The mitochondrial dicarboxylate carrier mediates in vivo hepatic gluconeogenesis
Year: 2024
Type: preprint
Abstract: SUMMARY Hepatic gluconeogenesis (GNG) is essential for maintaining euglycemia during prolonged fasting. However, GNG becomes pathologically elevated and drives chronic hyperglycemia in type 2 diabetes (T2D). Lactate/pyruvate is a major GNG substrate known to be imported into mitochondria for GNG. Yet, the subsequent mitochondrial carbon export mechanisms required to supply the extra-mitochondrial canonical GNG pathway have not been genetically delineated. Here, we evaluated the role of the mitochondrial dicarboxylate carrier (DiC) in mediating GNG from lactate/pyruvate. We generated liver-specific DiC knockout (DiC LivKO) mice. During lactate/pyruvate tolerance tests, DiC LivKO decreased plasma glucose excursion and 13 C-lactate/-pyruvate flux into hepatic and plasma glucose. In a Western diet (WD) feeding model of T2D, acute DiC LivKO after induction of obesity decreased lactate/pyruvate-driven GNG, hyperglycemia, and hyperinsulinemia. Our results show that mitochondrial carbon export through the DiC mediates GNG and that the DiC contributes to impaired glucose homeostasis in a mouse model of T2D.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: G303609221, Regulation of Hepatic Fuel Fluxes by the Mitochondrial Dicarboxylate Carrier, G3935655269, G4688961941, A Role for Mitochondrial Malate Transport in Hepatic Glucose Production during Type 2 Diabetes, G7222063055, G735473654, G8286602280, G9000069282, G9000124491, G9000127911, G9000181298, G9000189621, G9000252958, G9000268046, Role of ADH5 in the Regulation of Brown Adipose Tissue Metabolic Homeostasis, Medical Scientist Training Program
OpenAlex ID: W4402704374