Changes In Hepatic Metabolism Research Articles

The impact of short-term eucaloric low- and high-carbohydrate diets on liver triacylglycerol content in males with overweight and obesity: a randomized crossover study

BackgroundIntrahepatic triacylglycerol (liver TG) content is associated with hepatic insulin resistance and dyslipidemia. Liver TG content can be modulated within days under hypocaloric conditions. ObjectivesWe hypothesized that 4 d of eucaloric low-carbohydrate/high-fat (LC) intake would decrease liver TG content, whereas a high-carbohydrate/low-fat (HC) intake would increase liver TG content, and further that alterations in liver TG would be linked to dynamic changes in hepatic glucose and lipid metabolism. MethodsA randomized crossover trial in males with 4 d + 4 d of LC and HC, respectively, with ≥2 wk of washout. 1H-magnetic resonance spectroscopy (1H-MRS) was used to measure liver TG content, with metabolic testing before and after intake of an LC diet (11E% carbohydrate corresponding to 102 ± 12 {mean ± standard deviation [SD]) g/d, 70E% fat} and an HC diet (65E% carbohydrate corresponding to 537 ± 56 g/d, 16E% fat). Stable [6,6-2H2]-glucose and [1,1,2,3,3-D5]-glycerol tracer infusions combined with hyperinsulinemic-euglycemic clamps and indirect calorimetry were used to measure rates of hepatic glucose production and lipolysis, whole-body insulin sensitivity and substrate oxidation. ResultsEleven normoglycemic males with overweight or obesity (BMI 31.6 ± 3.7 kg/m2) completed both diets. The LC diet reduced liver TG content by 35.3% (95% confidence interval: −46.6, −24.1) from 4.9% [2.4–11.0] (median interquartile range) to 2.9% [1.4–6.9], whereas there was no change after the HC diet. After the LC diet, fasting whole-body fat oxidation and plasma beta-hydroxybutyrate concentration increased, whereas markers of de novo lipogenesis (DNL) diminished. Fasting plasma TG and insulin concentrations were lowered and the hepatic insulin sensitivity index increased after LC. Peripheral glucose disposal was unchanged. ConclusionsReduced carbohydrate and increased fat intake for 4 d induced a marked reduction in liver TG content and increased hepatic insulin sensitivity. Increased rates of fat oxidation and ketogenesis combined with lower rates of DNL are suggested to be responsible for lowering liver TG. This trial was registered at clinicaltrials.gov as NCT04581421.

A very-low-calorie diet (VLCD) intervention for the management of prediabetes and early Type 2 diabetes mellitus in a multi-ethnic cohort in Aotearoa New Zealand: The PROGRESS NZ feasibility study.

Very-low calorie diets (VLCD) achieve weight loss and remission of Type 2 diabetes (T2DM), but efficacy and acceptability in non-European populations is less clear. This feasibility study examines the impact of 10% weight loss through VLCD on metabolic and body composition outcomes in a multi-ethnic cohort of Aotearoa New Zealand (AoNZ) men with prediabetes/early T2DM, and VLCD tolerability/cultural acceptability. Participants followed a VLCD intervention (mean energy 3033kJ/day) until achievement of 10% weight loss. An oral glucose tolerance test (OGTT), hyperinsulinaemic isoglycaemic clamp with stable isotopes, hood calorimetry and dual-energy Xray absorptiometry (DXA) were undertaken before and after intervention. Qualitative data on VLCD tolerability/cultural acceptability were collected. Fifteen participants were enrolled; nine achieved 10% weight loss. In this group, mean HbA1c reduced by 4.8mmol/mol (2.4-7.1) and reverted to normoglycaemia in n=5/9; mean body weight reduced by 12.0 kg (11.0-13.1) and whole-body glucose disposal improved by 1.5 mg kgFFM-1 min-1 (0.7-2.2). Blood pressure and fasting triglycerides improved significantly. No changes in hepatic glu-cose metabolism were found. In all participants who attended completion testing, HbA1c reduced by 3.4mmol/mol (SD 3.5) and total weight by 9.0kg (SD 5.7). The intervention was highly tolerable/culturally acceptable however challenges with fulfilment of cultural obligations were described. Results support VLCD use in AoNZ however further work to investigate ethnic differences in physiological response to VLCDs and to optimise protocols for multi-ethnic populations are required.

