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Regulation of Hepatic Heme Metabolism

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The long-term goal of this research program is to understand the pathways and regulation of hepatic porphyrin and heme metabolism. Heme is a primordial molecule that is of critical importance to life on earth. The pathway of heme synthesis in humans and other higher animals is highly conserved. It requires the concerted action of eight enzymes, the first of which, called 5-aminolevulinate synthase (ALAS), is normally rate controlling. The pathway of heme breakdown is also highly conserved, and its rate is controlled by activity of the first enzyme of this pathway, called heme oxygenase (HO). Levels of expression of both hepatic ALAS-1 and HO-1 can be changed dramatically. The ALAS-1 gene can be up-regulated by certain drugs or chemicals, including drugs that may precipitate acute attacks of porphyria, and by chemicals that block heme synthesis. Activity of ALAS-1 can be decreased by heme, an example of end-product repression of a biosynthetic pathway. Heine may act on ALAS by both transcriptional and post-transcriptional mechanisms. The gene for the 1 isoform of HO (HO-1) can be up-regulated by a large number of chemical and physical perturbations, including oxidative stress, heat shock, transition metals, heavy metals, heme, and other metalloporphyrins. There is growing evidence that HO-1 (also called heat shock protein 32) plays a key role in protecting cells and tissues from oxidative and other stress and that products of the HO reaction are important antioxidants, neuro-muscular transmitters, and modulators of inflammatory and immune responses. The work proposed here will advance understanding of the molecular mechanisms that underlie the regulation of hepatic ALAS and HO-1, the two key enzymes of heme metabolism. The specific aims are as follows: A.I. Specific Aim #1: Complete characterization of the molecular mechanism(s) that are responsible for the up-regulation of the HO-1 gene by heme (iron protoporphyrin) and cobalt protoporphyrin (CoPP). A.2. Specific Aim #2: Complete characterization of the molecular mechanism(s) that are responsible for down-regulation of the ALAS-1 by heme and test whether CoPP or other selected metalloporphyrins have similar effects and mechanisms of down-regulation. A corollary to Specific Aims 1 and 2 will be to characterize the interrelationships between the reciprocal regulation of these two genes by metalloporphyrins. We will achieve these specific aims in cell culture systems, which provide physiologically relevant models of hepatic heme metabolism and in suitably treated intact mice. A.3. Specific Aim #3: Delineate the molecular mechanisms responsible for control of the stability of ALAS mRNA and how heme shortens the life of this mRNA. Our major hypotheses are that 1. heme or cobalt protoporphyrin up-regulate HO-1 gene expression and down-regulate ALAS-1 expression by specific interaction of transcription factor(s) with heme- or other metalloporphyrin- responsive sequences in the 5'-flanking regions of these genes;2. there is also an important post-transcriptional effect of heme to decrease stability of ALAS-1 mRNA;3. this post-transcriptional effect is mediated by HuR, the protein that plays a critical role in determining mRNA stability;4. The above actions of heme are due to effects of heme binding to Bach-l, leading to derepression of HO-1, repression of ALAS-l, and up-regulation of the HuR-dependent pathway of ALAS-1 by mRNA breakdown;and 5. the molecular mechanisms that mediate heme regulation of ALAS-1 and HO-1 are similar in avian, human, and murine hepatocytes in culture or in intact organisms.

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