The mitochondrial pyruvate carrier mediates high fat diet-induced increases in hepatic TCA cycle capacity

Abstract

ObjectiveExcessive hepatic gluconeogenesis is a defining feature of type 2 diabetes (T2D). Most gluconeogenic flux is routed through mitochondria. The mitochondrial pyruvate carrier (MPC) transports pyruvate from the cytosol into the mitochondrial matrix, thereby gating pyruvate-driven gluconeogenesis. Disruption of the hepatocyte MPC attenuates hyperglycemia in mice during high fat diet (HFD)-induced obesity but exerts minimal effects on glycemia in normal chow diet (NCD)-fed conditions. The goal of this investigation was to test whether hepatocyte MPC disruption provides sustained protection from hyperglycemia during long-term HFD and the differential effects of hepatocyte MPC disruption on TCA cycle metabolism in NCD versus HFD conditions.MethodWe utilized long-term high fat feeding, serial measurements of postabsorptive blood glucose and metabolomic profiling and 13C-lactate/13C-pyruvate tracing to investigate the contribution of the MPC to hyperglycemia and altered hepatic TCA cycle metabolism during HFD-induced obesity.ResultsHepatocyte MPC disruption resulted in long-term attenuation of hyperglycemia induced by HFD. HFD increased hepatic mitochondrial pyruvate utilization and TCA cycle capacity in an MPC-dependent manner. Furthermore, MPC disruption decreased progression of fibrosis and levels of transcript markers of inflammation.ConclusionsBy contributing to chronic hyperglycemia, fibrosis, and TCA cycle expansion, the hepatocyte MPC is a key mediator of the pathophysiology induced in the HFD model of T2D.

Two human patient mitochondrial pyruvate carrier mutations reveal distinct molecular mechanisms of dysfunction

“…Both MPC1 and MPC2 mouse knockout models display embryonic lethality during midgestation (21,31) and MPC1 hypomorphs caused early perinatal lethality (20). In contrast, postnatal liver-specific MPC disruption attenuates obesity-induced hyperglycemia (11,12) and decreases fibrosis and inflammation in mouse models of nonalcoholic fatty liver disease (NAFLD) and NASH (14,32). The contrast between the clearly pathological effects of whole-body MPC disruption during prenatal development versus potential therapeutic effects of liver MPC disruption after development highlights the need to better understand tissue-specific pyruvate metabolism across developmental stages.…”

“…Disruption of the liver MPC lowers blood glucose during diabetes (11,12), and attenuates non-alcoholic steatohepatitis (NASH; refs. 13,14). Conversely, decreased MPC expression and activity increases stemness in some cancers (15)(16)(17)(18)(19).…”

Melatonin attenuates renal fibrosis in diabetic mice by activating the AMPK/PGC1α signaling pathway and rescuing mitochondrial function

“…Pierelli et al (59) demonstrated that hyperglycemia-induced downregulation of uncoupling protein 2 expression impairs mitochondrial membrane potential and induces energy metabolism disorder. Besides, suppression of the mitochondrial tricarboxylic acid cycle due to chronic high glucose injury causes energy undersupply (60) and results in abnormal lipid metabolism. Similar to these reports, the present study demonstrated that high glucose induced excessive ROS production and impaired the glomerular anti-oxidative system, resulting in opening of the mPTP.…”

Glucagon up‐regulates hepatic mitochondrial pyruvate carrier 1 through cAMP‐responsive element‐binding protein; inhibition of hepatic gluconeogenesis by ginsenoside Rb1

“…Because MPC1 and MPC2 associate in an oligomer, loss of either protein can impair the stability of the other, resulting in loss of MPC function (Bender, Pena, & Martinou, 2015;Bricker et al, 2012;Herzig et al, 2012). In high fat diet-fed mice, MPC mediates increased hepatic mitochondrial pyruvate utilization, contributing to hyperglycaemia and liver fibrosis (Rauckhorst et al, 2017). In diabetic mice, MPC function is enhanced to ensure efficient gluconeogenesis while loss of MPC activity attenuates hyperglycaemia (Gray et al, 2015;McCommis et al, 2015).…”