Glucose Metabolism In Liver Research Articles

FTY-720 alleviates diabetes-induced liver injury by inhibiting oxidative stress and inflammation.

We aimed to investigate the protective effect of FTY-720 on liver injury and explore its potential mechanism in diabetic mice. The diabetic mouse model was induced with streptozotocin and FTY-720 was administered for 12 weeks. We assayed biocharacters and liver function, and used histopathology staining to evaluate the protective effects of FTY-720 against diabetic liver injury. Levels of oxidative stress and inflammation in the liver were observed. mRNA and protein levels of essential enzymes for glucose metabolism were quantified in the liver and the protein expression of TLR4, HIF1α, and NF-κB was determined. In vivo results revealed that FTY-720 significantly lowered blood glucose and lipids, and improved liver function and alleviated liver fibrosis in diabetic mice. FTY-720 reduced oxidative stress and inflammation, with the increased catalase activity and reduced levels of malondialdehyde, myeloperoxidase, IL-1β, IL-6, TNF-α, TGF-β and MCP1. Furthermore, FTY-720 modulated glucose metabolism in liver and elevated the ATP production, showing the promotion of glycogenesis and glycolysis and inhibition of gluconeogenesis. Moreover, FTY-720 inhibited the expression of TLR4 and HIF1α, contributing to restoration of liver function. In conclusion, FTY-720 ameliorates diabetes-induced liver injury and improves glucose homeostasis by inhibiting oxidative stress and inflammation, and may be a promise drug for treatment of liver disease.

Hepatocyte-specific knockout of HIF-2α cannot alleviate carbon tetrachloride-induced liver fibrosis in mice.

The effects of hypoxia inducible factor-2α (HIF-2α) deficiency on liver fibrosis have not been demonstrated in a fibrosis model induced by carbon tetrachloride (CCl4). We aimed to examine whether hepatocyte-specific HIF-2α deletion could ameliorate CCl4-induced liver fibrosis in mice. Hepatocyte-specific HIF-2α knockout mice were created using an albumin promoter-driven Cre recombinase. HIF-2α knockout (KO) mice and floxed control wild-type (WT) mice were fed a normal diet (ND) and received either twice weekly intraperitoneal injections of CCl4 solution (CCl4 dissolved in olive oil) or the corresponding amount of olive oil for 8 weeks. The indicators of liver function, glucose and lipid metabolism, and liver histology were compared among the different groups. Hepatocyte-specific HIF-2α knockout had no effect on the growth, liver function, glucose or lipid metabolism in mice. CCl4-treated KO and WT mice had a similar pattern of injury and inflammatory cell infiltration in the liver. Quantification of Masson staining, α-smooth muscle actin (α-SMA) immunohistochemistry, and the hydroxyproline (HYP) content revealed similar liver fibrosis levels between KO and WT mice injected intraperitoneally with CCl4. Immunohistochemistry analysis suggested that HIF-2α was mainly expressed in the portal area and hepatic sinusoids but not in hepatocytes. Bioinformatics analyses further indicated that HIF-2α expression was neither liver specific nor hepatocyte specific, and the effect of HIF-2α in hepatocytes on liver fibrosis may not be as important as that in liver sinuses. Hepatocyte HIF-2α expression may not be a key factor in the initiation of liver fibrogenesis, and hepatocyte-specific deletion of HIF-2α may not be the ideal therapeutic strategy for liver fibrosis.

Deuterium body array for the simultaneous measurement of hepatic and renal glucose metabolism and gastric emptying with dynamic 3D deuterium metabolic imaging at 7 T.

