The subject of this study is intercellular compartmentation of liver metabolism and its regulatory importance for the maintainance of the homeostasis of glucose. Metabolic cell heterogeneity is expected to be of considerable regulatory importance, especially where opposing catalytic steps proceed simultaneously. The extent to which functional heterogeneity prevents futile substrate cycling in opposing catalytic steps remains unclear and the characteristics of such heterogeneity are not yet established. The proposed study is to determine differences among hepatocytes along the sinusoid, with regard to metabolic parameters of glucose uptake and release and ketogenesis. This study uses microanalytical biochemistry as a unique means to quantitate regional differences in enzyme activity and metabolites, a methodology eliminating problems associated with biochemical studies of whole liver. Metabolic compartmentation will be examined under the following topics: 1) Differences in the contribution of hepatocytes along the sinusoid to overall glucose uptake and release; 2) It will be tested how glycogen metabolism correlates with regional differences in glucose uptake and release; 3) The influence of changes in enzyme activity on glucose flux will be tested using starved animals; 4) To understand the regional mechanism of replacement of glucose by ketone bodies, ketogenesis will be investigated in the fed and fasting state; 5) Carbohydrate metabolism and ketogenesis will be studied in male and female animals to differentiate between general and sex related characteristics of intercellular compartmentation. The ultimate objective is to gain understanding of the principles of the functional organization of liver parenchyma that can serve as a solid basis for the investigation of pathological alterations of liver metabolism in man.
