Hepatic Regulation Research Articles

Maternal Supplementation of Dietary Choline and Docosahexaenoic Acid during Gestational Nutrition Restriction Alters Hepatic mRNA and miRNA Expression Patterns in Full-Term Fetal Pigs.

Supplementing choline and docosahexaenoic acid (DHA) to pregnant gilts modified fetal pig hepatic global DNA methylation induced by gestational malnutrition, suggesting that gene expression and regulation and its associated metabolic pathways are affected in the liver of offspring during growth and development. To investigate the effect of maternal supplementation of choline, DHA and their interaction on hepatic mRNA expression, miRNA regulation and metabolic pathways in the fetal pigs born to malnourished mothers. The abundance of mRNA and miRNA was profiled in fetal liver from sows with undernutrition supplemented with choline and DHA in a 2 × 2 factorial design. The effects of choline, DHA, and their interaction on mRNA and miRNA expression were evaluated. Identification of the Biological Processes from the Gene Ontology database and miRNA Target Prediction Analysis were performed using the DAVID Functional Annotation Tool and Ingenuity Pathway Analysis. The identified miRNA-mRNA pairings were validated using RT-qPCR. 144 mRNA and 1 miRNA were altered by supplementation of choline and the alterations were associated with the inhibitions of cardiac hypertrophy signaling, IL-6 signaling, IL-3 signaling, the Th1 pathway, and the acute phase response signaling pathway. 151 mRNAs and 6 miRNAs were altered by maternal supplementation DHA and were associated with inhibition of 5 inositol-related pathways, 5 immune-related pathways, and 7 other pathways and the stimulation of PPAR signaling and RhoGDI signaling pathways. 383 mRNAs and 25 miRNAs displayed choline x DHA interactions including synergistic effects on acute phase response signaling, and antagonistic effects on tRNA splicing, PPARα/RXRα activation, and sirtuin signaling, NAD signaling and RNA polymerase I transcription pathways. 10 of the identified 20 miRNA-mRNA pairings were validated using RT-qPCR. We identified and confirmed that supplementation of choline, DHA or choline plus DHA to pregnant gilts modifies liver mRNA, miRNA, and pathways in fetal pigs during gestational undernutrition.

Insulin activates parasympathetic hepatic-related neurons of the paraventricular nucleus of the hypothalamus through mTOR signaling.

Integration of autonomic and metabolic regulation, including hepatic function, is a critical role played by the brain's hypothalamic region. Specifically, the paraventricular nucleus of the hypothalamus (PVN) regulates autonomic functions related to metabolism, such as hepatic glucose production. Although insulin can act directly on hepatic tissue to inhibit hepatic glucose production, recent evidence implicates central actions of insulin within PVN also regulates glucose metabolism. However, specific central circuits responsible for insulin signaling with relation to hepatic regulation are poorly understood. As a heterogenous nucleus essential to controlling parasympathetic motor output with notable expression of insulin receptors, PVN is an appealing target for insulin-dependent modulation of parasympathetic activity. Here, we tested the hypothesis that insulin activates hepatic-related PVN (PVNhepatic) neurons through a parasympathetic pathway. Using transsynaptic retrograde tracing, labeling within PVN was first identified 24 h after its expression in DMV and 72 h after hepatic injection. Critically, nearly all labeling in medial PVN was abolished after a left vagotomy, indicating that PVNhepatic neurons in this region are part of a central circuit innervating parasympathetic motor neurons. Insulin also significantly increased firing frequency of PVNhepatic neurons in this subregion. Mechanistically, rapamycin pretreatment inhibited insulin-dependent activation of PVNhepatic neurons. Therefore, central insulin signaling can activate a subset of PVNhepatic neurons which are part of a unique parasympathetic network in control of hepatic function. Taken together, PVNhepatic neurons related to parasympathetic output regulation could serve as a key central network in insulin's ability to control hepatic functions.

Identification of reversible OATP1B1 and time-dependent CYP3A4 inhibition as the major risk factors for drug-induced cholestasis (DIC).