Deuterium metabolic imaging (DMI) is a novel noninvasive method to assess tissue metabolism and organ (patho)physiology in vivo using deuterated substrates, such as [6,6'-2 H2 ]-glucose. The liver and kidneys play a central role in whole-body glucose homeostasis, and in type 2 diabetes, both hepatic and renal glucose metabolism are dysregulated. Diabetes is also associated with gastric emptying abnormalities. In this study, we developed a four-channel 2 H transmit/receive body array coil for DMI in the human abdomen at 7T and assessed its performance. In addition, the feasibility of simultaneously measuring gastric emptying, and hepatic and renal glucose uptake and metabolism with dynamic 3D DMI upon administration of deuterated glucose, was investigated. Simulated and measured B1 + patterns were in good agreement. The intrasession variability of the natural abundance deuterated water signal in the liver and right kidney, measured in nine healthy volunteers, was 5.6% ± 0.9% and 4.9% ± 0.7%, respectively. Dynamic 3D DMI scans with oral administration of [6,6'-2 H2 ]-glucose showed similar kinetics of deuterated glucose appearance and disappearance in the liver and kidney. The measured gastric emptying half time was 80 ± 10min, which is in good agreement with scintigraphy measurements. In conclusion, DMI with oral administration of [6,6'-2 H2 ]-glucose enables simultaneous assessment of gastric emptying and liver and kidney glucose uptake and metabolism. When applied in patients with diabetes, this approach may advance our understanding of the interplay between disturbances in liver and kidney glucose uptake and metabolism and gastric emptying, at a detail that cannot be achieved by any other method.

Untargeted metabonomic analysis of non-alcoholic fatty liver disease with iron overload in rats via UPLC/MS

Background/Aims In recent years, many metabolites specific to nonalcoholic fatty liver disease (NAFLD) have been identified thanks to the application of metabolomics techniques. This study aimed to investigate the candidate targets and potential molecular pathways involved in NAFLD in the presence of iron overload. Methods Male Sprague Dawley rats were fed with control or high-fat diet with or without excess iron. After 8, 16, 20 weeks of treatment, urine samples of rats were collected for metabolomics analysis using ultra-performance liquid chromatography/mass spectrometry (UPLC-MS). Blood and liver samples were also collected. Results High-fat, high-iron diet resulted in increased triglyceride accumulation and increased oxidative damage. A total of 13 metabolites and four potential pathways were identified. Compared to the control group, the intensities of adenine, cAMP, hippuric acid, kynurenic acid, xanthurenic acid, uric acid, and citric acid were significantly lower (p < 0.05) and the concentration of other metabolites was significantly higher in the high-fat diet group. In the high-fat, high-iron group, the differences in the intensities of the above metabolites were amplified. Conclusion Our findings suggest that NAFLD rats have impaired antioxidant system and liver function, lipid disorders, abnormal energy, and glucose metabolism, and that iron overload may further exacerbate these disorders.

Regulation of Liver Glucose and Lipid Metabolism by Transcriptional Factors and Coactivators.

The prevalence of nonalcoholic fatty liver disease (NAFLD) worldwide is on the rise and NAFLD is becoming the most common cause of chronic liver disease. In the USA, NAFLD affects over 30% of the population, with similar occurrence rates reported from Europe and Asia. This is due to the global increase in obesity and type 2 diabetes mellitus (T2DM) because patients with obesity and T2DM commonly have NAFLD, and patients with NAFLD are often obese and have T2DM with insulin resistance and dyslipidemia as well as hypertriglyceridemia. Excessive accumulation of triglycerides is a hallmark of NAFLD and NAFLD is now recognized as the liver disease component of metabolic syndrome. Liver glucose and lipid metabolisms are intertwined and carbon flux can be used to generate glucose or lipids; therefore, in this review we discuss the important transcription factors and coactivators that regulate glucose and lipid metabolism.

More Than an Antioxidant: Role of Dietary Astaxanthin on Lipid and Glucose Metabolism in the Liver of Rainbow Trout (Oncorhynchus mykiss).

This study investigated the influence of dietary astaxanthin (AX) on glucose and lipid metabolism in rainbow trout liver. Two iso-nitrogenous and iso-lipidic diets were tested for 12 weeks in rainbow trout with an initial mean weight of 309 g. The S-ASTA diet was supplemented with 100 mg of synthetic AX per kg of feed, whereas the control diet (CTRL) had no AX. Fish fed the S-ASTA diet displayed lower neutral and higher polar lipids in the liver, associated with smaller hepatocytes and lower cytoplasm vacuolization. Dietary AX upregulated adipose triglyceride lipase (atgl), hormone-sensitive lipase (hsl2) and 1,2-diacylglycerol choline phosphotransferase (chpt), and downregulated diacylglycerol acyltransferase (dgat2), suggesting the AX's role in triacylglycerol (TAG) turnover and phospholipid (PL) synthesis. Dietary AX may also affect beta-oxidation with the upregulation of carnitine palmitoyltransferase 1 (cpt1α2). Although hepatic cholesterol levels were not affected, dietary AX increased gene expression of sterol regulatory element-binding protein 2 (srebp2). Dietary AX upregulated the expression of 6-phosphogluconate dehydrogenase (6pgdh) and downregulated pyruvate kinase (pkl). Overall, results suggest that dietary AX modulates the oxidative phase of the pentose phosphate pathway and the last step of glycolysis, affecting TAG turnover, β-oxidation, PL and cholesterol synthesis in rainbow trout liver.

