Fibrogenesis. III. Posttranscriptional regulation of type I collagen

There are several independent metabolic steps that determine the level of a protein in eukaryotic cells. The steady-state level of the mRNA encoding the specific protein is determined by rate of transcription, percentage of transcripts that are ultimately processed and transported to the cytoplasm, and half-life of the mRNA in cytoplasm. The amount of protein that accumulates from a particular transcript is influenced not only by the amount of mRNA present in the cytoplasm but also by the rate of translation of the mRNA and stability of the protein product. There is compelling evidence that the steady-state level of many proteins is regulated at multiple steps, and when there is a large change in the amount of either mRNA or protein it is likely that multiple steps in the metabolism of the mRNA and protein have been altered. In the case of type I collagen production in the fibrotic liver, recent work has shown that there is regulation of multiple steps resulting in an approximately 70-fold increase in collagen production by the hepatic stellate cells. In addition to the well-documented relatively small effect on transcription, there are effects on processing/transport of the mRNA, translation of the mRNA, and stability of the mRNA. Large changes of protein levels are produced by altering the rates or efficiency of multiple steps. The molecular details of some of these posttranscriptional regulatory events are currently being elucidated. Here we review the various potential steps for regulation in the synthesis of a protein and discuss how the synthesis of type I collagen may be regulated in the fibrotic liver.