Hepatic bile acid regulation is a multifaceted process modulated by several hepatic transporters and enzymes. Drug-induced cholestasis (DIC), a main type of drug-induced liver injury (DILI), denotes any drug-mediated condition in which hepatic bile flow is impaired. Our ability in translating preclinical toxicological findings to human DIC risk is currently very limited, mainly due to important interspecies differences. Accordingly, the anticipation of clinical DIC with available in vitro or in silico models is also challenging, due to the complexity of the bile acid homeostasis. Herein, we assessed the in vitro inhibition potential of 47 marketed drugs with various degrees of reported DILI severity towards all metabolic and transport mechanisms currently known to be involved in the hepatic regulation of bile acids. The reported DILI concern and/or cholestatic annotation correlated with the number of investigated processes being inhibited. Furthermore, we employed univariate and multivariate statistical methods to determine the important processes for DILI discrimination. We identified time-dependent inhibition (TDI) of cytochrome P450 (CYP) 3A4 and reversible inhibition of the organic anion transporting polypeptide (OATP) 1B1 as the major risk factors for DIC among the tested mechanisms related to bile acid transport and metabolism. These results were consistent across multiple statistical methods and DILI classification systems applied in our dataset. We anticipate that our assessment of the two most important processes in the development of cholestasis will enable a risk assessment for DIC to be efficiently integrated into the preclinical development process.

Hepatic IL22RA1 deficiency promotes hepatic steatosis by modulating oxysterol in the liver.

Imbalance in lipid metabolism is the main cause of nonalcoholic fatty liver disease (NAFLD). While the pathogenesis of lipid accumulation mediated by extrahepatic regulators has been extensively studied, the intrahepatic regulators modulating lipid homeostasis remain unclear. Previous studies have shown that systemic administration of interleukin-22 (IL-22) protects against NAFLD; however, the role of IL-22/IL22RA1 signaling in modulating hepatic lipid metabolism remains uncertain. This study shows hepatic IL22RA1 is vital in hepatic lipid regulation. IL22RA1 is downregulated in palmitic acid-treated mouse primary hepatocytes, as well as in the livers of NAFLD model mice and patients. Hepatocyte-specific Il22ra1 knockout (HKO) mice display diet-induced hepatic steatosis, insulin resistance, impaired glucose tolerance, increased inflammation, and fibrosis compared with flox/flox mice. This is attributed to increased lipogenesis mediated by the accumulation of hepatic oxysterols, particularly, 3 beta-hydroxy-5-cholestenoic acid (3β HCA). Mechanistically, hepatic IL22RA1 deficiency facilitates 3β HCA deposition via the activating transcription factor 3 (ATF3)/oxysterol 7 alpha-hydroxylase (CYP7B1) axis. Notably, 3β HCA facilitates lipogenesis in MPHs and human liver organoids (HLOs) by activating LXR-alpha signaling, but IL-22 treatment attenuates this effect. Additionally, restoring CYP7B1 or silencing hepatic ATF3 reduces both hepatic 3β HCA and lipid contents in HKO mice. These findings indicate that IL22RA1 plays a crucial role in maintaining hepatic lipid homeostasis in an ATF3/CYP7B1-dependent manner, and establish a link between 3β HCA and hepatic lipid homeostasis.

Sex-Specific Effects of Cocoa on Hepatic Redox Regulation and Lipid Homeostasis in High-Fat Diet-Fed Mice

Sex-Specific Effects of Cocoa on Hepatic Redox Regulation and Lipid Homeostasis in High-Fat Diet-Fed Mice

Exploring the dynamic three-dimensional chromatin architecture and transcriptional landscape in goose liver tissues underlying metabolic adaptations induced by a high-fat diet

BackgroundGoose, descendants of migratory ancestors, have undergone extensive selective breeding, resulting in their remarkable ability to accumulate fat in the liver and exhibit a high tolerance for significant energy intake. As a result, goose offers an excellent model for studying obesity, metabolic disorders, and liver diseases in mammals. Although the impact of the three-dimensional arrangement of chromatin within the cell nucleus on gene expression and transcriptional regulation is widely acknowledged, the precise functions of chromatin architecture reorganization during fat deposition in goose liver tissues still need to be fully comprehended.ResultsIn this study, geese exhibited more pronounced changes in the liver index and triglyceride (TG) content following the consumption of the high-fat diet (HFD) than mice without significant signs of inflammation. Additionally, we performed comprehensive analyses on 10 goose liver tissues (5 HFD, 5 normal), including generating high-resolution maps of chromatin architecture, conducting whole-genome gene expression profiling, and identifying H3K27ac peaks in the livers of geese and mice subjected to the HFD. Our results unveiled a multiscale restructuring of chromatin architecture, encompassing Compartment A/B, topologically associated domains, and interactions between promoters and enhancers. The dynamism of the three-dimensional genome architecture, prompted by the HFD, assumed a pivotal role in the transcriptional regulation of crucial genes. Furthermore, we identified genes that regulate chromatin conformation changes, contributing to the metabolic adaptation process of lipid deposition and hepatic fat changes in geese in response to excessive energy intake. Moreover, we conducted a cross-species analysis comparing geese and mice exposed to the HFD, revealing unique characteristics specific to the goose liver compared to a mouse. These chromatin conformation changes help elucidate the observed characteristics of fat deposition and hepatic fat regulation in geese under conditions of excessive energy intake.ConclusionsWe examined the dynamic modifications in three-dimensional chromatin architecture and gene expression induced by an HFD in goose liver tissues. We conducted a cross-species analysis comparing that of mice. Our results contribute significant insights into the chromatin architecture of goose liver tissues, offering a novel perspective for investigating mammal liver diseases.