Changes of hepatic metabolism and lipidomic profile with biochemical improvement of acromegaly

Changes of hepatic metabolism and lipidomic profile with biochemical improvement of acromegaly

131 Selenium-form effects on hepatic function and selenoprotein mRNAs in the early pregnant heifer

Abstract Selenium (Se) is an integral component of selenoproteins, with effective scavenging of harmful reactive oxygen species (ROS) by selenoproteins necessary to protect cells from oxidative stress. Due to the presence of Se-deficient soils in large portions of the US, including the southeast cow-calf producing states, grazed forages are insufficient in this trace mineral and dietary supplementation is recommended. We have investigated the effects of providing Se in an inorganic form (ISe, the industry standard) versus a 1:1 mixture (MIX) of ISe to organic Se (OSe), and have observed significant effects on luteal function, endometrial function and conceptus development. Herein, our objective was to determine the effect of form of Se on 1) clinical markers of total antioxidant capacity and liver function, and 2) the expression of mRNAs encoding selenoproteins in the liver. Following consecutive 45-d periods of Se-depletion then repletion, Angus-cross heifers were assigned to 90 d of treatment with a vitamin-mineral mix containing 35-ppm Se as ISe or MIX. Heifers were then inseminated at estrus (d 0) with serum collected at d 0, 7 and 17 to quantify albumin, beta-hydroxybutyrate (BHBA) and aspartate aminotransferase (AST). Liver samples were collected at euthanasia on d 17 (n = 6 pregnant heifers per treatment) for the quantification of the relative abundance of 25 selenoprotein mRNAs using qPCR. There was no effect of treatment on circulating albumin (P > 0.05). Hepatocyte-secreted albumin is the most prominent antioxidant in the circulation, with this result suggesting that albumin-driven redox capacity is not sensitive to the form of Se supplied to achieve a Se-adequate status. Systemic concentrations of BHBA and AST were increased (P < 0.05) in MIX- versus ISe-treated heifers at d 7 and 17 of pregnancy. Circulating BHBA is considered a primary indicator of liver function and the hepatic response to increased metabolic demands, whereas increased AST is conventionally considered a marker for liver damage. These results suggest increased demands on the liver in MIX versus ISe-treated heifers, however not at the level indicative of dysfunction or disease. Additionally, the serum concentration of urea nitrogen was quantified and determined to be reduced (P < 0.05) at estrus in MIX- versus ISe-treated heifers, indicative of form-induced changes in hepatic nitrogen metabolism. Targeted qPCR analysis to determine the effect of treatment on the abundance of encoding selenoproteins by mRNA, including the iodothyronine deiodinases, glutathione peroxidases and thioredoxin reductases, was largely unaffected by treatment, with only the abundance of mRNA encoding Selenoprotein V tending to differ (P = 0.07) with treatment. Overall, this study revealed form of Se-effects on markers of hepatic health and function, as well as blood urea nitrogen, but did not reveal form of Se-effects on the expression of hepatic selenoproteins mRNAs.

Seasonal changes in hepatic lipid metabolism and apoptosis in Chinese soft-shelled turtle (Pelodiscus sinensis)

Chinese soft-shelled turtle (Pelodiscus sinensis) hibernates without eating and drinking when the ambient temperature is very low. To better understand the characteristics of energy utilization during hibernation, the turtles in the physiological phases of summer active (SA), Pre-Hibernation (Pre-H), Mid-Hibernation (Mid-H) and early arousal (EA) were sampled. The results showed that the levels of serum triglyceride and hepatic lipid droplet were markedly increased in Pre-H and decreased in Mid-H compared with that in SA, indicating that P. sinensis experiences lipid accumulation in Pre-H and lipid is the predominant energy reserve during hibernation. The mRNA expression levels of genes (FABP and CPT-2) involved in lipolysis and lipid oxidation were up-regulated in Mid-H, while the genes related to lipid synthesis (FAS, ACSL-1, ACC, elovl5, and SCD1) were inhibited in Mid-H. Meanwhile, the mRNA expression levels of endoplasmic reticulum stress marker gene Bip and key genes (ATF4, ATF6, and IRE1α) involving the unfolded protein response were significantly increased in Mid-H and EA. Also, the expression levels of genes (ASK1, JNK1, and Bax) associated with cell apoptosis increased in Mid-H and EA, however, the expression of Bcl2 was inhibited in Mid-H. Therefore, hibernation can cause endoplasmic reticulum stress and apoptosis. The findings will provide a theoretical framework for an animal's cold adaptation and offer insights into preventing and managing metabolic syndrome.

