A Gluconeogenesis-Related Genes Model for Predicting Prognosis, Tumor Microenvironment Infiltration, and Drug Sensitivity in Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) is a prevalent malignancy within the digestive system, known for its poor prognosis. Gluconeogenesis, a critical metabolic pathway, is responsible for the synthesis of glucose in the normal liver. This study aimed to examine the role of gluconeogenesis-related genes (GRGs) in HCC and evaluate their impact on the tumor microenvironment infiltration and drug sensitivity in HCC. Methods: We retrieved gene expression and clinical pathological data of HCC from The Cancer Genome Atlas (TCGA) database. This dataset was utilized to develop a prognosis model. The data from The International Cancer Genome Consortium (ICGC) served as an independent validation cohort. A least absolute shrinkage and selection operator (LASSO) regression analysis was applied to a curated panel of GRGs to construct and validate the predictive model. Furthermore, unsupervised consensus clustering, based on the expression levels of GRGs, categorized HCC patients into distinct subgroups. Results: A four-gene prognostic model, referred to as GRGs, has been successfully developed with high accuracy and stability for the prediction of HCC patient prognosis. This model enables the stratification of patients into high or low risk groups based on individual risk scores, revealing significant differences in immune infiltration patterns and anti-tumor drug responses. Unsupervised consensus clustering analysis delineated four distinct subgroups of patients, each characterized by a unique prognosis and tumor immune microenvironment (TIME). Conclusion: This study is the first to develop a prognostic model incorporating 4-GRGs that effectively predicts the prognosis, tumor microenvironment infiltration, and drug sensitivity in HCC patients. The model based on 4 GRGs may contribute to predict the prognosis, immunotherapy and chemotherapy response of HCC patients.

Dissociation between liver fat content and fasting metabolic markers of selective hepatic insulin resistance in humans.

OBJECTIVE: Fasting hyperglycemia and hypertriglyceridemia are characteristic of insulin resistance (IR) and rodent work has suggested this may be due to selective hepatic IR; defined by increased hepatic gluconeogenesis and de novo lipogenesis (DNL), but this has not been shown in humans. DESIGN: Cross-sectional study in men and women across a range of adiposity. METHODS: Medication-free participants (n=177) were classified as normoinsulinemic (NI) or hyperinsulinemic (HI) and as having low (LF) or high (HF) liver fat content measured by magnetic resonance spectroscopy. Fractional gluconeogenesis (frGNG) and hepatic DNL were measured using stable isotope tracer methodology following an overnight fast. RESULTS: Although HI and HF groups had higher fasting plasma glucose and triglyceride concentrations when compared to NI and LF groups respectively, there was no difference in frGNG. However, HF participants tended to have lower frGNG than LF participants. HI participants had higher DNL compared to NI participants but there was no difference observed between liver fat groups. CONCLUSIONS: Taken together, we found no metabolic signature of selective hepatic IR in fasting humans. DNL may contribute to hypertriglyceridemia in individuals with HI but not those with HF. Glycogenolysis and systemic glucose clearance may have a larger contribution to fasting hyperglycemia than gluconeogenesis, especially in those with HF and these pathways should be considered for therapeutic targeting.

Silencing the glycerol-3-phosphate acyltransferase-1 gene in the liver of mice fed a high-fat diet, enhances insulin sensitivity and glucose metabolism by promoting fatty acid beta-oxidation.

BACKGROUND: Liver plays a central role in systemic glucose and lipid metabolism. High-fat diet (HFD) and obesity are related to hepatic lipid accumulation and insulin resistance (InsR). Diacylglycerols (DAG) play a key role in the induction of InsR, however their involvement in hepatic InsR remains debated. This study aimed to clarify and confirm the role of glycero-3-phosphate acyltransferase 1 (GPAT1), a rate-limiting enzyme in DAG synthesis, in the progression of hepatic InsR in the context of HFD-induced lipid accumulation and insulin resistance in the liver. METHODS: Liver-targeted GPAT1 silencing was performed using shRNA-mediated hydrodynamic gene delivery. Lipid species including LCA-CoA, sphingolipids, DAG and acyl-carnitines were quantified using UHPLC/MS/MS while insulin signalling was assessed at protein level by Western Blot. Hepatic glucose metabolism, including glucose-6-pasphate content and gluconeogenesis rate was evaluated using GC/MS. RESULTS: HFD-fed animals developed InsR, evidenced by increased HOMA-IR, enhanced gluconeogenesis and reduced glycogen content compared to controls. Hepatic GPAT1 silencing in HFD-fed animals resulted in a significant reduction of DAG and TAG levels, increased acyl-carnitines content and upregulated mitochondrial ß-oxidation protein expression. These changes were accompanied by improved insulin signalling, enhanced glycogen storage, and reduced gluconeogenesis. CONCLUSIONS: Silencing GPAT1, and thereby reducing glycerolipid synthesis, promotes ß-oxidation and ameliorates HFD-induced hepatic insulin resistance, confirming the enzyme's pivotal role in liver metabolic dysfunction associated with increased lipid supply.