Cullin 3 RING E3 ligase inactivation causes NRF2-dependent NADH reductive stress, hepatic lipodystrophy, and systemic insulin resistance

Cullin RING E3 ligases (CRL) have emerged as key regulators of disease-modifying pathways and therapeutic targets. Cullin3 (Cul3)-containing CRL (CRL3) has been implicated in regulating hepatic insulin and oxidative stress signaling. However, CRL3 function in liver pathophysiology is poorly defined. Here, we report that hepatocyte Cul3 knockout results in rapid resolution of steatosis in obese mice. However, the remarkable resistance of hepatocyte Cul3 knockout mice to developing steatosis does not lead to overall metabolic improvement but causes systemic metabolic disturbances. Liver transcriptomics analysis identifies that CRL3 inactivation causes persistent activation of the nuclear factor erythroid 2-related factor 2 (NRF2) antioxidant defense pathway, which also reprograms the lipid transcriptional network to prevent TG storage. Furthermore, global metabolomics reveals that NRF2 activation induces numerous NAD+-consuming aldehyde dehydrogenases to increase the cellular NADH/NAD+ ratio, a redox imbalance termed NADH reductive stress that inhibits the glycolysis-citrate-lipogenesis axis in Cul3 knockout livers. As a result, this NRF2-induced cellular lipid storage defect promotes hepatic ceramide accumulation, elevates circulating fatty acids, and worsens systemic insulin resistance in a vicious cycle. Hepatic lipid accumulation is restored, and liver injury and hyperglycemia are attenuated when NRF2 activation and NADH reductive stress are abolished in hepatocyte Cul3/Nrf2 double-knockout mice. The resistance to hepatic steatosis, hyperglycemia, and NADH reductive stress are observed in hepatocyte Keap1 knockout mice with NRF2 activation. In summary, our study defines a critical role of CRL3 in hepatic metabolic regulation and demonstrates that the CRL3 downstream NRF2 overactivation causes hepatic metabolic maladaptation to obesity and insulin resistance.

Nuclear receptor corepressors non-canonically drive glucocorticoid receptor-dependent activation of hepatic gluconeogenesis.

Nuclear receptor corepressors (NCoRs) function in multiprotein complexes containing histone deacetylase 3 (HDAC3) to alter transcriptional output primarily through repressive chromatin remodelling at target loci1-5. In the liver, loss of HDAC3 causes a marked hepatosteatosis largely because of de-repression of genes involved in lipid metabolism6,7; however, the individual roles and contribution of other complex members to hepatic and systemic metabolic regulation are unclear. Here we show that adult loss of both NCoR1 and NCoR2 (double knockout (KO)) in hepatocytes phenocopied the hepatomegalic fatty liver phenotype of HDAC3 KO. In addition, double KO livers exhibited a dramatic reduction in glycogen storage and gluconeogenic gene expression that was not observed with hepatic KO of individual NCoRs or HDAC3, resulting in profound fasting hypoglycaemia. This surprising HDAC3-independent activation function of NCoR1 and NCoR2 is due to an unexpected loss of chromatin accessibility on deletion of NCoRs that prevented glucocorticoid receptor binding and stimulatory effect on gluconeogenic genes. These studies reveal an unanticipated, non-canonical activation function of NCoRs that is required for metabolic health.

Osteocytes/Osteoblasts Produce SAA3 to Regulate Hepatic Metabolism of Cholesterol.

Hypercholesterolaemia is a systemic metabolic disease, but the role of organs other than liver in cholesterol metabolism is unappreciated. The phenotypic characterization of the Tsc1Dmp1 mice reveal that genetic depletion of tuberous sclerosis complex 1 (TSC1) in osteocytes/osteoblasts (Dmp1-Cre) triggers progressive increase in serum cholesterol level. The resulting cholesterol metabolic dysregulation is shown to be associated with upregulation and elevation of serum amyloid A3 (SAA3), a lipid metabolism related factor, in the bone and serum respectively. SAA3, elicited from the bone, bound to toll-like receptor 4 (TLR4) on hepatocytes to phosphorylate c-Jun, and caused impeded conversion of cholesterol to bile acids via suppression on cholesterol 7 α-hydroxylase (Cyp7a1) expression. Ablation of Saa3 in Tsc1Dmp1 mice prevented the CYP7A1 reduction in liver and cholesterol elevation in serum. These results expand the understanding of bone function and hepatic regulation of cholesterol metabolism and uncover a potential therapeutic use of pharmacological modulation of SAA3 in hypercholesterolaemia.

