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

ABSTRACT: BACKGROUND AND PURPOSE:Hepatic mitochondrial pyruvate carrier (MPC) transports pyruvate into mitochondria. This study investigated the involvement of MPC1 in hepatic glucagon response, in order to identify a possible pharmacological intervention. EXPERIMENTAL APPROACH:The correlation between hepatic glucagon response and MPC1 induction was investigated in fasted mice and primary hepatocytes. The effects of ginsenoside Rb1 on MPC1 function were observed. KEY RESULTS:Glucagon challenge raised blood glucose with hepatic MPC1 induction, and inhibition of MPC induction coincided with a reduced rise in blood glucose. cAMP-responsive element-binding protein (CREB) knockdown blocked glucagon-induced MPC1 expression, while CREB overexpression increased MPC1 expression. Luciferase reporter, chromatin immunoprecipitation assay, and promoter mutation confirmed that CREB increased MPC1 transcription through gene promoter induction. CREB regulated transcription co-activator 2 nuclear translocation was also required for CREB to promote MPC1 induction. Glucagon shifted mitochondrial pyruvate towards carboxylation for gluconeogenesis via the opposite regulation of pyruvate dehydrogenase and carboxylase with respect to MPC1 induction. MPC1 induction was necessary for glucagon to promote pyruvate-driven hepatic glucose production (HGP), but glucagon failed to influence HGP from other gluconeogenic substrates routed into the tricarboxylic acid cycle, independent of MPC. Rb1 blocked cAMP signalling by inhibiting AC activity and deactivated CREB by dephosphorylation, possibly contributing to inhibiting MPC1 induction to reduce HGP. CONCLUSIONS AND IMPLICATIONS:CREB transcriptionally up-regulates MPC1 to provide pyruvate for gluconeogenesis. Rb1 reduced cAMP formation which consequently reduced CREB-mediated MPC1 induction and thereby might contribute to limiting pyruvate-dependent HGP. These results suggest a therapeutic strategy to reduce hyperglycaemia in diabetes.

SUBMITTER: Lou MD

PROVIDER: S-EPMC6637041 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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

Lou Meng-Die MD Li Jia J Cheng Yao Y Xiao Na N Ma Gaoxiang G Li Ping P Liu Baolin B Liu Qun Q Qi Lian-Wen LW

British journal of pharmacology 20190706 16

<h4>Background and purpose</h4>Hepatic mitochondrial pyruvate carrier (MPC) transports pyruvate into mitochondria. This study investigated the involvement of MPC1 in hepatic glucagon response, in order to identify a possible pharmacological intervention.<h4>Experimental approach</h4>The correlation between hepatic glucagon response and MPC1 induction was investigated in fasted mice and primary hepatocytes. The effects of ginsenoside Rb1 on MPC1 function were observed.<h4>Key results</h4>Glucagon ...[more]

PMID: 31166615

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Project description:Hepatitis B virus (HBV) is a major risk factor for serious liver diseases. The liver plays a unique role in controlling carbohydrate metabolism to maintain the glucose level within the normal range. Chronic HBV infection has been reported to associate with a high prevalence of diabetes. However, the detailed molecular mechanism underlying the potential association remains largely unknown. Here, we report that liver-targeted delivery of small HBV surface antigen (SHBs), the most abundant viral protein of HBV, could elevate blood glucose levels and impair glucose and insulin tolerance in mice by promoting hepatic gluconeogenesis. Hepatocytes with SHB expression also exhibited increased glucose production and expression of gluconeogenic genes glucose-6-phosphatase (G6pc) and phosphoenolpyruvate carboxykinase (PEPCK) in response to glucagon stimulation. Mechanistically, SHBs increased cellular levels of cyclic AMP (cAMP) and consequently activated protein kinase A (PKA) and its downstream effector cAMP-responsive element binding protein (CREB). SHBs-induced activation of CREB enhanced transcripts of gluconeogenic genes, thus promoting hepatic gluconeogenesis. The elevated cAMP level resulted from increased transcription activity and expression of adenylyl cyclase 1 (AC1) by SHBs through a binary E-box factor binding site (BEF). Taken together, we unveiled a novel pathogenic role and mechanism of SHBs in hepatic gluconeogenesis, and these results might highlight a potential target for preventive and therapeutic intervention in the development and progression of HBV-associated diabetes. IMPORTANCE Chronic HBV infection causes progressive liver damage and is found to be a risk factor for diabetes. However, the mechanism in the regulation of glucose metabolism by HBV remains to be established. In the current study, we demonstrate for the first time that the small hepatitis B virus surface antigen (SHBs) of HBV elevates AC1 transcription and expression to activate cAMP/PKA/CREB signaling and subsequently induces the expression of gluconeogenic genes and promotes hepatic gluconeogenesis both in vivo and in vitro. This study provides a direct link between HBV infection and diabetes and implicates that SHBs may represent a potential target for the treatment of HBV-induced metabolic disorders.

Dataset Information

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

Publications

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

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