Fibroblast growth factor 1 (FGF1) improves glucose homeostasis, modulates gut microbial composition, and reduces inflammatory responses in rainbow trout (Oncorhynchus mykiss) fed a high-fat diet.

High-fat diets (HFDs) are widely used in aquaculture due to their lipid and protein-conserving effects, thereby reducing feed costs. However, prolonged feeding of HFD often leads to metabolic disorders in fish, such as disruption of hepatic lipid homeostasis, liver injury, and disruption of glucose homeostasis. Fibroblast growth factor 1 (FGF1) plays an essential role in controlling glucose levels in the body and dampening immune reactions. However, its impact on teleosts remains poorly researched. The therapeutic potential of recombinant FGF1 (rFGF1) was examined in a 6-week culture experiment involving rainbow trout (Oncorhynchus mykiss) that were fed an HFD. The results revealed that rFGF1 significantly reduced serum glucose levels and hepatic PEPCK and G6PC activities, but improved hepatic glycogen (P < 0.05), compared to the HFD + PBS group. Further experiments indicated that the inhibitory effect of rFGF1 on hepatic gluconeogenesis was mediated by the cAMP signaling pathway and was dependent on the high expression of PDE4. In addition, rFGF1 increased hepatic glycogen content, which involves the AKT-GSK3ß axis. Despite this increase, rFGF1 did not lead to glycogen storage disease, as shown by reduced hepatic inflammation as a result of decreased GOT (glutamic oxaloacetic transaminase), GPT (glutamic pyruvic transaminase), and elevated SOD (superoxide dismutase) in the rFGF1-treated group, accompanied by decreased il-1ß, il-6, and xbp-1, and elevated nrf2 and number of hepatocyte autophagosomes. Alterations in gut microbes and short-chain fatty acids (SCFAs) were noted, indicating that rFGF1 caused a notable rise in intestinal Lactobacillus, acetic acid, and butyric acid levels. This study investigated the molecular mechanisms of rFGF1 on glucose metabolism and inflammatory responses in an HFD-fed rainbow trout model, providing new insights to improve the regulation of glucose metabolism in carnivorous fish.

Hypoxanthine ameliorates diet-induced insulin resistance by improving hepatic lipid metabolism and gluconeogenesis via AMPK/mTOR/PPARα pathway.

AIM: Insulin resistance (IR) is a pivotal metabolic disorder associated with type 2 diabetes and metabolic syndrome. This study investigated the potential of hypoxanthine (Hx), a purine metabolite and uric acid precursor, in ameliorating IR and regulating hepatic glucose and lipid metabolism. METHODS: We utilized both in vitro IR-HepG2 cells and in vivo diet-induced IR mice to investigate the impact of Hx. The HepG2 cells were treated with Hx to evaluate its effects on glucose production and lipid deposition. Activity-based protein profiling (ABPP) was applied to identify Hx-target proteins and the underlying pathways. In vivo studies involved administration of Hx to IR mice, followed by assessments of IR-associated indices, with explores on the potential regulating mechanisms on hepatic glucose and lipid metabolism. KEY FINDINGS: Hx intervention significantly reduced glucose production and lipid deposition in a dose-dependent manner without affecting cell viability in IR-HepG2 cells. ABPP identified key Hx-target proteins engaged in fatty acid and pyruvate metabolism. In vivo, Hx treatment reduced IR severities, as evidenced by decreased HOMA-IR, fasting blood glucose, and serum lipid profiles. Histological assessments confirmed reduced liver lipid deposition. Mechanistic insights revealed that Hx suppresses hepatic gluconeogenesis and fatty acid synthesis, and promotes fatty acid oxidation via the AMPK/mTOR/PPARα pathway. SIGNIFICANCE: This study delineates a novel role of Hx in regulating hepatic metabolism, offering a potential therapeutic strategy for IR and associated metabolic disorders. The findings provide a foundation for further investigation into the role of purine metabolites in metabolic regulation and their clinical implications.