Effects of Environmental Enrichments on Welfare and Hepatic Metabolic Regulation of Broiler Chickens.

The aims of this study were to find suitable environmental enrichment (EE) and evaluate the combined effect of two EEs, variable light intensity (VL) lighting program and EH, on mental health and hepatic metabolic regulation in commercial broilers. To find the advantageous EEs for broilers, three different EEs (board, hut, and ramp) were tested in trial 1. EEs were placed and the engagement of birds to EEs, dustbathing behavior, and daily physical activity were observed. Birds treated with huts showed higher engagement than the board- or ramp-treated birds (p < 0.05). The results of dustbathing behavior and daily physical activity indicated that the environmental hut (EH) is the most favorable enrichment for broilers. In the second trial, to test the effect of EHs on mental health and hepatic metabolic conditions, the brain and liver were sampled from the four treatment birds (20 lx_Con, 20 lx_Hut, VL_Con and VL_Hut) on day 42. The lower expression of TPH2 (tryptophan hydroxylase 2) of VL_Hut birds than those of VL_Con and 20 lx_Hut treated birds suggests the combining effect of EHs with the VL lighting program on the central serotonergic homeostasis of broilers. Reduced expressions of TH (tyrosine hydroxylase), GR (glucocorticoid receptor), BDNF (brain-derived neurotrophic factor) of VL_Hut treated birds compared to those of VL_Con and 20 lx_Hut birds suggest lower stress, stress susceptibility, and chronic social stress in VL_Hut treated birds. The expression of CPT1A (carnitine palmitoyl transferase 1) increased over three-fold in the liver of VL_Con birds compared to 20 lx_Con birds (p < 0.05). EHs treatment in VL birds (VL_Hut) significantly decreased CPT1A but not in 20 lx birds (20 lx_Hut). The expression of ACCα (acetyl-CoA carboxylase alpha) was significantly decreased in VL_Con birds compared to 20 lx_Con birds. There was no significant difference in the hepatic FBPase (fructose-1,6-bisphosphatase), GR, and 11β-HSD1 (11 β-hydroxysteroid dehydrogenease-1) expression between 20 lx_Con and VL_Con birds, but EHs significantly stimulated GR in 20 lx_Hut birds, and stimulated FBPase and 11β-HSD1 expression in the VL_Hut birds compared to 20 lx_Con birds, suggesting that the VL lighting program reduced fatty acid synthesis and increased fatty acid β-oxidation in the broilers' liver and VL_Hut improved the hepatic de novo glucose production. Taken together, the results suggest that the stimulated voluntary activity by EHs in the light-enriched broiler house improved mental health and hepatic metabolic function of broilers and may indicate that the improved hepatic metabolic function contributes to efficient nutritional support for broilers.

Maternal Diet High in Linoleic Acid Alters Offspring Lipids and Hepatic Regulators of Lipid Metabolism in an Adolescent Rat Model.

Linoleic acid (LA), an n-6 polyunsaturated fatty acid (PUFA), is essential for fetal growth and development. A maternal high LA (HLA) diet alters cardiovascular development in adolescent rats and hepatic function in adult rats in a sex-specific manner. We investigated the effects of an HLA diet on adolescent offspring hepatic lipids and hepatic lipid metabolism gene expression, and the ability of the postnatal diet to alter these effects. Female Wistar Kyoto rats were fed low LA (LLA; 1.44% energy from LA) or high LA (HLA; 6.21% energy from LA) diets during pregnancy and gestation/lactation. Offspring, weaned at postnatal day (PN) 25, were fed LLA or HLA and euthanised at PN40 (n = 6-8). Maternal HLA increased circulating uric acid, decreased hepatic cholesterol and increased hepatic Pparg in males, whereas only hepatic Srebf1 and Hmgcr increased in females. Postnatal (post-weaning) HLA decreased liver weight (% body weight) and increased hepatic Hmgcr in males, and decreased hepatic triglycerides in females. Maternal and postnatal HLA had an interaction effect on Lpl, Cpt1a and Pparg in females. These findings suggest that an HLA diet both during and after pregnancy should be avoided to improve offspring disease risk.

