Nur77 suppresses hepatocellular carcinoma via switching glucose metabolism toward gluconeogenesis through attenuating phosphoenolpyruvate carboxykinase sumoylation

The liver is essential in maintaining and regulating glucose homeostasis during prolonged exercise. IL-6 has been shown to be secreted from skeletal muscle during exercise and has been suggested to signal to the liver. Therefore, the aim of this study was to investigate the role of skeletal muscle IL-6 on hepatic glucose regulation and substrate choice during prolonged exercise. Skeletal muscle-specific IL-6 knockout (IL-6 MKO) mice (age, 12–14 wk) and littermate lox/lox (Control) mice were either rested (Rest) or completed a single bout of exercise for 10, 60, or 120 min, and the liver was quickly obtained. Hepatic IL-6 mRNA was higher at 60 min of exercise, and hepatic signal transducer and activator of transcription 3 was higher at 120 min of exercise than at rest in both genotypes. Hepatic glycogen was higher in IL-6 MKO mice than control mice at rest, but decreased similarly during exercise in the two genotypes, and hepatic glucose content was lower in IL-6 MKO than control mice at 120 min of exercise. Hepatic phosphoenolpyruvate carboxykinase mRNA and protein increased in both genotypes at 120 min of exercise, whereas hepatic glucose 6 phosphatase protein remained unchanged. Furthermore, IL-6 MKO mice had higher hepatic pyruvate dehydrogenase (PDH)Ser232 and PDHSer300 phosphorylation than control mice at rest. In conclusion, hepatic gluconeogenic capacity in mice is increased during prolonged exercise independent of muscle IL-6. Furthermore, Skeletal muscle IL-6 influences hepatic substrate regulation at rest and hepatic glucose metabolism during prolonged exercise, seemingly independent of IL-6 signaling in the liver.

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The regulation of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase by autophagy in low-glycolytic hepatocellular carcinoma cells

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2015.05.103 ◽

2015 ◽

Vol 463 (3) ◽

pp. 440-446 ◽

Cited By ~ 9

Author(s):

Jeong Yong Jeon ◽

Hyangkyu Lee ◽

Jeayeo Park ◽

Misu Lee ◽

Sae Whan Park ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Phosphoenolpyruvate Carboxykinase ◽

Carcinoma Cells ◽

Hepatocellular Carcinoma Cells

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Effect of nighttime light exposure on glucose metabolism in protein-restricted mice.

Journal of Endocrinology ◽

10.1530/joe-21-0133 ◽

2021 ◽

Author(s):

Patricia Cristine Borck ◽

Sarah Rickli ◽

Jean Franciesco Vettorazzi ◽

Thiago Martins Batista ◽

Antonio Carlos Boschero ◽

...

Keyword(s):

Energy Metabolism ◽

Glucose Metabolism ◽

Phosphoenolpyruvate Carboxykinase ◽

Metabolic Diseases ◽

Light Exposure ◽

Biological Rhythms ◽

Fibroblast Growth Factor 21 ◽

Low Protein ◽

Nighttime Light ◽

Fgf21 Expression

Disruption of biological rhythms due exposure to artificial light at night (ALAN) has been emerged as new risk factor for metabolic diseases. However, it remains largely unexplored the effects induced by exposure to ALAN on energy metabolism with concomitant misalignment in the circadian system caused by nutritional imbalance. Objective: Here we evaluate whether low-protein diet could enhance the effects induced by exposure to ALAN on the energy metabolism and consequently predispose to metabolic disorders. Male C57BL6/J mice were weaned on a normal protein (NP) or a low-protein (LP) diet and housed on 12h light/dark (L/D) cycle. After 6 weeks, mice maintained on their respective diets were subdivided into normal light/dark cycle or exposed to ALAN for 8 weeks. We observed that exposure to ALAN concomitant to LP diet disrupts the behavioral rhythms, without shifting the timing of food intake. Furthermore, exposure to ALAN lead to increased body and fat pad weights, higher levels of fast and fed glycemia and glucose intolerance independent of the diet consumed. Importantly the insulin resistance developed in mice exposed to ALAN was diet-dependent. At the molecular level, exposure to ALAN concurrent with LP diet increased the expression of Phosphoenolpyruvate carboxykinase 1 in both periods analyzed and inverted the pattern of Fibroblast growth factor 21 (Fgf21) expression in the liver. Our data suggest that dietary protein restriction modulates the effects induced by nighttime light exposure on glucose metabolism, which could be partially related with the dysregulation on hepatic Fgf21 expression.