Harnessing de novo transcriptome sequencing to identify and characterize genes regulating carbohydrate biosynthesis pathways in Salvia guaranitica L.

Introduction: Carbohydrate compounds serve multifaceted roles, from energy sources to stress protectants, found across diverse organisms including bacteria, fungi, and plants. Despite this broad importance, the molecular genetic framework underlying carbohydrate biosynthesis pathways, such as starch, sucrose, and glycolysis/gluconeogenesis in Salvia guaranitica, remains largely unexplored. Methods: In this study, the Illumina-HiSeq 2500 platform was used to sequence the transcripts of S. guaranitica leaves, generating approximately 8.2 Gb of raw data. After filtering and removing adapter sequences, 38 million reads comprising 210 million high-quality nucleotide bases were obtained. De novo assembly resulted in 75,100 unigenes, which were annotated to establish a comprehensive database for investigating starch, sucrose, and glycolysis biosynthesis. Functional analyses of glucose-6-phosphate isomerase (SgGPI), trehalose-6-phosphate synthase/phosphatase (SgT6PS), and sucrose synthase (SgSUS) were performed using transgenic Arabidopsis thaliana. Results: Among the unigenes, 410 were identified as putatively involved in these metabolic pathways, including 175 related to glycolysis/gluconeogenesis and 235 to starch and sucrose biosynthesis. Overexpression of SgGPI, SgT6PS, and SgSUS in transgenic A. thaliana enhanced leaf area, accelerated flower formation, and promoted overall growth compared to wild-type plants. Discussion: These findings lay a foundation for understanding the roles of starch, sucrose, and glycolysis biosynthesis genes in S. guaranitica, offering insights into future metabolic engineering strategies for enhancing the production of valuable carbohydrate compounds in S. guaranitica or other plants.

Piperlongumine, a natural alkaloid from Piper longum L. ameliorates metabolic-associated fatty liver disease by antagonizing the thromboxane A2 receptor.

Metabolic dysfunction-associated fatty liver disease (MAFLD) encompasses a broad spectrum of hepatic disorders, including hyperglycemia, hepatic steatosis, and insulin resistance. Piperlongumine (PL), a natural amide alkaloid extracted from the fruits of Piper longum L., exhibited hepatoprotective effects in zebrafish and liver injury mice. This study aimed to investigate the therapeutic potential of PL on MAFLD and its underlying mechanisms. The findings demonstrate that PL effectively combats MAFLD induced by a high-fat diet (HFD) and improves metabolic characteristics in mice. Additionally, our results suggest that the anti-MAFLD effect of PL is attributed to the suppression of excessive hepatic gluconeogenesis, inhibition of de novo lipogenesis, and alleviation of insulin resistance. Importantly, the results indicate that, on the one hand, the hypoglycemic effect of PL is closely associated with CREB-regulated transcriptional coactivators (CRTC2)-dependent cyclic AMP response element binding protein (CREB) phosphorylation; on the other hand, the lipid-lowering effect of PL is attributed to reducing the nuclear localization of sterol regulatory element-binding proteins 1c (Srebp-1c). Mechanistically, PL could alleviate insulin resistance induced by endoplasmic reticulum stress by antagonizing the thromboxane A2 receptor (TP)/Ca2+ signaling, and the TP receptor serves as the potential target for PL in the treatment of MAFLD. Therefore, our results suggested PL effectively improved the major hallmarks of MAFLD induced by HFD, highlighting a potential therapeutic strategy for MAFLD.

Effects of Feeding Rates on Growth Performance and Liver Glucose Metabolism in Juvenile Largemouth Bronze Gudgeon (Coreius guichenoti).