Hepatic regulator of G protein signaling 14 ameliorates NAFLD through activating cAMP-AMPK signaling by targeting Giα1/3

ObjectiveNonalcoholic fatty liver disease (NAFLD) is an emerging public health threat as the most common chronic liver disease worldwide. However, there remains no effective medication to improve NAFLD. G protein-coupled receptors (GPCRs) are the most frequently investigated drug targets family. The Regulator of G protein signaling 14 (RGS14), as an essential negative modulator of GPCR signaling, plays important regulatory roles in liver damage and inflammatory responses. However, the role of RGS14 in NAFLD remains largely unclear. Methods and resultsIn this study, we found that RGS14 was decreased in hepatocytes in NAFLD individuals in a public database. We employed genetic engineering technique to explore the function of RGS14 in NAFLD. We demonstrated that RGS14 overexpression ameliorated lipid accumulation, inflammatory response and liver fibrosis in hepatocytes in vivo and in vitro. Whereas, hepatocyte specific Rgs14-knockout (Rgs14-HKO) exacerbated high fat high cholesterol diet (HFHC) induced NASH. Further molecular experiments demonstrated that RGS14 depended on GDI activity to attenuate HFHC-feeding NASH. More importantly, RGS14 interacted with Guanine nucleotide-binding protein (Gi) alpha 1 and 3 (Giα1/3, gene named GNAI1/3), promoting the generation of cAMP and then activating the subsequent AMPK pathways. GNAI1/3 knockdown abolished the protective role of RGS14, indicating that RGS14 binding to Giα1/3 was required for prevention against hepatic steatosis. ConclusionsRGS14 plays a protective role in the progression of NAFLD. RGS14-Giα1/3 interaction accelerated the production of cAMP and then activated cAMP-AMPK signaling. Targeting RGS14 or modulating the RGS14-Giα1/3 interaction may be a potential strategy for the treatment of NAFLD in the future.

Nutritional and physiological responses of female and male largemouth bass (Micropterus salmoides) to different dietary starch levels

In this study, we adopted a 2 × 2 factorial design incorporating different dietary starch levels and sexes to assess the impact of dietary starch on the growth performance, feeding response, and glucolipid metabolism of female and male largemouth bass. Two isonitrogenous (49.6%) and isolipidic (10.4%) diets were formulated with 10% starch (low-starch level) and 20% starch (high-starch level). The results indicated that male largemouth bass exhibited superior growth performance compared to females regardless of the dietary starch levels. Furthermore, males demonstrated enhanced feed utilization of the high-starch diet compared to females. Males also exhibited significantly lower mRNA expressions of feeding inhibition molecules (cholecystokinin, leptin b, leptin b receptor, or cocaine and amphetamine-regulated transcript 2) in the brain compared to females, a phenomenon unrelated to dietary starch levels. Compared to females, males fed the high-starch diet displayed elevated mRNA expression of genes associated with glycolysis (hexokinase, pyruvate kinase, and phosphofructokinase) in the liver, as well as lower expression of gluconeogenesis-related genes (glucose-6-phosphatase and phosphoenolpyruvate carboxykinase), which coincided with lower hepatic glycogen in males. Furthermore, males fed with the high-starch diet exhibited higher mRNA expression of genes involved in hepatic lipid catabolism (carnitine palmitoyl transferase 1, hormone-sensitive lipase, and adipose triglyceride lipase). In contrast, males exhibited lower expression of hepatic lipid synthesis regulation (acetyl-CoA carboxylase 1, peroxisome proliferator-activated receptor γ, and fatty acid synthase) in the liver compared with females fed with the low-starch diet. Additionally, upon comparing the hepatic transcriptomes of males and females fed with the high-starch diet, the males exhibited a significant up-regulation of glucokinase2 and hexokinase, coupled with down-regulation of glucose-6-phosphatase. In summary, male largemouth bass exhibited superior growth performance at this developmental stage compared to females regardless of dietary starch levels. Males also exhibited higher feed utilization when fed the high-starch diet, which was likely due to increased activity in glycolytic processes and enhanced fatty acid decomposition compared to females.

Lemon extract reduces the hepatic oxidative stress and persulfidation levels by upregulating the Nrf2 and Trx1 expression in old rats.