Remodeling of Hepatic Glucose Metabolism in Response to Early Weaning in Piglets.

This study aimed to investigate the dynamic changes in hepatic glucose metabolism in response to early weaning. A total of 60 piglets were randomly selected and weaned at 21 days old. Six piglets were slaughtered on the weaning day (d0) and at 1 (d1), 4 (d4), 7 (d7), and 14 (d14) days postweaning. The results illustrated that body weight significantly increased from d4 to d14 (p < 0.001). Serum glucose fell sharply after weaning and then remained at a low level from d1 to d14 (p < 0.001). Serum insulin decreased from d4 (p < 0.001), which caused hepatic glycogen to be broken down (p = 0.007). The glucose-6-phosphatase activity increased from d0 to d4 and then decreased from d4 to d14 (p = 0.039). The pyruvate carboxylase activity presented a significant sustained increase from d0 to d14 (p < 0.001). The succinate (p = 0.006) and oxaloacetate (p = 0.003) content on d4 was lower than that on d0. The succinate dehydrogenase activity (p = 0.008) and ATP (p = 0.016) production decreased significantly on d4 compared to that on d0. Taken together, these findings reveal the dynamic changes of metabolites and enzymes related to hepatic glycometabolism and the TCA (tricarboxylic acid) cycle in piglets after weaning. Our findings enrich weaning stress theory and might provide a reference for dietary intervention.

Age-Related Changes in Hepatic Lipid Metabolism and Abdominal Adipose Deposition in Yellow-Feathered Broilers Aged from 1 to 56 Days.

The objective of this study was to evaluate the age-related changes in hepatic lipid metabolism, adipocyte hyperplasia, hypertrophy, and lipid metabolism in the abdominal adipose tissue of yellow-feathered broilers. Blood, liver, and abdominal adipose samples were collected on days 1, 7, 14, 21, 28, 35, 42, 49, and 56. Body, liver, and abdominal weight increased (p < 0.05) with age-related changes. The triacylglycerol content peaked on day 14, and total cholesterol content peaked on day 56. The adipocyte diameter and area peaked on day 56, and total DNA content peaked on day 7. The age-related changes in hepatic lipogenesis-related gene (ChREBP, SREBP-1c, ACC, FAS, SCD1) expression mainly occurred during days 1 to 21, hepatic lipolysis-related gene (CPT1, LPL, ApoB) expression mainly occurred during days 1 to 14, and abdominal adipose-deposition-related gene (PPARα, CPT1, LPL, PPARγ, C/EBPβ) expression occurred during days 1 to 14. These results demonstrated a dynamic pattern of hepatic lipid metabolism and abdominal adipose deposition in yellow-feathered broilers, which provides practical strategies to regulate hepatic lipid metabolism and reduce abdominal adipose deposition in yellow-feathered broilers.

Broodstock nutritional programming differentially affects the hepatic transcriptome and genome-wide DNA methylome of farmed gilthead sea bream (Sparus aurata) depending on genetic background

BackgroundBroodstock nutritional programming improves the offspring utilization of plant-based diets in gilthead sea bream through changes in hepatic metabolism. Attention was initially focused on fatty acid desaturases, but it can involve a wide range of processes that remain largely unexplored. How all this can be driven by a different genetic background is hardly underlined, and the present study aimed to assess how broodstock nutrition affects differentially the transcriptome and genome-wide DNA methylome of reference and genetically selected fish within the PROGENSA® selection program.ResultsAfter the stimulus phase with a low fish oil diet, two offspring subsets of each genetic background received a control or a FUTURE-based diet. This highlighted a different hepatic transcriptome (RNA-seq) and genome-wide DNA methylation (MBD-seq) pattern depending on the genetic background. The number of differentially expressed transcripts following the challenge phase varied from 323 in reference fish to 2,009 in genetically selected fish. The number of discriminant transcripts, and associated enriched functions, were also markedly higher in selected fish. Moreover, correlation analysis depicted a hyper-methylated and down-regulated gene expression state in selected fish with the FUTURE diet, whereas the opposite pattern appeared in reference fish. After filtering for highly represented functions in selected fish, 115 epigenetic markers were retrieved in this group. Among them, lipid metabolism genes (23) were the most reactive following ordering by fold-change in expression, rendering a final list of 10 top markers with a key role on hepatic lipogenesis and fatty acid metabolism (cd36, pitpna, cidea, fasn, g6pd, lipt1, scd1a, acsbg2, acsl14, acsbg2).ConclusionsGene expression profiles and methylation signatures were dependent on genetic background in our experimental model. Such assumption affected the magnitude, but also the type and direction of change. Thus, the resulting epigenetic clock of reference fish might depict an older phenotype with a lower methylation for the epigenetically responsive genes with a negative methylation-expression pattern. Therefore, epigenetic markers will be specific of each genetic lineage, serving the broodstock programming in our selected fish to prevent and mitigate later in life the risk of hepatic steatosis through changes in hepatic lipogenesis and fatty acid metabolism.