Importance of curcumin effect and asprosin level on glucose metabolism in diabetic rats

Asprosin is a new hormone secreted mainly from white adipose tissue. It may be associated with the pathogenesis of obesity, diabetes and some metabolic diseases. The changes in plasma asprosin levels of experimental diabetic rats and the relation of these changes with liver glucose metabolism and some diabetes parameters were investigated, and the effects of metformin, gliclazide or curcumin treatment on plasma asprosin levels were tried. The study was designed as an animal model in diabetic rats The albino rats were divided into five groups. To induce diabetes, a single dose of STZ was injected intraperitoneally. Diabetics rats were treated intragastrically with metformin (D+Metformin group), gliclazide (D+Giliclazide group) or 20 curcumin (D+Curcumin group) for eight weeks. Fasting blood glucose, insulin levels and other parameters were measured. Plasma asporsin levels of untreated diabetic rats increased significantly (P&lt;.001). Although the plasma asprosin levels of diabetic rats treated with the rugs were significantly lower (P&lt;.001). Fasting blood glucose levels of diabetic rats treated with the drugs were found to be remarkably lower than the diabetic control values (P&lt;.001, respectively). There was no significant difference in the insulin levels and HOMA-IR between these three groups. Curcumin treatment provides significant improvements in plasma asprosin level and diabetes parameters. The increase in plasma asprosin level in diabetic rats may be one of the main reasons that facilitate the development of the disease or is responsible for its pathogenesis. Our findings support the idea that curcumin may be an important treatment option for diabetes.

The glucocorticoid dexamethasone inhibits HIF-1α stabilization and metabolic reprogramming in lipopolysaccharide-stimulated primary macrophages.

Synthetic glucocorticoids are used to treat many chronic and acute inflammatory conditions. Frequent adverse effects of prolonged exposure to glucocorticoids include disturbances of glucose homeostasis caused by changes in glucose traffic and metabolism in muscle, liver, and adipose tissues. Macrophages are important targets for the anti-inflammatory actions of glucocorticoids. These cells rely on aerobic glycolysis to support various pro-inflammatory and antimicrobial functions. Employing a potent pro-inflammatory stimulus in two commonly used model systems (mouse bone marrow-derived and human monocyte-derived macrophages), we showed that the synthetic glucocorticoid dexamethasone inhibited lipopolysaccharide-mediated activation of the hypoxia-inducible transcription factor HIF-1α, a critical driver of glycolysis. In both cell types, dexamethasone-mediated inhibition of HIF-1α reduced the expression of the glucose transporter GLUT1, which imports glucose to fuel aerobic glycolysis. Aside from this conserved response, other metabolic effects of lipopolysaccharide and dexamethasone differed between human and mouse macrophages. These findings suggest that glucocorticoids exert anti-inflammatory effects by impairing HIF-1α-dependent glucose uptake in activated macrophages. Furthermore, harmful and beneficial (anti-inflammatory) effects of glucocorticoids may have a shared mechanistic basis, depending on the alteration of glucose utilization.

Serpentine Enhances Insulin Regulation of Blood Glucose through Insulin Receptor Signaling Pathway