The experiment was conducted to investigate the effects of feeding rates on growth performance, liver glycolysis, gluconeogenesis, glycogen synthesis, and glycogen decomposition in juvenile largemouth bronze gudgeon (Coreius guichenoti). A total number of 600 fish were randomly distributed into 12 cylindrical plastic tanks with 50 fish per tank and triplicate tanks per treatment. Fish were fed with 2%, 3%, 4%, and 5% feeding rates (body weight per day) three times day-1 for 8 w. The results indicated that the feeding rates significantly increased the body weight, weight gain rate, and specific growth rate (p < 0.05), while showing no significant effects on the condition factor and survival rate (p > 0.05). The feed conversion ratio was significantly enhanced by the feeding rate (p < 0.05), although no significant differences were observed when the feeding rate exceeded 3% (p > 0.05). The plasma glucose levels in the 4% and 5% groups were significantly higher than those in the 2% and 3% groups. Compared with other groups, the 5% group significantly increased the crucial rate-limiting enzyme activities and mRNA levels of glycolysis (PFKL and PK) (p < 0.05), while showing no significant differences on enzyme activities (PC, PEPCK, and G6P) and mRNA (pepck and g6p) levels of gluconeogenesis (p > 0.05). In addition, the mRNA levels of hepatic glut2 and glut4 in the 5% group reached the highest levels (p < 0.05). When the feeding rate exceeded 3%, hepatic glycogen and lipid accumulation were significantly increased, leading to a fatty liver phenotype. Meanwhile, the mRNA level of liver glycogen synthetase (gysl) was significantly increased (p < 0.05), while no significant difference was observed in glycogen phosphorylase (pygl) (p > 0.05). In summary, under the conditions of this study, a feeding rate exceeding 3% significantly accelerated hepatic glycogen and lipid accumulation, which ultimately induced fatty liver formation.

Marine thermal fluctuation induced gluconeogenesis by the transcriptional regulation of CgCREBL2 in Pacific oysters.

Marine thermal fluctuation profoundly influences energy metabolism, physiology, and survival of marine life. In the present study, short-term and long-term high-temperature stresses were found to affect gluconeogenesis by inhibiting PEPCK activity in the Pacific oyster (Crassostrea gigas), which is a globally distributed species that encounters significant marine thermal fluctuations in intertidal zones worldwide. CgCREBL2, a key molecule in the regulation of gluconeogenesis, plays a critical role in the transcriptional regulation of PEPCK in gluconeogenesis against high-temperature stress. CgCREBL2 was able to increase the transcription of CgPEPCK by either binding the promoter of CgPEPCK gene or activating CgPGC-1α and CgHNF-4α after short-term (6 h) high-temperature stress, while only by binding CgPEPCK after long-term (60 h) high-temperature stress. These findings will further our understanding of the effect of marine thermal fluctuation on energy metabolism on marine organisms.

Gluconeogenesis unraveled: A proteomic Odyssey with machine learning.

The metabolic pathway known as gluconeogenesis, which produces glucose from non-carbohydrate substrates, is essential for maintaining balanced blood sugar levels while fasting. It's extremely important to anticipate gluconeogenesis rates accurately to recognize metabolic disorders and create efficient treatment strategies. The implementation of deep learning and machine learning methods to forecast complex biological processes has been gaining popularity in recent years. The recognition of both the regulation of the pathway and possible therapeutic applications of proteins depends on accurate identification associated with their gluconeogenesis patterns. This article analyzes the uses of machine learning and deep learning models, to predict gluconeogenesis efficiency. The study also discusses the challenges that come with restricted data availability and model interpretability, as well as possible applications in personalized healthcare, metabolic disease treatment, and the discovery of drugs. The predictor utilizes statistics moments on the structures of gluconeogenesis and their enzymes, while Random Forest is utilized as a classifier to ensure the accuracy of this model in identifying the best outcomes. The method was validated utilizing the independent test, self-consistency, 10 k fold cross-validations, and jackknife test which achieved 92.33 %, 91.87 %, 87.88 %, and 87.02 %. An accurate prediction of gluconeogenesis has significant implications for understanding metabolic disorders and developing targeted therapies. This study contributes to the rising field of predictive biology by mixing algorithms for deep learning, and machine learning, with metabolic pathways.

Intestinal gluconeogenesis controls the neonatal development of hypothalamic feeding circuits.

