Thursday, December 26, 2024
12/26/2024
PROJECT SUMMARY Hepatic fuel fluxes underly numerous processes critical to whole-body physiology that become dysregulated in type 2 diabetes (T2D). Among these is the basic biosynthetic process of gluconeogenesis (GNG), which increases during and contributes to the pathophysiology of T2D. Thus, understanding the regulation of the fuel fluxes supplying hepatic GNG is important for understanding both normal and T2D whole-body physiology and metabolism. The TCA cycle anaplerotic (refilling) mechanisms sustaining carbon flux into GNG have been investigated intensively. However, the greatest hypothesized net TCA cycle cataplerotic (withdrawing) pathway, malate export through the mitochondrial dicarboxylate carrier (DiC), has received sparse direct experimental attention in vivo. Elegant, early, ex vivo biochemical studies suggest that mitochondrial malate export through the DiC supports hepatic GNG. However, this idea has been almost totally unaddressed in the molecular era. The overall goal of this application is to understand how the DiC contributes to hepatic GNG in normal and T2D states and the mechanisms by which hepatic DiC function is altered during T2D. Based on our preliminary data, the central hypothesis of this application is that the DiC feeds hepatic GNG by supplying carbon and reducing equivalents, becomes misregulated during T2D and contributes to excessive GNG, and may be disrupted to attenuate T2D. Using mouse genetics, primary cell culture systems, stable-isotope metabolomic tracing, luciferase reporter assays, and proteomic analysis, we will test this hypothesis by pursuing two specific aims: 1) Determine the role of the DiC in hepatic gluconeogenesis (GNG) in normal and T2D states; and 2) Define the mechanistic regulation of DiC abundance and gluconeogenic activity. This research is significant because successful completion will delineate the role of the hepatic DiC as a fundamental regulator of liver and whole-body metabolism and in the elevated GNG of T2D. This research is innovative because it will utilize novel genetic DiC loss- and gain-of-function models to finally test the role of the DiC in linking mitochondrial metabolism and GNG in T2D. The consequence of not doing this research is that the role of the DiC in hepatic GNG and its contribution to T2D will remain undefined.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).