Insulin sensitizers targeting insulin receptors (IR) are a potential drug for the treatment of diabetes. Serpentine is an alkaloid component in the root of Catharanthus roseus (L.) G. Don. Serpentine screened by surface plasmon resonance (SPR) technology has the ability to target IR. The objective of this study was to investigate whether serpentine could modulate the role of insulin in regulating blood glucose through insulin receptors in cells and in animal models of diabetes. SPR technology was used to detect the affinity of different concentrations of serpentine with insulin receptors. The Western blotting method was used to detect the expression levels of key proteins of the insulin signaling pathway in C2C12 cells and 3T3-L1 cells as well as in muscle and subcutaneous adipose tissue of diabetic mice after serpentine and insulin treatment. Diabetic mice were divided into four groups and simultaneously injected with insulin or serpentine, and the blood glucose concentration and serum levels of insulin, glucagon, and C-peptide were measured 150 min later. mRNA levels of genes related to lipid metabolism and glucose metabolism in liver, muscle, and subcutaneous adipose tissue were detected by RT-PCR. Serpentine was able to bind to the extracellular domain of IR with an affinity of 2.883 × 10-6 M. Serpentine combined with insulin significantly enhanced the ability of insulin to activate the insulin signaling pathway and significantly enhanced the glucose uptake capacity of C2C12 cells. Serpentine enhanced the ability of low-dose insulin (1 nM) and normal-dose insulin (100 nM) to activate the insulin signaling pathway. Serpentine also independently activated AMPK phosphorylation, thus stimulating glucose uptake by C2C12 cells. In high-fat-diet/streptozotocin (HFD/STZ)-induced diabetic mice, serpentine significantly prolonged the hypoglycemic time of insulin, significantly reduced the use of exogenous insulin, and inhibited endogenous insulin secretion. In addition, serpentine alone significantly increased the expression of GSK-3β mRNA in muscle tissue, thus enhancing glucose uptake, and at the same time, serpentine significantly increased glucagon secretion and liver gluconeogenesis. Serpentine enhances the ability of insulin to regulate blood glucose through the insulin receptor, and can also regulate blood glucose alone, but it has a negative regulation mechanism and cannot produce a hypoglycemic effect. Therefore, serpentine may be useful as an insulin sensitizer to assist insulin to lower blood glucose.

Dietary sodium acetate improves high-fat diet utilization through promoting differential nutrients metabolism between liver and muscle in Nile tilapia (Oreochromis niloticus)

High-fat diet (HFD) often causes many negative effects and impairs fish growth. Short-chain fatty acids (SCFAs) such as acetates modify metabolic disorders and regulate body homeostasis. However, the effects of sodium acetate on alleviating HFD in fish is currently unknown. This study investigated the role of using dietary sodium acetate to alleviate adverse effects caused by HFD in fish. Three replicates (thirty fish each) of 4.8 ± 0.30 g Nile tilapia (Oreochromis niloticus) were fed with control diet (Con), high-fat diet (HFD) or HFD containing sodium acetate diet (HFD + NaAc) for eight weeks. After the feeding trial, Nile tilapia fed with HFD increased significantly tissue lipid deposition, reduced insulin sensitivity and suppressed glucose and lipid metabolism in both liver and muscle, accompanied with signs of metabolic disorders and liver damage. Moreover, HFD feeding inhibited muscle protein synthesis and impaired fish growth performance. However, the fish fed on HFD + NaAc improved significantly oxidative stress, inflammation, apoptosis and injury in liver compared to those fed on HFD. More importantly, dietary sodium acetate supplementation enhanced insulin sensitivity, promoted glucose catabolic utilization and protein synthesis in muscle through activation of insulin and mTOR signaling pathways, respectively, and markedly improved the growth performance. In contrast, dietary sodium acetate promoted hepatic pentose phosphate pathway, hepatic glycogen accumulation, and activated lipid catabolism to alleviate hepatic lipid deposition. Our study illustrates that sodium acetate alleviates differentially the adverse effects induced by feeding Nile tilapia with HFD in muscle and liver. SCFAs such as acetate may be used for improving HFD utilization in fish nutrition.

Magnetic Resonance Imaging and Spectroscopy Methods to Study Hepatic Glucose Metabolism and Their Applications in the Healthy and Diabetic Liver.

The liver plays an important role in whole-body glucose homeostasis by taking up glucose from and releasing glucose into the blood circulation. In the postprandial state, excess glucose in the blood circulation is stored in hepatocytes as glycogen. In the postabsorptive state, the liver produces glucose by breaking down glycogen and from noncarbohydrate precursors such as lactate. In metabolic diseases such as diabetes, these processes are dysregulated, resulting in abnormal blood glucose levels. Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) are noninvasive techniques that give unique insight into different aspects of glucose metabolism, such as glycogenesis, glycogenolysis, and gluconeogenesis, in the liver in vivo. Using these techniques, liver glucose metabolism has been studied in regard to a variety of interventions, such as fasting, meal intake, and exercise. Moreover, deviations from normal hepatic glucose metabolism have been investigated in both patients with type 1 and 2 diabetes, as well as the effects of antidiabetic medications. This review provides an overview of current MR techniques to measure hepatic glucose metabolism and the insights obtained by the application of these techniques in the healthy and diabetic liver.