OBJECTIVE: Intestinal gluconeogenesis (IGN) regulates adult energy homeostasis in part by controlling the same hypothalamic targets as leptin. In neonates, leptin exhibits a neonatal surge controlling axonal outgrowth between the different hypothalamic nuclei involved in feeding circuits and autonomic innervation of peripheral tissues involved in energy and glucose homeostasis. Interestingly, IGN is induced during this specific time-window. We hypothesized that the neonatal pic of IGN also regulates the development of hypothalamic feeding circuits and sympathetic innervation of adipose tissues. METHODS: We genetically induced neonatal IGN by overexpressing G6pc1 the catalytic subunit of glucose-6-phosphatase (the mandatory enzyme of IGN) at birth or at twelve days after birth. The neonatal development of hypothalamic feeding circuits was studied by measuring Agouti-related protein (AgRP) and Pro-opiomelanocortin (POMC) fiber density in hypothalamic nuclei of 20-day-old pups. The effect of the neonatal induction of intestinal G6pc1 on sympathetic innervation of the adipose tissues was studied via tyrosine hydroxylase (TH) quantification. The metabolic consequences of the neonatal induction of intestinal G6pc1 were studied in adult mice challenged with a high-fat/high-sucrose (HFHS) diet for 2 months. RESULTS: Induction of intestinal G6pc1 at birth caused a neonatal reorganization of AgRP and POMC fiber density in the paraventricular nucleus of the hypothalamus, increased brown adipose tissue tyrosine hydroxylase levels, and protected against high-fat feeding-induced metabolic disorders. In contrast, inducing intestinal G6pc1 12 days after birth did not impact AgRP/POMC fiber densities, adipose tissue innervation or adult metabolism. CONCLUSION: These findings reveal that IGN at birth but not later during postnatal life controls the development of hypothalamic feeding circuits and sympathetic innervation of adipose tissues, promoting a better management of metabolism in adulthood.

Sirt2 Regulates Liver Metabolism in a Sex-Specific Manner.

Sirtuin-2 (Sirt2), an NAD+-dependent lysine deacylase enzyme, has previously been implicated as a regulator of glucose metabolism, but the specific mechanisms remain poorly defined. Here, we observed that Sirt2-/- males, but not females, have decreased body fat, moderate hypoglycemia upon fasting, and perturbed glucose handling during exercise compared to wild type controls. Conversion of injected lactate, pyruvate, and glycerol boluses into glucose via gluconeogenesis was impaired, but only in males. Primary Sirt2-/- male hepatocytes exhibited reduced glycolysis and reduced mitochondrial respiration. RNAseq and proteomics were used to interrogate the mechanisms behind this liver phenotype. Loss of Sirt2 did not lead to transcriptional dysregulation, as very few genes were altered in the transcriptome. In keeping with this, there were also negligible changes to protein abundance. Site-specific quantification of the hepatic acetylome, however, showed that 13% of all detected acetylated peptides were significantly increased in Sirt2-/- male liver versus wild type, representing putative Sirt2 target sites. Strikingly, none of these putative target sites were hyperacetylated in Sirt2-/- female liver. The target sites in the male liver were distributed across mitochondria (44%), cytoplasm (32%), nucleus (8%), and other compartments (16%). Despite the high number of putative mitochondrial Sirt2 targets, Sirt2 antigen was not detected in purified wild type liver mitochondria, suggesting that Sirt2's regulation of mitochondrial function occurs from outside the organelle. We conclude that Sirt2 regulates hepatic protein acetylation and metabolism in a sex-specific manner.

The mitochondrial dicarboxylate carrier mediates in vivo hepatic gluconeogenesis.

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 13C-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.

GSM1 Requires Hap4 for Expression and Plays a Role in Gluconeogenesis and Utilization of Nonfermentable Carbon Sources.

Multiple transcription factors in the budding yeast Saccharomyces cerevisiae are required for the switch from fermentative growth to respiratory growth. The Hap2/3/4/5 complex is a transcriptional activator that binds to CCAAT sequence elements in the promoters of many genes involved in the tricarboxylic acid cycle and oxidative phosphorylation and activates gene expression. Adr1 and Cat8 are required to activate the expression of genes involved in the glyoxylate cycle, gluconeogenesis, and utilization of nonfermentable carbon sources. Here, we characterize the regulation and function of the zinc cluster transcription factor Gsm1 using Western blotting and lacZ reporter-gene analysis. GSM1 is subject to glucose repression, and it requires a CCAAT sequence element for Hap2/3/4/5-dependent expression under glucose-derepression conditions. Genome-wide CHIP analyses revealed many potential targets. We analyzed 29 of them and found that FBP1, LPX1, PCK1, SFC1, and YAT1 require both Gsm1 and Hap4 for optimal expression. FBP1, PCK1, SFC1, and YAT1 play important roles in gluconeogenesis and utilization of two-carbon compounds, and they are known to be regulated by Cat8. GSM1 overexpression in cat8Δ mutant cells increases the expression of these target genes and suppresses growth defects in cat8Δ mutants on lactate medium. We propose that Gsm1 and Cat8 have shared functions in gluconeogenesis and utilization of nonfermentable carbon sources and that Cat8 is the primary regulator.