Analysis of bioactive components and synergistic action mechanism of ShuGan-QieZhi Capsule for treating non-alcoholic fatty liver disease

BackgroundShuGan-QieZhi capsule (SGQZC) is a traditional Chinese preparation used to treat hyperlipidemia and obesity, even non-alcoholic fatty liver disease (NAFLD). However, its therapeutic effects, main bioactive ingredients, as well as potential mechanisms for NAFLD are still unclear. PurposeTo investigate the pharmacological effect, main active ingredients, and mechanisms of SGQZC against high-fat diet (HFD)-induced NAFLD in mice. MethodsNAFLD models were established by feeding C57BL/6 J mice an HFD for 24 weeks. From the 12th week, HFD-fed mice received daily gavage of either SGQZC or silibinin for 12 weeks. Hepatic hypertrophy parameters, along with hepatic and systemic lipid metabolism changes in NAFLD mice, were assessed. Oil red O and histopathological staining techniques determined lipid accumulation and liver injury severity. qRT-PCR analysis measured the expression of genes tied to liver lipid metabolism and inflammation. HPLC-MS/MS identified the primary components of SGQZC in the serum. Human normal hepatocytes (LO2) and hepatic stellate cells (LX-2) were used to screen SGQZC's bioactive ingredients. Network pharmacological analysis, transcriptomics, and western blotting delved into SGQZC's synergistic mechanisms against NAFLD. ResultsSGQZC ameliorated abnormal lipid metabolism and liver hypertrophy in mice with HFD-induced NAFLD, consequently reducing hepatic lipid accumulation, inflammatory cell infiltration, and liver impairment. Eight crucial components of SGQZC were detected in serum using HPLC-MS/MS and were found to effectively attenuate lipid accumulation and inflammation in liver cells. Further investigation indicated that SGQZC modulates MAPK pathway and AKT/NF-κB pathway, subsequently improving lipid metabolism and inflammation. ConclusionSGQZC alleviates NAFLD by synergistically modulating the MAPK-mediated lipid metabolism and inhibiting AKT/NF-κB pathways-mediated inflammation. Our findings reveal the enormous potential of SGQZC for the treatment of NAFLD, providing a possible new clinical therapeutic strategy.

Comparative analysis of hepatic transcriptomes and metabolomes of Changshun green-shell laying hens based on different green eggshell color intensities

The eggshell color of avian species is an important trait that is predominantly determined by the pigments biliverdin and protoporphyrin. Various factors affect eggshell pigment deposition and coloration; however, the underlying mechanisms remain unclear. We analyzed the hepatic transcriptomes and metabolomes of Changshun green-shell hens laying dark green and light green eggs to investigate the potential role of the liver in regulating the intensity of the green eggshell color. In total, 350 differentially expressed genes and 211 differentially altered metabolites were identified. Gene set enrichment analysis revealed that the enriched pathways and Gene Ontology (GO) terms were mainly associated with energy, immunity, and nutrient metabolism. Metabolite set enrichment analysis revealed that the enriched pathways were mainly associated with amino acid, vitamin, bile acid, and lipid metabolism. Moreover, gene-metabolite interaction network analysis revealed 1 subnetwork. Most genes and metabolites in this subnetwork were determined to be related to melanin metabolism and transport. In conclusion, our results suggest that hepatic melanin metabolism and transport are critical for eggshell coloration. Six candidate genes (CDKN2B, DDC, PYCR1, ABCG5, SLC3A1, and P2RX2) and 7 candidate metabolites (serotonin, 5-hydroxyindoleacetic acid, ornithine, acetylcholine, L-tryptophan, D-ornithine, and ADP) were suggested to play important roles in this process. Meanwhile, this study suggests that changes in hepatic energy metabolism, immune status, antioxidation activity, nutrient availability, and bile acid synthesis can impair eggshell coloration.