Protein Targeting to Glycogen (PTG): A Promising Player in Glucose and Lipid Metabolism.

Protein phosphorylation and dephosphorylation are widely considered to be the key regulatory factors of cell function, and are often referred to as "molecular switches" in the regulation of cell metabolic processes. A large number of studies have shown that the phosphorylation/dephosphorylation of related signal molecules plays a key role in the regulation of liver glucose and lipid metabolism. As a new therapeutic strategy for metabolic diseases, the potential of using inhibitor-based therapies to fight diabetes has gained scientific momentum. PTG, a protein phosphatase, also known as glycogen targeting protein, is a member of the protein phosphatase 1 (PP1) family. It can play a role by catalyzing the dephosphorylation of phosphorylated protein molecules, especially regulating many aspects of glucose and lipid metabolism. In this review, we briefly summarize the role of PTG in glucose and lipid metabolism, and update its role in metabolic regulation, with special attention to glucose homeostasis and lipid metabolism.

Probiotics for the improvement of metabolic profiles in patients with metabolic-associated fatty liver disease: A systematic review and meta-analysis of randomized controlled trials.

This meta-analysis of randomized controlled trials (RCTs) was conducted to assess the efficacy of probiotics in the treatment of metabolic-associated fatty liver disease (MAFLD) mainly in terms of liver function, glucose and lipid metabolism, and inflammation. RCTs were searched on PubMed, Web of Science, Embase, and the Cochrane Library until June 2022.A meta-analysis was performed on the therapeutic efficacy of probiotics on liver function, glucose and lipid metabolism, and inflammatory biomarkers by using RevMan 5.4 software. A total of 772 patients from 15 studies were included in the analysis. The methodological quality varied across studies. We found that adding probiotic therapies could reduce the levels of alanine aminotransferase [mean difference (MD): -11.76 (-16.06, -7.46), p<0.00001], aspartate aminotransferase (MD: -9.08 (-13.60, -4.56), p < 0.0001], γ-glutamyltransferase [MD: -5.67 (-6.80, -4.54), p<0.00001] and homeostasis model assessment-insulin resistance [MD: -0.62 (-1.08, -0.15), p = 0.01], in patients with MAFLD compared with those in control individuals. However, there was no statistically significant improvement in the levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol, C-reactive protein and tumor necrosis factor α among patients with MAFLD. Subgroup analyses showed that other key factors, such as age, participants' baseline body mass index, and the duration of intervention, may influence probiotic therapy outcomes. There is promising evidence that probiotic supplementation can reduce liver enzyme levels and regulate glycometabolism in patients with MAFLD. Further rigorous and long-term trials exploring these novel therapeutic perspectives are warranted to confirm these results.

Potential Mechanisms of Gut-Derived Extracellular Vesicle Participation in Glucose and Lipid Homeostasis.

The intestine participates in the regulation of glucose and lipid metabolism in multiple facets. It is the major site of nutrient digestion and absorption, provides the interface as well as docking locus for gut microbiota, and harbors hormone-producing cells scattered throughout the gut epithelium. Intestinal extracellular vesicles are known to influence the local immune response, whereas their roles in glucose and lipid homeostasis have barely been explored. Hence, this current review summarizes the latest knowledge of cargo substances detected in intestinal extracellular vesicles, and connects these molecules with the fine-tuning regulation of glucose and lipid metabolism in liver, muscle, pancreas, and adipose tissue.

Molecular programming modulates hepatic lipid metabolism and adult metabolic risk in the offspring of obese mothers in a sex-specific manner

Male and female offspring of obese mothers are known to differ extensively in their metabolic adaptation and later development of complications. We investigate the sex-dependent responses in obese offspring mice with maternal obesity, focusing on changes in liver glucose and lipid metabolism. Here we show that maternal obesity prior to and during gestation leads to hepatic steatosis and inflammation in male offspring, while female offspring are protected. Females from obese mothers display important changes in hepatic transcriptional activity and triglycerides profile which may prevent the damaging effects of maternal obesity compared to males. These differences are sustained later in life, resulting in a better metabolic balance in female offspring. In conclusion, sex and maternal obesity drive differently transcriptional and posttranscriptional regulation of major metabolic processes in offspring liver, explaining the sexual dimorphism in obesity-associated metabolic risk.