The deubiquitinase OTUB1 inhibits gluconeogenesis by stabilizing YWHAB.

Hepatic gluconeogenesis plays a crucial role in maintaining glucose homeostasis and serves as a potential therapeutic target for type 2 diabetes, while its underlying mechanisms are not fully understood. This study elucidates the role of the deubiquitinase OTU domain-containing ubiquitin aldehyde binding protein 1 (OTUB1) in gluconeogenesis. We found that hepatic OTUB1 expression is reduced in both db/db mice and patients with type 2 diabetes. Deletion of hepatic OTUB1 significantly elevates fasting blood glucose levels and increases the expression of key gluconeogenic genes. Conversely, overexpression of OTUB1 in hepatocytes mitigates diabetic hyperglycemia and enhances insulin sensitivity. It is known that the tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein ß (YWHAB) functions as an inhibitor of hepatic gluconeogenesis by interacting with forkhead box protein O (FOXO1) and glucagon receptor (GPCR), but its own modification mechanism remains unclear. Our findings indicate that OTUB1 interacts with YWHAB and deubiquitinates it through a catalytic process, which in turn suppresses gluconeogenesis. Therefore, OTUB1 plays a pivotal role in inhibiting hepatic gluconeogenesis, highlighting its potential as a therapeutic target for type 2 diabetes.

Effects of resveratrol on rheumatic symptoms and hepatic metabolism of arthritic rats.

OBJECTIVES: Resveratrol has been studied as a potential agent for treating rheumatic conditions; however, this compound suppresses glucose synthesis and glycogen catabolism when infused in perfused livers of both arthritic and healthy rats. This study investigated the effects of oral administration of resveratrol on inflammation and liver metabolism in rats with arthritis induced by Freund's adjuvant, which serves as rheumatoid arthritis model. METHODS: Holtzman rats, both healthy and exhibiting arthritic symptoms, were orally treated with resveratrol at doses varying from 25 to 500 mg/kg for a 5-day period preceding arthritis induction, followed by an additional 20-day period thereafter. Paw edema, arthritic score and hepatic myeloperoxidase activity were assessed to evaluate inflammation. Glycogen catabolism and gluconeogenesis from lactate were respectively evaluated in perfused livers from fed and fasted rats. RESULTS: Resveratrol decreased the liver myeloperoxidase activity at doses above 100 mg/kg, and decreased the paw edema and delayed the arthritic score at doses above 250 mg/kg. The hepatic gluconeogenesis was decreased in arthritic rats and resveratrol did not improve it. However, resveratrol did not negatively modify the gluconeogenesis in livers of healthy and arthritic rats. Glycogen catabolism was in part and slightly modified by resveratrol in the liver of arthritic and healthy rats. CONCLUSIONS: It is improbable that resveratrol negatively affects the liver metabolism, especially considering that gluconeogenesis is highly fragile to changes in cellular architecture. The findings suggest that resveratrol could serve as alternative for treating rheumatoid arthritis. Nevertheless, prudence is advised regarding its transient effects on liver metabolism.

CPS1 augments hepatic glucagon response through CaMKII/FOXO1 pathway.

Introduction: Elevated glucagon levels are a characteristic feature of type 2 diabetes. This abnormal increase in glucagon can lead to an accelerated rate of gluconeogenesis. Glucagon also stimulates hepatic metabolism of amino acids, particularly promoting the formation of urea. The specific role of carbamoyl phosphate synthetase 1 (CPS1), a rate-limiting enzyme in the urea cycle, in the development versus the persistence of glucagon-induced hyperglycemia has not been previously established. Methods: The study employed both in vivo and in vitro approaches to assess the impact of CPS1 modulation on glucagon response. CPS1 was knockdown or overexpression to evaluate its influence on hepatic gluconeogenesis. In addition, an in-silico strategy was employed to identify a potential CPS1 inhibitor. Results: Knockdown of CPS1 significantly reduced the glucagon response both in vivo and in vitro. Conversely, overexpression of CPS1 resulted in an overactive hepatic gluconeogenic response. Mechanistically, CPS1 induced the release of calcium ions from the endoplasmic reticulum, which in turn triggered the phosphorylation of CaMKII. The activation of CaMKII then facilitated the dephosphorylation and nuclear translocation of FOXO1, culminating in the enhancement of hepatic gluconeogenesis. Furthermore, cynarin, a natural CPS1 inhibitor derived from the artichoke plant, had the capacity to attenuate the hepatic glucagon response in a CPS1-dependent manner. Discussion: CPS1 played a pivotal role in mediating glucagon-induced hepatic gluconeogenesis. The discovery of cynarin as a natural inhibitor of CPS1 suggested its potential as a therapeutic agent for diabetes treatment.