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Antibiotic-induced microbiome depletion alters renal glucose metabolism and exacerbates renal injury after ischemia-reperfusion injury in mice

AJP Renal Physiology ◽

10.1152/ajprenal.00111.2021 ◽

2021 ◽

Author(s):

Yuika Osada ◽

Shunsaku Nakagawa ◽

Kanako Ishibe ◽

Shota Takao ◽

Aimi Shimazaki ◽

...

Keyword(s):

Glucose Metabolism ◽

Glucose Homeostasis ◽

Phosphoenolpyruvate Carboxykinase ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Critical Role ◽

Kidney Injury ◽

Short Chain Fatty Acids ◽

Glucose Levels ◽

The Impact

Recent studies have revealed the impact of antibiotic-induced microbiome depletion (AIMD) on host glucose homeostasis. The kidney has a critical role in systemic glucose homeostasis; however, information regarding the association between AIMD and renal glucose metabolism remains limited. Hence, we aimed to determine the effects of AIMD on renal glucose metabolism by inducing gut microbiome depletion using an antibiotic cocktail (ABX) composed of ampicillin, vancomycin, and levofloxacin in mice. The results showed that the bacterial 16s rRNA expression, luminal concentrations of short-chain fatty acids and bile acids, and plasma glucose levels were significantly lower in ABX-treated mice than in vehicle-treated mice. In addition, ABX treatment significantly reduced renal glucose and pyruvate levels. The mRNA expression levels of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase in the renal cortex were significantly higher in ABX-treated mice than in vehicle-treated mice. We further examined the impact of AIMD on the altered metabolic status in mice after ischemia-induced kidney injury. After exposure to ischemia for 60 min, the renal pyruvate concentrations were significantly lower in ABX-treated mice than in vehicle-treated mice. ABX treatment caused a more severe tubular injury after ischemia-reperfusion (IR). Our findings confirm that AIMD is associated with decreased pyruvate levels in the kidney, which may have been caused by the activation of renal gluconeogenesis. Thus, we hypothesized that AIMD would increase the vulnerability of the kidney to IR injury.

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Transcathether arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): Report on TACE-related glucose metabolism impairement and survival

Hepatology ◽

10.1016/0270-9139(94)90397-2 ◽

1994 ◽

Vol 19 (4) ◽

pp. I57

Author(s):

N De Maria

Keyword(s):

Hepatocellular Carcinoma ◽

Glucose Metabolism ◽

Arterial Chemoembolization

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Inhibiting histone deacetylases suppresses glucose metabolism and hepatocellular carcinoma growth by restoring FBP1 expression

Scientific Reports ◽

10.1038/srep43864 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 25

Author(s):

Jing Yang ◽

Xin Jin ◽

Yuqian Yan ◽

Yingjie Shao ◽

Yunqian Pan ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Glucose Metabolism ◽

Histone Deacetylases

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PCK1 Deficiency Shortens the Replicative Lifespan of Saccharomyces cerevisiae through Upregulation of PFK1

BioMed Research International ◽

10.1155/2020/3858465 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10 ◽

Cited By ~ 1

Author(s):

Yuan Yuan ◽

Jia-ying Lin ◽

Hong-jing Cui ◽

Wei Zhao ◽

Hui-ling Zheng ◽

...