Hepatic glycerol shunt and glycerol-3-phosphate phosphatase control liver metabolism and glucodetoxification under hyperglycemia

ObjectiveGlycerol-3-phosphate (Gro3P) phosphatase (G3PP) hydrolyzes Gro3P to glycerol that exits the cell, thereby operating a “glycerol shunt”, a metabolic pathway that we identified recently in mammalian cells. We have investigated the role of G3PP and the glycerol shunt in the regulation of glucose metabolism and lipogenesis in mouse liver. MethodsWe generated hepatocyte-specific G3PP-KO mice (LKO), by injecting AAV8-TBG-iCre to male G3PPfl/fl mice. Controls received AAV8-TBG-eGFP. Both groups were fed chow diet for 10 weeks. Hyperglycemia (16–20 mM) was induced by glucose infusion for 55 h. Hepatocytes were isolated from normoglycemic mice for ex vivo studies and targeted metabolomics were measured in mice liver after glucose infusion. ResultsLKO mice showed no change in body weight, food intake, fed and fasted glycemia but had increased fed plasma triglycerides. Hepatic glucose production from glycerol was increased in fasted LKO mice. LKO mouse hepatocytes displayed reduced glycerol production, elevated triglyceride and lactate production at high glucose concentration. Hyperglycemia in LKO mice led to increased liver weight and accumulation of triglycerides, glycogen and cholesterol together with elevated levels of Gro3P, dihydroxyacetone phosphate, acetyl-CoA and some Krebs cycle intermediates in liver. Hyperglycemic LKO mouse liver showed elevated expression of proinflammatory cytokines and M1-macrophage markers accompanied by increased plasma triglycerides, LDL/VLDL, urea and uric acid and myocardial triglycerides. ConclusionsThe glycerol shunt orchestrated by G3PP acts as a glucose excess detoxification pathway in hepatocytes by preventing metabolic disturbances that contribute to enhanced liver fat, glycogen storage, inflammation and lipid build-up in the heart. We propose G3PP as a novel therapeutic target for hepatic disorders linked to nutrient excess.

KCNH6 Enhanced Hepatic Glucose Metabolism through Mitochondrial Ca2+ Regulation and Oxidative Stress Inhibition.

KCNH6 has been proven to affect glucose metabolism and insulin secretion both in humans and mice. Further study revealed that Kcnh6 knockout (KO) mice showed impaired glucose tolerance. However, the precise function of KCNH6 in the liver remains unknown. Mitochondria have been suggested to maintain intracellular Ca2+ homeostasis; ROS generation and defective mitochondria can cause glucose metabolism disorders, including type 2 diabetes (T2D). Here, we found that Kcnh6 attenuated glucose metabolism disorders by decreasing PEPCK and G6pase abundance and induced Glut2 and IRS2 expression. Overexpression of Kcnh6 increased hepatic glucose uptake and glycogen synthesis. Kcnh6 attenuated intracellular and mitochondrial calcium levels in primary hepatocytes and reduced intracellular ROS and mitochondrial superoxide production. Kcnh6 suppressed oxidative stress by inhibiting mitochondrial pathway activation and NADPH oxidase expression. Experiments demonstrated that Kcnh6 expression improved hepatic glucose metabolism disorder through the c-Jun N-terminal kinase and p38MAPK signaling pathways. These results were confirmed by experiments evaluating the extent to which forced Kcnh6 expression rescued metabolic disorder in KO mice. In conclusion, KCNH6 enhanced hepatic glucose metabolism by regulating mitochondrial Ca2+ levels and inhibiting oxidative stress. As liver glucose metabolism is key to T2D, understanding KCNH6 functions may provide new insights into the causes of diabetes.