Citrus flavanones are recognized as promising bioactives within the concept of healthy aging. Thus, the present study investigated the effects of a nutritionally relevant dose of lemon extract (LE) on liver redox regulation and persulfidation levels in 24-month-old Wistar rats. LE (40 mg/kg b.m.) was administered orally once daily for 4 weeks. Control groups received either vehicle (sunflower oil) or remained intact. The applied methodology considered qPCR, Western blot, protein persulfidation levels evaluation, histochemistry in line with immunofluorescence, liver biochemical assays (glutathione, total -SH groups and malonaldehyde; MDA), liver enzymes in serum and in silico analysis to explore the potential interaction/binding between the proteins studied in the paper. Our results showed that LE increased glutathione peroxidase (GPx), reductase (GR), glutamate-cysteine ligase catalytic and modifier subunit, respectively, as well as Nrf2 gene expressions, but decreased the expression of superoxide dismutase 2 (SOD2). Upon LE application, protein expression showed upregulation of NRF2, SOD2, GPx, GR, and thioredoxin 1 (Trx1). LE significantly decreased the protein persulfidation levels and concentration of MDA, a marker of oxidative damage in the cell. Histological analysis showed a normal liver histoarchitecture without pathological changes, aligning with the normal serum level of hepatic enzymes. Obtained results showed that LE, by modulating hepatic redox regulators Nrf2 and Trx1, diminishes oxidative stress and alters the persulfidation levels, suggesting a considerable beneficial antioxidant potential of lemon flavanones in the old-aged liver.

Biochemical Impact of Nickel‐Induced Metabolic Impairment and the Protective Effects of Resveratrol and Ascorbic Acid

Nickel exposure is known to induce oxidative stress and inflammation and disrupt critical metabolic pathways, leading to hepatic dysfunction and impaired glucose regulation. This study aimed to evaluate the biochemical effects of nickel‐induced metabolic impairments in an animal model, using a variety of techniques, including ELISA and instrumental analysis, with a specific focus on the expression of key genes involved in insulin regulation and glucose homeostasis. The experiment included four groups: Control, Nickel‐exposed, Nickel‐exposed with standard treatment (ascorbic acid, AA), and Nickel‐exposed with resveratrol (RSV). Serum nickel levels, measured via ICP‐MS, showed a significant increase in the exposed group, with a mean value of 125.74 ± 6.20 ppb. The analysis of various metabolic biomarkers demonstrated that nickel exposure resulted in hyperglycemia, elevated HOMA‐IR, HbA1c, and DPP‐4, increased level of inflammatory cytokines, altered lipid profiles, and impaired liver and kidney function. Nickel exposure triggered inflammation, disrupted carbohydrate metabolism, induced oxidative stress, and altered the expression of genes related to hepatic inflammation, endoplasmic reticulum (ER) stress, and glucose and lipid metabolism. These changes culminated in mitochondrial dysfunction, impaired glucose metabolism, and insulin resistance, as evidenced by reduced expression of GLUT‐2 and GCK—genes critical for glucose uptake and insulin secretion. Elevated serum levels of amino acids, such as glutamate and valine, further indicated disruptions in amino acid metabolism and oxidative stress. Therapeutic interventions with AA and RSV demonstrated significant protective effects: Both compounds mitigated oxidative stress, reduced inflammatory cytokines, and restored normal expression levels of GCK and GLUT‐2, improving glucose metabolism and insulin sensitivity. Additionally, AA and RSV alleviated mitochondrial dysfunction, suppressing the overexpression of UCP2, a protein linked to impaired energy metabolism. Serum amino acid levels were also normalized, highlighting their role in reestablishing metabolic balance. In conclusion, this study highlights the therapeutic potential of AA and RSV in mitigating nickel‐induced hepatic and metabolic disturbances. These findings emphasize the importance of addressing oxidative stress and inflammation in metabolic disorders and position RSV as promising candidate for restoring metabolic homeostasis. Further research is warranted to elucidate the precise molecular mechanisms underlying their protective effects.

The impact of high polymerization inulin on body weight reduction in high-fat diet-induced obese mice: correlation with cecal Akkermansia.

Obesity presents a significant public health challenge, demanding effective dietary interventions. This study employed a high-fat diet-induced obesity mouse model to explore the impacts of inulin with different polymerization degrees on obesity management. Our analysis reveals that high-degree polymerization inulin (HDI) exhibited a significantly higher oil binding capacity and smaller particle size compared to low-degree polymerization inulin (LDI) (p < 0.05). HDI was more effective than LDI in mitigating body weight gain in high-diet induced obese mice, although neither LDI nor HDI affected blood sugar levels when compared to the high-fat diet control group (p < 0.05). Both HDI and LDI administrations reduced liver weight and enhanced brown adipose tissue thermogenesis compared to the high-fat diet induced control group (p < 0.05). Additionally, HDI suppressed hepatic lipogenesis, resulting in a further reduction in liver triglycerides compared to the high-fat diet-induced obese mice (p < 0.05). Notably, HDI improved gut health by enhancing intestinal morphology and modulating gut microbiota structure. HDI administration notably increased the relative abundance of cecal Akkermansia, a gut microbe associated with improved metabolic health, while LDI showed limited efficacy (p < 0.05 and p > 0.05, respectively). These findings underscore the importance of the structural properties of inulin in its potential to combat obesity and highlight the strategic use of inulin with varying polymerization degrees as a promising dietary approach for obesity management, particularly in its influence on gut microbiota composition and hepatic lipid metabolism regulation.