Glucagon promotes increased hepatic mitochondrial oxidation and pyruvate carboxylase flux in humans with fatty liver disease.

We assessed in vivo rates of hepatic mitochondrial oxidation, gluconeogenesis, and ß-hydroxybutyrate (ß-OHB) turnover by positional isotopomer NMR tracer analysis (PINTA) in individuals with metabolic-dysfunction-associated steatotic liver (MASL) (fatty liver) and MASL disease (MASLD) (steatohepatitis) compared with BMI-matched control participants with no hepatic steatosis. Hepatic fat content was quantified by localized 1H magnetic resonance spectroscopy (MRS). We found that in vivo rates of hepatic mitochondrial oxidation were unaltered in the MASL and MASLD groups compared with the control group. A physiological increase in plasma glucagon concentrations increased in vivo rates of hepatic mitochondrial oxidation by 50%-75% in individuals with and without MASL and increased rates of glucose production by ∼50% in the MASL group, which could be attributed in part to an ∼30% increase in rates of mitochondrial pyruvate carboxylase flux. These results demonstrate that (1) rates of hepatic mitochondrial oxidation are not substantially altered in individuals with MASL and MASLD and (2) glucagon increases rates of hepatic mitochondrial oxidation.

Polysaccharides extracted from tucum-do-cerrado fruits (Bactris setosa Mart) have antineoplastic effects in mice while preserving hepatic gluconeogenesis.

This study investigated the antitumoral, anti-inflammatory and oxidative effects of polysaccharides from tucum (Bactris setosa, TUC) using the Ehrlich carcinoma as a tumor model. Additionally, the glycogen content, cytochrome P levels, and gluconeogenesis from lactate were assessed in the liver of healthy animals. Tumor-bearing female mice were orally treated with 50 and 100 mg.kg-1 of TUC or vehicle, once a day, or with 1.5 mg.kg-1 methotrexate via i.p., every 3 days, along 21 days. Both doses of TUC reduced the tumor weight and volume. In the tumor tissue, it decreased GSH and IL-1ß levels, and increased LPO, NAG, NO and TNF-α levels. The tumor histology showed necrosis and leukocytes infiltration. The metabolic effects of TUC were investigated by measurement of total cytochrome P (CYP) and glycogen in tumor-bearing mice, and by ex vivo liver perfusion on non-bearing tumor male mice, using lactate as gluconeogenic precursor. Metabolically, the hepatic glucose and pyruvate productions, oxygen uptake, and the total CYP concentration were not modified by TUC. Thus, tucum-do-cerrado polysaccharides have antitumor effects through the modulation of oxidative stress and inflammation, without impairing glucose production from lactate in the liver, the main organ responsible for the metabolism of organic and xenobiotic compounds.

SlPPDK modulates sugar and acid metabolism to influence flavor quality during tomato fruit ripening.

Fruit ripening is a highly intricate process, where the dynamic interplay of soluble sugar and organic acid metabolism is crucial for developing the characteristic flavor qualities. Pyruvate orthophosphate dikinase (PPDK) plays a pivotal role in modulating the process of gluconeogenesis during plant development. However, the specific physiological role of PPDK in fruit development has yet to be elucidated. In this study, we investigated the expression pattern, subcellular localization and functional significance of SlPPDK in tomato fruits. Our results reveal that SlPPDK is highly expressed in fruits and flowers, with its expression progressively increasing as the fruit ripens. Subcellular localization analyses demonstrate that SlPPDK is distributed in the cell membrane, cytoplasm, and nucleus. Using CRISPR/Cas9 technology, we generated SlPPDK knockout mutants, which exhibited a marked reduction in enzyme activity, leading to significant alterations in sugar and organic acid metabolism. These findings highlight the critical role of SlPPDK in maintaining the sugar-acid balance essential for tomato flavor quality and provide a foundation for future breeding strategies aimed at enhancing tomato fruit flavor.