Keyword(s):

Saccharomyces Cerevisiae ◽

Glucose Metabolism ◽

Aging Process ◽

Phosphoenolpyruvate Carboxykinase ◽

Critical Role ◽

Ros Generation ◽

High Throughput Analysis ◽

Replicative Lifespan ◽

Regulatory Pathways ◽

Glucose Levels

The cytosolic isozyme of phosphoenolpyruvate carboxykinase (PCK1) was the first rate-limiting enzyme in the gluconeogenesis pathway, which exerted a critical role in maintaining the blood glucose levels. PCK1 has been established to be involved in various physiological and pathological processes, including glucose metabolism, lipid metabolism, diabetes, and tumorigenesis. Nonetheless, the association of PCK1 with aging process and the detailed underlying mechanisms of PCK1 on aging are still far to be elucidated. Hence, we herein constructed the PCK1-deficient (pck1Δ) and PCK1 overexpression (PCK1 OE) Saccharomyces cerevisiae. The results unveiled that PCK1 deficiency significantly shortened the replicative lifespan (RLS) in the S. cerevisiae, while overexpression of PCK1 prolonged the RLS. Additionally, we noted that the ROS level was significantly enhanced in PCK1-deficient strain and decreased in PCK1 OE strain. Then, a high throughput analysis by deep sequencing was performed in the pck1Δ and wild-type strains, in an attempt to shed light on the effect of PCK1 on the lifespan of aging process. The data showed that the most downregulated mRNAs were enriched in the regulatory pathways of glucose metabolism. Fascinatingly, among the differentially expressed mRNAs, PFK1 was one of the most upregulated genes, which was involved in the glycolysis process and ROS generation. Thus, we further constructed the pfk1Δpck1Δ strain by deletion of PFK1 in the PCK1-deficient strain. The results unraveled that pfk1Δpck1Δ strain significantly suppressed the ROS level and restored the RLS of pck1Δ strain. Taken together, our data suggested that PCK1 deficiency enhanced the ROS level and shortened the RLS of S. cerevisiae via PFK1.

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Polybrominated Diphenyl Ethers Alter Hepatic Phosphoenolpyruvate Carboxykinase Enzyme Kinetics in Male Wistar Rats: Implications for Lipid and Glucose Metabolism

Journal of Toxicology and Environmental Health Part A ◽

10.1080/15287394.2012.738457 ◽

2013 ◽

Vol 76 (2) ◽

pp. 142-156 ◽

Cited By ~ 33

Author(s):

Jessica T. Nash ◽

David T. Szabo ◽

Gale B. Carey

Keyword(s):

Glucose Metabolism ◽

Enzyme Kinetics ◽

Polybrominated Diphenyl Ethers ◽

Wistar Rats ◽

Phosphoenolpyruvate Carboxykinase ◽

Diphenyl Ethers ◽

Male Wistar Rats

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MiR-130a-3p Regulates the Glycolysis via Targeting PDK1 in Hepatocellular Carcinoma

10.21203/rs.3.rs-1155969/v1 ◽

2021 ◽

Author(s):

Hai-Long Li ◽

Jie Shi ◽

Qi Qi ◽

Yue Huang ◽

Chi Liu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Glucose Metabolism ◽

Pyruvate Dehydrogenase ◽

Pyruvate Dehydrogenase Kinase ◽

Luciferase Reporter ◽

Luciferase Reporter Gene ◽

And Migration ◽

Low Expression ◽

Hcc Cells

Abstract MiR-130a-3p has been certified to have low expression in several types of tumors. However, the function of miR-130a-3p in glucose metabolism and hepatocellular carcinoma progression is still elusive. Here we report that miR-130a-3p has explicitly low expression in human HCC tissues and cells and is closely related to the patient's tumor size and grade. Overexpression of miR-130a-3p significantly inhibits the glucose metabolism, proliferation and migration of HCC cells in vitro. In order to further study the effects of miR-130a-3p in the glucose metabolism of HCC cells, we found that overexpression of miR-130a-3p significantly inhibited the expression of pyruvate dehydrogenase kinase 1 (PDK1). Consistently, we confirmed that PDK1 is the target gene of miR-130a-3p through dual luciferase reporter gene assays. Cell rescue experiments showed that PDK1 inhibitors reversed the enhancement of cell proliferation, migration and glucose metabolism by miR-130a-3p inhibitor in Hep3B cells. In terms of mechanism, overexpression of miR-130a-3p targeted and inhibited the expression of PDK1, after which pyruvate dehydrogenase (PDH) is activated, thus glycolysis is inhibited, the production of lactic acid and ATP is reduced, and the ability to proliferate and migrate in HCC cells is weakened. In conclusion, our study highlights efforts to target PDK1 and miR-130a-3p as potential therapeutic strategies for the treatment of HCC.

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