MiR-20a-5p targeting mfn2-mediated mitochondria-lipid droplet contacts regulated differential changes in hepatic lipid metabolism induced by two Mn sources in yellow catfish

Understanding the hazards of different forms of metal elements provided innovative insights into their toxicity and environmental risk assessment. To date, few studies had been conducted to investigate the differential effects and mechanisms of MnO2 NPs and MnSO4, two widely distributed environmental pollutants, on hepatic toxicity and lipid metabolism since lipid metabolism-relevant parameters were broadly used as biomarkers for risk assessment of hazardous contaminants. Thus, using yellow catfish Pelteobagrus fulvidraco, an ecologically and economically important freshwater fish as the model, the present study investigated the differential effects and mechanisms of MnO2 NPs and MnSO4 influencing hepatic lipid metabolism. Compared to MnSO4, MnO2 NPs increased hepatic Mn content, induced lipotoxicity, up-regulated the mRNA expression of lipogenic genes, increased peridroplet mitochondrial (PDM) contents, intensified the contact between mitochondria and lipid droplets (LDs), and downregulated miR-20a-5p abundance. Importantly, miR-20a-5p targeted mfn2, which mediated the contact between mitochondria and LDs and influenced changes in lipid metabolism induced by MnO2 NPs. Mechanistically, the direct Mfn2-Plin2 binding and Mfn2 GTPase activity promoted the MnO2 NPs-induced interactions between mitochondria and LDs, which in turn influenced MnO2 NPs-induced changes in hepatic lipid metabolism. For the first time, our findings indicated the significant differences between the changes in body metabolism induced by nanoparticles and inorganic elements, which helped to illuminate different mechanisms governing the responses of aquatic vertebrates to hazardous metal pollutants (MnO2 NPs and MnSO4).

Dietary Nε-(carboxymethyl)lysine is a trigger of non-alcoholic fatty liver disease under high-fat consumption.

The irreversible glycation of proteins produces advanced glycation end products (AGEs) which are triggered to bind the receptor for AGE (RAGE), thereby activating mitogen-activated protein kinase/nuclear factor-κB signaling pathway and stimulating proinflammatory cytokines, ultimately leading to chronic disorders. In this study, we focus the promoting effect of Nε-carboxymethyl-lysine (CML), one of the most dietary AGEs, on non-alcoholic fatty liver disease (NAFLD) and evaluated NAFLD-related biomarkers. Oxidative stress and hepatic steatosis were assessed in oleic acid (OA)-induced HepG2 cells. Using OA-induced HepG2 cells, we show that CML results in oxidative stress and steatosis and drives major changes in hepatic lipid metabolism. Administration of CML exacerbated NAFLD-related symptoms by increasing body and liver weight gain, serum alanine aminotransferase and lipid levels, and insulin resistance in mild high-fat diet-induced mice. Moreover, hepatic histological analysis data, such as staining, western blotting, and RNA-seq, indicate that CML aggravates NAFLD in association with activation of the de novo lipogenesis pathway, consistent with the in vitro assays. Our findings could contribute to model studies related to the prevention and treatment of NAFLD progression due to excessive consumption of dietary AGEs.

Hepatic steatosis is associated with dysregulated cholesterol metabolism and altered protein acetylation dynamics in chickens