Formation of EGCG oxidation self-assembled nanoparticles and their antioxidant activity in vitro and hepatic REDOX regulation activity in vivo.

(-)-Epigallocatechin-3-gallate (EGCG) is a major polyphenol in tea and exerts several health-promoting effects. It easily autoxidizes into complex polymers and becomes deactivated due to the presence of multiple phenolic hydroxyl structures. Nonetheless, the morphology and biological activity of complex EGCG polymers are yet to be clarified. The present study demonstrated that EGCG autoxidation self-assembled nanoparticles (ENPs) exhibit antioxidant activity in vitro and hepatic REDOX homeostasis regulation activity in vivo. Also, the formation of ENPs during the EGCG autoxidation process was based on the intermolecular interaction forces that maintain the stability of the nanoparticles. Similar to EGCG, ENPs are scavengers of reactive oxygen species and hydroxyl radicals in vitro and also regulate hepatic REDOX activity through liver redox enzymes, including thioredoxin reductase (TrxR), thioredoxin (Trx), glutathione reductase (GR), glutaredoxin (Grx), and glutathione S-transferase (GST) in vivo. Moreover, ENPs activate the NRF2 antioxidant-responsive element pathway, exerting a detoxification effect at high doses. Unlike EGCG, ENPs do not cause liver damage at low doses and also maintain liver biosafety at high doses through self-assembly, forming large particles, which is supported by the unchanged levels of liver damage biomarkers, including serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), liver γ-phosphorylated histone 2AX (γ-H2AX), and P53-related genes (Thbs, MDM2, P53, and Bax). Collectively, these findings revealed that ENPs, with adequate biosafety and regulation of hepatic redox activity in vivo, may serve as substitutes with significant potential for antioxidant applications or as food additives to overcome the instability and liver toxicity of EGCG.

Hepatic ChREBP orchestrates intrahepatic carbohydrate metabolism to limit hepatic glucose 6-phosphate and glycogen accumulation in a mouse model for acute Glycogen Storage Disease type Ib

ObjectiveCarbohydrate Response Element Binding Protein (ChREBP) is a glucose 6-phosphate (G6P)-sensitive transcription factor that acts as a metabolic switch to maintain intracellular glucose and phosphate homeostasis. Hepatic ChREBP is well-known for its regulatory role in glycolysis, the pentose phosphate pathway, and de novo lipogenesis. The physiological role of ChREBP in hepatic glycogen metabolism and blood glucose regulation has not been assessed in detail, and ChREBP's contribution to carbohydrate flux adaptations in hepatic Glycogen Storage Disease type 1 (GSD I) requires further investigation. MethodsThe current study aimed to investigate the role of ChREBP as a regulator of glycogen metabolism in response to hepatic G6P accumulation, using a model for acute hepatic GSD type Ib. The immediate biochemical and regulatory responses to hepatic G6P accumulation were evaluated upon G6P transporter inhibition by the chlorogenic acid S4048 in mice that were either treated with a short hairpin RNA (shRNA) directed against ChREBP (shChREBP) or a scrambled shRNA (shSCR). Complementary stable isotope experiments were performed to quantify hepatic carbohydrate fluxes in vivo. ResultsShChREBP treatment normalized the S4048-mediated induction of hepatic ChREBP target genes to levels observed in vehicle- and shSCR-treated controls. In parallel, hepatic shChREBP treatment in S4048-infused mice resulted in a more pronounced accumulation of hepatic glycogen and further reduction of blood glucose levels compared to shSCR treatment. Hepatic ChREBP knockdown modestly increased glucokinase (GCK) flux in S4048-treated mice while it enhanced UDP-glucose turnover as well as glycogen synthase and phosphorylase fluxes. Hepatic GCK mRNA and protein levels were induced by shChREBP treatment in both vehicle- and S4048-treated mice, while glycogen synthase 2 (GYS2) and glycogen phosphorylase (PYGL) mRNA and protein levels were reduced. Finally, knockdown of hepatic ChREBP expression reduced starch domain binding protein 1 (STBD1) mRNA and protein levels while it inhibited acid alpha-glucosidase (GAA) activity, suggesting reduced capacity for lysosomal glycogen breakdown. ConclusionsOur data show that ChREBP activation controls hepatic glycogen and blood glucose levels in acute hepatic GSD Ib through concomitant regulation of glucose phosphorylation, glycogenesis, and glycogenolysis. ChREBP-mediated control of GCK enzyme levels aligns with corresponding adaptations in GCK flux. In contrast, ChREBP activation in response to acute hepatic GSD Ib exerts opposite effects on GYS2/PYGL enzyme levels and their corresponding fluxes, indicating that GYS2/PYGL expression levels are not limiting to their respective fluxes under these conditions.