Proper regulation of β-adrenergic signal requires Btg2 gene for lipolysis and thermogenesis in response to starvation or cold acclimation in female mice

Mammals maintain constant body temperature in cold environment by activating thermogenesis via adrenergic/protein kinase A (PKA) signaling. B-cell translocation gene 2 (BTG2/Tis21), induced by PKA signaling, regulates glucose and lipid metabolism in liver, yet its role in lipolysis and in thermogenesis is not explored. Here, Btg2-knockout (KO) mice failed to maintain body temperature under starvation, or in cold acclimation. And norepinephrine-induced thermogenic response was turned off earlier in the KO mice. Gender specifically, gonadal white adipose tissues (gWAT) of female-KO were very active in lipolysis in fed state, however, the fat degradation was diminished upon fasting or cold acclimation. Also, insulin sensitivity was increased in female-KO, but not in male-KO mice, along with the low bone mineral density and small brown adipose tissues (BAT). In the mechanistic aspect, expressions of UCP1 and lipases (LPL, ATGL, HSL) in gWAT of female-KO mice were significantly reduced in response to adrenergic signals. Here, we present some data that Btg2 gene is essential for properly respond to β-adrenergic signals, and plays as a negative regulator of insulin signaling in female mice.

Simulation of the crosstalk between glucose and acetaminophen metabolism in a liver zonation model.

The liver metabolizes a variety of substances that sometimes interact and regulate each other. The modeling of a single cell or a single metabolic pathway does not represent the complexity of the organ, including metabolic zonation (heterogeneity of functions) along with liver sinusoids. Here, we integrated multiple metabolic pathways into a single numerical liver zonation model, including drug and glucose metabolism. The model simulated the time-course of metabolite concentrations by the combination of dynamic simulation and metabolic flux analysis and successfully reproduced metabolic zonation and localized hepatotoxicity induced by acetaminophen (APAP). Drug metabolism was affected by nutritional status as the glucuronidation reaction rate changed. Moreover, sensitivity analysis suggested that the reported metabolic characteristics of obese adults and healthy infants in glucose metabolism could be associated with the metabolic features of those in drug metabolism. High activities of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphate phosphatase in obese adults led to increased APAP oxidation by cytochrome P450 2E1. In contrast, the high activity of glycogen synthase and low activities of PEPCK and glycogen phosphorylase in healthy infants led to low glucuronidation and high sulfation rates of APAP. In summary, this model showed the effects of glucose metabolism on drug metabolism by integrating multiple pathways into a single liver metabolic zonation model.

Dietary bile acids supplementation modulates immune response, antioxidant capacity, glucose, and lipid metabolism in normal and intrauterine growth retardation piglets.

Intrauterine growth retardation (IUGR) results in intestinal dysfunction contributing to metabolic syndrome and growth lag of piglets. Bile acid (BA) presents various bioactivities, including regulation roles in antioxidant, anti-inflammation, and glucose and lipid metabolism. Forty-eight weaned piglets were allocated to four groups in a 2 × 2 factorial arrangement with the effects of BA supplementation and IUGR challenge. Twenty-four IUGR piglets and 24 normal birth weight (NBW) piglets were allocated into two groups, respectively, including the control group fed with a basal diet, and the treatment group fed a basal diet supplemented with 400 mg/kg BA. The experiment lasted 28 days. The results indicated that BA improved liver and spleen indexes in IUGR piglets, whereas decreased blood RDW-CV and RDW-SD regardless of IUGR (P < 0.05). Dietary BA supplementation decreased plasma CAT activity and liver GSH concentration regardless of IUGR, whereas increased plasma GSH and liver H2O2 and decreased liver T-AOC in weaned piglets (P < 0.05). In addition, IUGR downregulated liver Nrf1 and Nrf2 expression levels, while BA supplementation upregulated the Nrf2 expression of liver in weaned piglets (P < 0.05). Dietary BA decreased (P < 0.05) jejunal GSH concentration and ileal CAT activity regardless of IUGR. Furthermore, IUGR upregulated (P < 0.05) jejunal SOD and CAT expression levels; however, dietary BA upregulated ileal Nrf1 (P < 0.05) and Keap1 (P = 0.07) expression levels in piglets regardless of IUGR. Moreover, IUGR upregulated the liver lipid synthesis (FAS) and downregulated HSL and SCD1 expression levels, while dietary BA downregulated liver FAS and SCD1 expression levels (P < 0.05). However, BA supplementation could enhance liver gluconeogenesis by upregulating (P < 0.05) the liver G6PC and PCK1 expression levels in the NBW piglets but not in the IUGR piglets. Collectively, these findings suggest that BA could regulate the redox status of weaned piglets by regulating the Nrf2/Keap1 pathway and improving liver glucose and lipid metabolism of IUGR piglets. These findings will provide a reference for the application of BA in swine production; moreover, considering the physiological similarity between pigs and humans, these findings will provide a reference for IUGR research in humans.