BackgroundHepatic steatosis is a prevalent manifestation of fatty liver, that has detrimental effect on the health and productivity of laying hens, resulting in economic losses to the poultry industry. Here, we aimed to systematically investigate the genetic regulatory mechanisms of hepatic steatosis in laying hens.MethodsNinety individuals with the most prominent characteristics were selected from 686 laying hens according to the accumulation of lipid droplets in the liver, and were graded into three groups, including the control, mild hepatic steatosis and severe hepatic steatosis groups. A combination of transcriptome, proteome, acetylome and lipidome analyses, along with bioinformatics analysis were used to screen the key biological processes, modifications and lipids associated with hepatic steatosis.ResultsThe rationality of the hepatic steatosis grouping was verified through liver biochemical assays and RNA-seq. Hepatic steatosis was characterized by increased lipid deposition and multiple metabolic abnormalities. Integration of proteome and acetylome revealed that differentially expressed proteins (DEPs) interacted with differentially acetylated proteins (DAPs) and were involved in maintaining the metabolic balance in the liver. Acetylation alterations mainly occurred in the progression from mild to severe hepatic steatosis, i.e., the enzymes in the fatty acid oxidation and bile acid synthesis pathways were significantly less acetylated in severe hepatic steatosis group than that in mild group (P < 0.05). Lipidomics detected a variety of sphingolipids (SPs) and glycerophospholipids (GPs) were negatively correlated with hepatic steatosis (r ≤ −0.5, P < 0.05). Furthermore, the severity of hepatic steatosis was associated with a decrease in cholesterol and bile acid synthesis and an increase in exogenous cholesterol transport.ConclusionsIn addition to acquiring a global and thorough picture of hepatic steatosis in laying hens, we were able to reveal the role of acetylation in hepatic steatosis and depict the changes in hepatic cholesterol metabolism. The findings provides a wealth of information to facilitate a deeper understanding of the pathophysiology of fatty liver and contributes to the development of therapeutic strategies.

Pregnancy related hormones increase CYP3A mediated buprenorphine metabolism in human hepatocytes: a comparison to CYP3A substrates nifedipine and midazolam.

Introduction: Pregnancy increases the clearance of CYP3A4 substrate drugs and pregnancy-related hormones (PRHs) induce hepatic CYP3A4 expression and metabolism. However, it remains unclear to what extent the magnitude of PRH-evoked changes in hepatic CYP3A metabolism varies across multiple substrates. This study quantified the impact of PRHs on CYP3A protein concentrations and buprenorphine metabolism in human hepatocytes, and compared the magnitude of these effects to nifedipine and midazolam metabolism. Methods: Sandwich-cultured human hepatocytes (SCHH) from female donors were exposed to PRHs, administered in combination across a range of physiologically relevant concentrations, for 72h. Absolute protein concentrations of CYP3A4, CYP3A5, and CYP3A7 in SCHH membrane fractions were quantified by nanoLC-MS/MS, and norbuprenorphine (nor-BUP), dehydro-nifedipine (dehydro-NIF), and 1-hydroxy-midazolam (1-OH-MDZ) formation was evaluated. Results: Compared to control, PRH exposure increased CYP3A4, CYP3A7, and total CYP3A protein concentrations, but not CYP3A5 concentrations, and increased nor-BUP, dehydro-NIF, and 1-OH-MDZ formation in a concentration-dependent manner. The formation of nor-BUP, dehydro-NIF, and 1-OH-MDZ each positively correlated with PRH-mediated changes in total CYP3A protein concentrations. The PRH-evoked increase in nor-BUP formation was evident in all donors; however, the PRH induction of dehydro-NIF and 1-OH-MDZ formation was diminished in a hepatocyte donor with high basal CYP3A5 expression. Discussion: These findings demonstrate that PRHs increase buprenorphine, nifedipine, and midazolam metabolism in SCHH via induction of CYP3A4 and total CYP3A protein concentrations, and the magnitude of these effects vary across hepatocyte donors in a substrate-specific manner. These data provide insight into the contribution of PRH induction of CYP3A4 metabolism to increased buprenorphine clearance during pregnancy.

Hepatoprotective effect of Artemisia Argyi essential oil on bisphenol A-induced hepatotoxicity via inhibition of ferroptosis in mice.

The environmental pollutant bisphenol A (BPA), used in the manufacture of plastic packaging materials for various diets, is widely distributed in the environment and causes severe hepatotoxicity by inducing oxidative stress. Artemisia argyi essential oil (AAEO), a volatile oil component isolated from Artemisia argyi H.Lév. & Vaniot, has pharmacological effects, especially for hepatoprotective actions. However, the potential effect of AAEO in BPA induced hepatotoxicity has not been characterized. First, we analyzed the chemical composition in AAEO by gas chromatography-mass spectrometry. Herein, we investigated the effect of AAEO on hepatic metabolic changes in mice exposed to BPA. Results showed that compared with the BPA group, AAEO could reduce the level of liver function enzymes in BPA mice serum, and ameliorate hepatic lesions and fibrosis. Additionally, 20 differential metabolites screened by metabolomics were mainly involved in the reprogramming of glutathione metabolism, purine metabolism, and polyunsaturated fatty acid synthesis. Moreover, AAEO could reduce hepatic ferroptosis induced by BPA, as demonstrated by reducing xanthine oxidase activity, up-regulating the activities of glutathione peroxidase 4 (GPX4), superoxide dismutase, and catalase and the expression of SLC7A11 to promote the glutathione synthetic, while inhibiting transferrin receptor 1 (TFR1) expression to reduce the accumulation of Fe2+ in cells. Therefore, our study identified AAEO as a hepatic protectant against BPA-induced hepatotoxicity by reversing the occurrence of ferroptosis.

