Fat–Storing Cells of the Rat Liver Synthesize and Secrete C1–Esterase Inhibitor; Modulation by Cytokines

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Abstract
During liver fibrogenesis, fat–storing cells transform into myofibroblast–like cells and produce increasing amounts of extracellular matrix proteins. Because fat–storing cells produce α2–macroglobulin, an important serine protease inhibitor (serpin), we investigated whether fat–storing cells also synthesize C1–esterase inhibitor, another important serpin. C1–esterase inhibitor synthesis was studied in rat fatstoring cells at day 0, 3 and 7 after isolation by biosynthetic labeling, immunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Messenger RNA was examined by Northern–blot analysis. C1–esterase inhibitor gene expression and synthesis were detectable in freshly isolated fat–storing cells and increased distinctly during the time in culture. The cellular source of C1–esterase inhibitor in fat–storing cell cultures was also identified by in situ hybridization of cells at different times after isolation. By inhibition of the N–glycosylation using tunicamycin, rat C1–esterase inhibitor was identified as a glycoprotein. The time course of C1–esterase inhibitor secretion was determined by pulse–chase experiments. C1–esterase inhibitor synthesis was increased 6–fold to 10–fold by interferon–γ. Specific messenger RNA levels were also raised distinctly by this cytokine. In contrast, interferon–α and dexamethasone did not alter C1–esterase inhibitor gene expression. Because C1–esterase inhibitor synthesis is increased by advancing culture time and by the inflammatory mediator interferon–γ, we suggest that fat–storing cells may enhance the deposition of extracellular matrix proteins by inhibiting their degradation. (Hepatology 1992;16:794-802.)