Zonation of glucose and fatty acid metabolism in the liver: mechanism and metabolic consequences

The liver is generally considered as a relatively homogeneous organ containing four different cell types. It is however well-known that the liver is not homogeneous and consists of clearly demarcated metabolic zones. Hepatocytes from different zones show phenotypical heterogeneity in metabolic features, leading to zonation of metabolic processes across the liver acinus. Zonation of processes involved in glucose and fatty acid metabolism is rather flexible and therefore prone to change under (patho)physiological conditions. Hepatic zonation appears to play an important role in the segregation of the different metabolic pathways in the liver. As a consequence, perturbations in metabolic zonation may be a part of metabolic liver diseases. The metabolic syndrome is characterized by the inability of insulin to adequately suppress hepatic gluconeogenesis, leading to hyperglycemia, hyperinsulinemia and eventually to type II diabetes. As insulin promotes lipogenesis through the transcription factor sterol regulatory element binding protein (SREBP)-1c, one would expect that lipogenesis should also be impaired in insulin-resistant states. However, in the metabolic syndrome hepatic de novo lipogenesis is increased, leading to hyperlipidemia and hepatosteatosis, primarily in the pericentral zone. These observations suggest the co-existence of insulin resistant glucose metabolism and insulin sensitive lipid metabolism in the metabolic syndrome. Here we provide a theoretical framework to explain this so-called 'insulin signaling paradox' in the context of metabolic zonation of the liver.