254-LB: In Vivo Mapping of Postprandial Hepatic Glucose Metabolism Using Stable Isotope-Assisted Metabolic Imaging in Roux-en-Y Gastric Bypass Adults and Nonoperated Controls

We aimed to assess the impact of Roux-en-Y gastric bypass (RYGB) on hepatic glucose (glc) kinetics using stable isotope-assisted magnetic resonance spectroscopy (MRS). Ten post-RYGB adults (2M, age=39.2±3.1 y, BMI=28±1 kg/m2; mean±SE) and ten non-operated adults (HC; 5M, age=36.4±3.2 y, BMI=26±1 kg/m2) underwent metabolic imaging in a 7T (Terra, Siemens) scanner with a triple-tuned surface coil over the liver. Scanning was performed before (T0) and up to 150 min (T150) after oral intake of 60g of deuterated [6,6′-2H2]-Glc using interleaved sequences of 2H2-MRS imaging (hepatic 2H2-glc signal) and 13C-MRS (glycogen). Blood samples were collected for profiling of plasma glc, glc enrichment, insulin and glucagon. General Additive Mixed Models were used for comparative analyses. We observed distinct postprandial profiles of hepatic glc signal (Fig 1). RYGB subjects showed earlier and higher glc peaks, which were mirrored by hepatic glc signal in both groups. Insulin peak levels were higher and glc nadir lower in RYGB. Postprandial endogenous glc was higher in RYGB, which was paralleled by a fall in hepatic glc. In HC, hepatic glc remained elevated until the end of the experiment. Non-invasive stable isotope-assisted MRS imaging has the potential to unravel changes in postprandial hepatic metabolism induced by RYGB and other treatments. Disclosure N. F. Lange: None. S. Poli: None. D. Herzig: None. M. Schiavon: None. C. Dalla man: Research Support; Sanofi-Aventis Deutschland GmbH, Becton, Dickinson and Company. R. Kreis: None. L. Bally: Research Support; Dexcom, Inc., Ypsomed AG. Funding Swiss National Science Foundation (PCEGP3_186978)

Metabolomics reveals the role of Lactobacillus plantarum SHY130 in hepatic metabolic regulation in a mouse model of type 2 diabetes.

Among type 2 diabetes (T2D) patients, the incidence rate of liver metabolic disorders is much higher than that in healthy subjects. It was observed in our previous research that diabetic symptoms were improved by Lactobacillus plantarum SHY130 (LPSHY130) isolated from yak yogurt in a murine model of type 2 diabetes (T2D). This study sought to investigate the LPSHY130-mediated hepatic metabolic regulation in a murine model of T2D. Treatment with LPSHY130 improved liver function and pathological damage in diabetic mice. Untargeted metabolome analysis revealed the T2D-induced changes in 11 metabolites were regulated after LPSHY130 treatment, mainly involving purine metabolism, amino acid metabolism, choline metabolism, and pantothenate and CoA biosynthesis pathways. In addition, correlation analysis indicated that hepatic metabolic changes can be adjusted by the intestinal microbiota. Overall, this study suggests that treatment with LPSHY130 relieves liver injury and regulates liver metabolism in a murine model of T2D, thus providing a theoretical basis for the use of probiotics as dietary supplements to regulate hepatic metabolic disorders associated with T2D. This article is protected by copyright. All rights reserved.

Adipose tissue-derived exosomes contribute to obesity-associated liver diseases in long-term high-fat diet-fed mice, but not in short-term.

