The mechanistic target of rapamycin complex 1 pathway involved in hepatic gluconeogenesis through peroxisome-proliferator-activated receptorγcoactivator-1a

Cattle can efficiently perform de novo generation of glucose through hepatic gluconeogenesis to meet post-weaning glucose demand.Substantial evidence points to cattle and non-ruminant animals being characterized by phylogenetic features in terms of their differing capacity for hepatic gluconeogenesis,a process that is highly efficient in cattle yet the underlying mechanism remains unclear.Here we used a variety of transcriptome data,as well as tissue and cell-based methods to uncover the mechanisms of high-efficiency hepatic gluconeogenesis in cattle.We showed that cattle can efficiently convert propionate into pyruvate,at least partly,via high expression of acyl-CoA synthetase short-chain family member 1(ACSS1),propionyl-CoA carboxylase alpha chain(PCCA),methylmalonyl-CoA epimerase(MCEE),methylmalonyl-CoA mutase(MMUT),and succinate-CoA ligase(SUCLG2)genes in the liver(P<0.01).Moreover,higher expression of the rate-limiting enzymes of gluconeogenesis,such as phosphoenolpyruvate carboxykinase(PCK)and fructose 1,6-bisphosphatase(FBP),ensures the efficient operation of hepatic gluconeogenesis in cattle(P<0.01).Mechanistically,we found that cattle liver exhibits highly active mechanistic target of rapamycin complex 1(mTORC1),and the expressions of PCCA,MMUT,SUCLG2,PCK,and FBP genes are regulated by the activation of mTORC1(P<0.001).Finally,our results showed that mTORC1 promotes hepatic gluconeogenesis in a peroxisome proliferator-activated receptor γ coactivator 1a(PGC-1a)dependent manner.Collectively,our results not only revealed an important mechanism responsible for the quantitative differences in the efficiency of hepatic gluconeogenesis in cattle versus non-ruminant animals,but also established that mTORC1 is indeed involved in the regulation of hepatic gluconeogenesis through PGC-1a.These results provide a novel potential insight into promoting hepatic gluconeogenesis through activated mTORC1 in both ruminants and mammals.

Role of small leucine zipper protein in hepatic gluconeogenesis and metabolic disorder

Hepatic gluconeogenesis is the central pathway for glucose generation in the body.The imbalance between glucose synthesis and uptake leads to metabolic diseases such as obesity,diabetes,and cardiovascular diseases.Small leucine zipper protein(sLZIP)is an isoform of LZIP and it mainly functions as a transcription factor.Although sLZIP is known to regulate the transcription of genes involved in various cellular processes,the role of sLZIP in hepatic glucose metabolism is not known.In this study,we investigated the regulatory role of sLZIP in hepatic gluconeogenesis and its involvement in metabolic disorder.We found that sLZIP expression was elevated during glucose starvation,leading to the promotion of phosphoenolpyruvate carboxylase and glucose-6-phosphatase expression in hepatocytes.However,sLZIP knockdown suppressed the expression of the gluconeogenic enzymes under low glucose conditions.sLZIP also enhanced glucose production in the human liver cells and mouse primary hepatic cells.Fasting-induced cyclic adenosine monophosphate impeded sLZIP degradation.Results of glucose and pyruvate tolerance tests showed that sLZIP transgenic mice exhibited abnormal blood glucose metabolism.These findings suggest that sLZIP is a novel regulator of gluconeogenic enzyme expression and plays a role in blood glucose homeostasis during starvation.

Ginsenoside Rg1 inhibits glucagon-induced hepatic gluconeogenesis through Akt-FoxO1 interaction

With the support by the National Natural Science Foundation of China,a collaborative study by the research groups led by Prof.Qi Lianwen(齐炼文)from the Clinical Metabolomics Center,Profs.Li Ping(李萍)and Liu Baolin(刘保林)from the State Key Laboratory of Natural Medicines。