Metabolic consequences of zonal defects in gluconeogenesis

Ut Southwestern Medical Center, Dallas TX

Investigators

Abstract

PROJECT SUMMARY Liver metabolic zonation refers to how liver cells, or hepatocytes, are spatially organized to perform diverse functions such as breaking down toxins or maintaining systemic metabolic homeostasis. This division of labor is crucial for the liver's efficiency but, when disrupted, may underlie various liver diseases, including metabolic disorders and cancer. The lack of genetic tools to specifically target hepatocytes within different liver zones of live mice has hampered our understanding of how zonation impacts disease. In this project, I aim to bridge this gap by employing novel Zone-specific-CreER mouse models developed in our laboratory. These models will enable precise spatial inhibition of key metabolic processes—gluconeogenesis and glycogenolysis—within distinct liver zones: near the portal vein (zone 1), in the middle of the lobule (zone 2), and adjacent to the central vein (zone 3). Gluconeogenesis and glycogenolysis are dysfunctional in Glycogen Storage Disease Type 1a (GSD1a), a condition affecting 1 in 100,000 newborns in the U.S., caused by mutations in the G6PC1 gene. GSD1a manifests through specific and measurable signs including fasting hypoglycemia, lactic acidosis, and hyperuricemia. Patients also develop hepatic adenomas during their teen years, with some tumors progressing to hepatocellular carcinoma (HCC). In mice, G6pc1 deletion from all hepatocytes mimics human GSD1a, including tumorigenesis. Somatic loss of function mutations in G6PC1 are found in >2% of sporadic, adult-onset HCC, and decreased G6PC1 expression is correlated with poor outcomes, implying a role for G6PC1 in HCC even beyond GSD1a. Given that gluconeogenesis and glycogenolysis are highly localized processes, predominantly occurring in zone 1, I hypothesize that specific knockout of G6pc1 in this zone will reproduce GSD1a symptoms. To test this hypothesis, I will undertake two aims. Aim 1 focuses on measuring key metabolic indicators of GSD1a after zone-specific G6pc1 knockout (KO) and assessing compensatory mechanisms of hepatocytes across different liver zones. Aim 2 explores how zonal G6pc1 KO influences hepatocyte competition dynamics, clonal expansion, and tumorigenesis, addressing the unique cancer development pathway seen in GSD1a patients. This study is poised to provide significant insights into the role of metabolic zonation in liver health and disease, aligning closely with the NIDDK's mission to enhance our understanding of liver metabolic diseases. Through detailed genetic, biochemical, and sequencing analyses, I will explore the relationship between liver zonation and disease, potentially leading to novel therapeutic strategies for conditions like GSD1a and beyond. This approach not only advances fundamental liver biology but also offers a new lens through which to examine liver disease pathophysiology.