Featuring molecular regulation of bile acid homeostasis in pediatric short bowel syndrome.

Disturbed bile acid homeostasis may foster development of short bowel syndrome (SBS) associated liver disease during and after weaning off parenteral nutrition (PN). Our aim was to study hepatic molecular regulation of bile acid homeostasis in relation to serum and fecal bile acid profiles in pediatric SBS. Liver histopathology and mRNA expression of genes regulating synthesis, uptake and export of bile acids, and cellular receptors involved in bile acid signaling were measured in SBS patients (n=33, median age 3.2 years). Simultaneously, serum (n=24) and fecal (n=10) bile acid profiles were assessed. Sixteen patients were currently on PN. Results of patients were compared to healthy control subjects. Nine of ten (90%) patients with histological cholestasis received current PN, while portal inflammation was present in 60% (6/10) of patients with cholestasis compared to 13% (3/23) without cholestasis (P=0.01). In all SBS patients, hepatic synthesis and uptake of bile acids was increased. Patients on current PN showed widespread repression of hepatic FXR target genes, including downregulated canalicular (BSEP, MDR3) and basolateral (MRP3) bile acid exporters. Serum and fecal primary bile acids were increased both during and after weaning off PN. Bile acid homeostasis in SBS is characterized by interrupted enterohepatic circulation promoting increased hepatic synthesis and conservation of bile acids. In PN dependent SBS patients with hepatic cholestasis and inflammation, the molecular fingerprint of downregulated hepatocyte canalicular and basolateral bile acid export with simultaneously increased synthesis and uptake of bile acids could favor their accumulation in hepatocytes and predispose to liver disease.

Selenium and vitamin B2 cosupplementation alleviates high‐fat‐diet‐induced nonalcoholic fatty liver disease in rats by regulating hepatic lipid metabolism

AbstractSelenium (Se) and vitamin B2 (VitB2) all play essential roles in participating in hepatic lipid metabolism regulation. In this study, we aimed to identify whether Se combined with VitB2 could meliorate nonalcoholic fatty liver disease (NAFLD) caused by high‐fat (HF) diet in rats. To this end, 50 SD male rats were randomly allotted into five groups equally after receiving a HF diet for 2 weeks. Rats were fed high‐fat diets and gavaged daily with 0.83 or 8.33 µg kg–1 Se combined with 0.70 or 3.50 mg kg–1 VitB2 for 8 weeks. Another 10 rats were given a conventional diet as a control group. The result showed that Se combined with VitB2 decreased NAFLD activity score and liver lipid's levels, relieved hepatic steatosis and lipid deposition and promoted the balance of ApoA1/ApoB ratio. The hepatic 3‐hydroxy‐3‐methyl glutaryl coenzyme A reductase (HMGR) level was declined, and the serum HL level was increased in NAFLD rats through the combined intervention. In addition, Se and VitB2 regulated hepatic metabolism factor's (FAS, ACC, ACAT1, PPARγ, and SREBP‐1c) expression level. Taken together, the combined intervention of Se and VitB2 can alleviate HF‐diet‐induced NAFLD in rats. The molecular mechanism may be related to affecting the activities of lipid metabolic enzymes such as FAS, ACC, HMGR, ACAT1, and HL by inhibiting the expression of PPARγ and SREBP‐1c.Practical Applications: The present study showed that a combination of Se and VitB2 can effectively reduce hepatic lipid accumulations, exert hepatoprotective effects and regulate hepatic lipid metabolism in NAFLD rats caused by a high‐fat diet. The possible molecular mechanism may be related to affecting the activities of lipid metabolic enzymes such as FAS, ACC, HMGR, ACAT1, and HL, and inhibiting the expression of PPARγ and SREBP‐1c. Se and VitB2 cosupplementation may be a potential therapeutic strategy in overcoming hepatic lipid disorders' adverse effects beyond pharmacological interventions to ameliorate NAFLD.