Our study aimed to investigate the changes in hepatic endoplasmic reticulum (ER) stress, inflammation, insulin signaling, and lipid metabolism during the administration of a high-fat diet (HFD) in mice in order to identify correlations between obesity and metabolic disease development in the liver. We used short-, medium-, and long-term HFD periods, corresponding to 4, 8, and 12 weeks, respectively, and isolated exosomes from adipose tissue. We confirmed the effect of adipose tissue-derived exosomes on metabolic disorders in obesity in alpha mouse liver 12 (AML12) hepatocytes. Adipose tissue-derived exosomes from HFD mice did not affect the AML12 cells after 4 weeks, but ER stress, inflammatory response, insulin resistance, and lipid synthesis were observed after 8 and 12 weeks. Furthermore, we confirmed that an HFD increases the amount of adipose tissue-derived exosomes in mice. Consequently, we can infer that adipose tissue-derived exosomes from HFD-fed mice significantly increase ER stress, inflammatory response, insulin resistance, and lipid synthesis in AML12 cells. Our results demonstrate that obesity alters the effects of adipose tissue-derived exosomes in the liver, potentially becoming a risk factor in the development of obesity-induced liver diseases.

Increased GH/IGF-I Axis Activity Relates to Lower Hepatic Lipids and Phosphor Metabolism.

Non-alcoholic fatty liver disease (NAFLD) is a leading causes of liver-related morbidity and mortality. While data on acromegaly, a state of chronic growth hormone (GH)/insulin-like growth factor I (IGF-I) excess, suggest an inverse relationship with intrahepatic lipid (IHL) content, less is known about the impact of the GH/IGF-I axis on IHL, lipid composition, and phosphor metabolites in individuals without disorders of GH secretion. The aim was to investigate the relation between activity of the GH/IGF-I axis and IHL content and phosphor metabolism. We performed a cross-sectional study in 59 otherwise metabolically healthy individuals (30 females), of which 16 met the criteria of NAFLD with IHL of ≥5.6%. The GH/IGF-I axis was evaluated in a fasting state and during an oral glucose tolerance test (OGTT). Insulin sensitivity was estimated by validated indices. IHL, lipid composition (unsaturation index), and phosphate metabolites were analyzed by using 1H/31P magnetic resonance spectroscopy. In the overall cohort (40.6 ± 15 years; body mass index: 24.5 ± 3 kg/m2; IGF-I: 68.0 ± 17% upper limit of normal), fasting GH (R = -0.31; P = .02), GH during oral glucose tolerance test (R = -0.51; P < .01), and IGF-I (R = -0.28; P = .03) inversely correlated with IHL. GH levels during OGTT were significantly lower in NAFLD than in controls (47.7 [22; 143] ng/mL/min vs 16.8 [7; 32] ng/mL/min; P = .003). GH/IGF-I axis activity correlated with lipid composition and with phosphor metabolites. In multiple regression analysis, the GH/IGF-I axis activity was a strong predictor for IHL and lipid composition independent from insulin sensitivity. GH/IGF-I axis activity impacts hepatic lipid and phosphate metabolism in individuals without disorders in GH secretion. Lower GH axis activity is associated with higher IHL and an unfavorable lipid composition, probably mediated by changes in hepatic energy metabolism.

Glycophagy mediated glucose-induced changes of hepatic glycogen metabolism via OGT1-AKT1-FOXO1Ser238 pathway

Glycophagy is the autophagy degradation of glycogen. However, the regulatory mechanisms for glycophagy and glucose metabolism remain unexplored. Herein, we demonstrated that high-carbohydrate diet (HCD) and high glucose (HG) incubation induced glycogen accumulation, protein kinase B (AKT)1 expression and AKT1-dependent phosphorylation of forkhead transcription factor O1 (FOXO1) at Ser238 in the liver tissues and hepatocytes. The glucose-induced FOXO1 phosphorylation at Ser238 prevents FOXO1 entry into the nucleus and the recruitment to the GABA(A) receptor-associated protein like 1 (gabarapl1) promoter, reduces the gabarapl1 promoter activity, and inhibits glycophagy and glucose production. The glucose-dependent O-GlcNAcylation of AKT1 by O-GlcNAc transferase (OGT1) enhances the stability of AKT1 protein and promotes its binding with FOXO1. Moreover, the glycosylation of AKT1 is crucial for promoting FOXO1 nuclear translocation and inhibiting glycophagy. Our studies elucidate a novel mechanism for glycophagy inhibition by high carbohydrate and glucose via OGT1-AKT1-FOXO1Ser238 pathway in the liver tissues and hepatocytes, which provides critical insights into potential intervention strategies for glycogen storage disorders in vertebrates, as well as human beings.