the three inducible clones isolated, we have identified one as being apolipoprotein A-IV (apo A-IV) by its extensive homology with a rat apolipoprotein A-IV cDNA sequence. The level of liver apo A-IV mRNA increases rapidly in response to either of two porphyrogenic drugs. When the ferrochelatase-inhibited drug, 3,5-dicarbethoxy-1,4-dihydrocollidine (DDC) is used, a 6 and 28 fold induction of liver apo A-IV mRNA is observed in male and female mice, respectively. If the heme-destroying porphyrogenic drug, allylisopropylacetamide (AIA) is the inducing agent, liver apo A-IV mRNA levels increase 2-3 fold in both males and females. The level of apo A-IV mRNA reaches a maximum within 6-10 hr. after drug administration. Intestine apo A-IV mRNA levels do not change during either of these drug-induced porphyrias. RNA from acute-phase responsive liver or liver from mice treated with bilirubin, porphobilinogen, or protoporphyrin IX show no increase in apo A-IV mRNA. These results indicate that apo A-IV induction is tied to a disruption in porphyrin-heme biosynthesis but is not directly affected by several heme intermediates nor by the major heme degradation product, bilirubin.
Insights
Porphyria drug treatments significantly increase liver apolipoprotein A-IV (apo A-IV) mRNA levels in mice. This induction is linked to disruptions in porphyrin-heme biosynthesis, not heme intermediates or bilirubin.
Area of Science:
- Biochemistry
- Molecular Biology
- Genetics
Background:
- Porphyrias are genetic disorders affecting heme biosynthesis.
- Apolipoprotein A-IV (apo A-IV) is a lipid-binding protein involved in lipoprotein metabolism.
- Understanding gene regulation in disease states is crucial for therapeutic development.
Purpose of the Study:
- To identify genes induced by porphyria in mouse liver.
- To investigate the regulation of apolipoprotein A-IV (apo A-IV) mRNA expression during drug-induced porphyria.
Main Methods:
- Isolation of cDNA clones from a mouse liver library.
- Homology screening to identify specific cDNA sequences.
- Quantitative analysis of apo A-IV mRNA levels using Northern blotting or similar techniques.
- Administration of porphyrogenic drugs (DDC and AIA) to mice.
Main Results:
- Identified an apolipoprotein A-IV (apo A-IV) cDNA clone among those induced by porphyria.
- Observed significant, rapid induction of liver apo A-IV mRNA in response to DDC (6-28 fold) and AIA (2-3 fold).
- Found no change in intestinal apo A-IV mRNA levels or induction by heme intermediates or bilirubin.
Conclusions:
- Apo A-IV gene expression is strongly induced in the liver during drug-induced porphyria.
- The induction of apo A-IV mRNA is specifically related to a disruption in porphyrin-heme biosynthesis.
- Apo A-IV induction is not a general acute-phase response and is independent of specific heme precursors or bilirubin.
