Dietary Regulation of Gene Expression: Enzymes Involved in Carbohydrate and Lipid Metabolism

The mechanisms of the responses of an enzyme to different hormones and metabolites or several enzymes to a single hormone are surprisingly varied. There is neither an operon for lipogenic enzymes nor a common step at which hormones and metabolites coordinately regulate the expression of lipogenic genes. In bacteria, coordinated expression of several enzymes in a single metabolic pathway often is achieved by organizing the genes into operons. An operon is a group of genes linked together in a linear fashion and producing a polycistronic mRNA. Trans-acting factors regulate the transcription of these genes by interacting with promoter/regulatory sequences in the 5'-flanking region of the most 5'-ward of the genes. In vertebrate animals, however, coordinated control of gene transcription is not achieved by linking the individual genes, but by putting in the 5'-flanking regions of these genes a regulatory sequence that interacts with common trans-acting factors. Genes controlled by different hormones are expected to have regulatory elements for each hormone. The presence of glucocorticoid and cyclic AMP regulatory elements at the 5'-end of the PEPCK gene is consistent with this notion. Transcription is not the only step at which hormones and metabolites control the pathways for gene expression. The levels of the mRNAs for L-PK, ME, S11, and S14 are increased by T3 at post-transcriptional steps. Glucagon also regulates the accumulation of ME mRNA post-transcriptionally. Neither the mechanism nor the sequence organization of regulatory elements is known for post-transcriptional control of gene expression. In the case of PEPCK and HMG-CoA reductase, the next steps will be to determine more precisely the sequences in the 5'-region that mediate hormone sensitivity and feedback inhibition, respectively, and whether trans-acting factors are involved. For the other genes discussed, identification of the regulated step must precede identification of sequences that confer hormone or metabolite-sensitive regulation on a specific gene. In general, it is probable that the hybrid gene approach, so successful for PEPCK and HMG-CoA reductase, also will be effective in defining cis-acting hormone- or metabolite-regulatory elements in other genes. These techniques should be applicable to both transcriptional and post-transcriptional mechanisms. Our long-term objective is to understand the molecular basis of each event that intervenes between the binding of hormone or metabolite to its appropriate receptor and altered enzyme level.(ABSTRACT TRUNCATED AT 400 WORDS)