Journal of Nutritional Biochemistry最新文献

Background: Metabolic dysfunction-associated fatty liver disease (MAFLD) affected approximately 25% of the global population, resulting in a huge economic burden. Silymarin, a traditional European herbal remedy with known hepatoprotective properties, has not been fully explored for its therapeutic potential in MAFLD.

Methods: MAFLD mice fed with high-fat diet (HFD) and palmitic acid (PA)-induced HepG2 cells were used to investigate the mechanism of silymarin in vivo and in vitro. HE and Oil Red were utilized to determine the lipotoxic injury in liver. The levels of glutathione (GSH), Malondialdehyde (MDA), iron, and reactive oxygen species (ROS) were measured via corresponding kits to verify the status of ferroptosis. The target of silymarin was validated through western blot, qPCR, immunohistochemistry and immunofluorescence. Targeted amino acid metabolomics was applied to detect the amino acid alteration in liver by LC-MS/MS.

Results: Silymarin reduced the weight and fat accumulation in MAFLD mice. The decreased levels of MDA and ROS and the increased level of GSH indicated that silymarin diminished hepatic ferroptosis. xCT is the potent target of silymarin in MAFLD. Cystine deprivation experiment indicated that cystine played a critical role in silymarin therapy. And silymarin treatment also resulted in amino acid reprogramming in liver.

Conclusions: These results suggested that silymarin alleviated MAFLD by targeting xCT and inhibiting ferroptosis. The alteration in amino acid by silymarin provided new clues for MAFLD therapy.

Glutamine (Gln) is the body's most abundant and versatile amino acid, playing a crucial role in immune responses. The liver, a highly vascularized and metabolically active organ, has a strong regenerative capacity and is vital for immune function, detoxification of xenobiotics, and maintaining metabolic balance. This study aimed to clarify the molecular mechanisms involved in Gln's regulation of liver functions. Dietary supplementation with 1% Gln for weaned Kele × Large White (Yorkshire) hybrid piglets (castrated male) was administered over a period of 28 days. Our findings indicate that Gln enhances liver development processes. Through mRNA sequencing, 444 differentially expressed genes (DEGs) were identified between the control group and the Gln group. Gene Ontology (GO) enrichment analysis of DEGs revealed that the top 2 enriched biological processes were the immune system and the immune response. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis highlighted several T cell-related immune pathways, including Th1 / Th2 cell differentiation, Th17 cell differentiation, and T cell receptor signaling pathway. Analysis of the KEGG pathway network and protein-protein interaction (PPI) network showed that DEGs encoding CD8 α-chain (CD8A), lymphocyte-specific protein tyrosine kinase (LCK), and linker for activation of T cells (LAT) occupy central hub positions, suggesting their critical role in immune regulation. Real-time quantitative PCR (RT-qPCR) results were consistent with the RNA sequencing data. Furthermore, Western blot analysis showed significantly increased protein expression of LCK and LAT in the Gln group, indicating the activation of the CD8A / LCK / LAT signaling axis. These results highlight Gln's immunomodulatory effects through hepatic T-cell signaling and establish a foundation for further investigation into Gln's impact on liver physiology.

Epidemiological studies describe a positive correlation between sugar consumption during pregnancy and the risk for atopic respiratory diseases in the progeny. In the present study we developed an experimental model to test whether the offspring born to and/or breastfed by mice exposed to liquid fructose would manifest changes in the allergic airway disease induced by sensitization and challenge with ovalbumin (OVA). Male mice born to mothers consuming fructose during pregnancy and/or lactation exhibited exacerbated infiltration of eosinophils and lymphocytes in the bronchoalveolar lavage (BAL) after challenge with OVA. Such changes were not detected in the female progeny. On the other hand, the OVA-challenged female progeny born to and breastfed by mothers consuming fructose exhibited higher concentrations of IL-4, IL-5 and TGF-β1 in the BAL and IgE in serum. Additional characteristics that were specifically programmed in the male progeny born to mothers exposed to fructose during pregnancy and lactation comprised increased BAL levels of IL-10, eosinophil infiltration in the lung parenchyma, lung collagen deposition and goblet cell numbers and ccl11, muc5b and receptor for advanced glycation endproducts expression in the lung. Altogether, our experimental approach reveals a previously undescribed causal relationship between maternal fructose consumption and changes in the allergic response in the offspring exposed to the OVA model. Such changes are sex-specific and while the female progeny exhibits higher IL-4, IL-5, TGF-β1 and IgE levels upon challenge with OVA, only the male offspring manifested exacerbated hallmarks of severe disease, including cellular infiltration, goblet cell hyperplasia, and collagen deposition.

Dietary (poly)phenols and methylxanthines may help lower the risk of developing neurodegenerative diseases. However, the relationship between (poly)phenols and methylxanthines and age-related cognitive impairment has not been fully explored, in particular (poly)phenol-rich diets using biomarkers. A cross-sectional analysis was conducted on 202 participants aged 60 - 80 diagnosed with mild cognitive impairment (MCI) or two or more cardiometabolic disorders (CMD). The associations between metabolic signature/metabolites, cognition, and cardiometabolic risk were assessed using linear models, adjusted for covariates and multiple testing (FDR < 0.05). The metabolic signature of (poly)phenol-rich diet score (PPS) was linked with Quality of Episodic Memory (QEM), sustained attention, attentional fluctuation and intensity in the subgroups with CMD or MCI (FDR-adjusted p < 0.05). In plasma, 8 (poly)phenol metabolites presented significant inverse associations with MCI diagnosis, with 4-O-caffeoylquinic acid showing the strongest association (odds ratio: 0.84 (95% CI: 0.72, 0.98)). In cerebrospinal fluid (CSF), 6 metabolites were significantly associated with 4 cognitive outcomes, including QEM (FDR-adjusted p < 0.05). As for cardiometabolic outcomes, 5 plasma metabolites were inversely associated with Framingham risk score, while (-)-epicatechin in CSF showed negative associations with LDL-C and TC (FDR-adjusted p < 0.05). Plasma methylxanthine showed favourable associations with cardiometabolic markers, including paraxanthine and HDL-C (stdBeta: 0.17 (0.15, 0.30)), and 3-methylxanthine and HbA1c (stdBeta: -0.25 (-0.43, -0.07)). The PPS signature and (poly)phenol/methylxanthine metabolites from plasma and CSF are significantly associated with favourable cognitive and cardiometabolic outcomes, highlighting the potential role of a (poly)phenol-rich diet, particularly phenolic acids, in promoting cognitive and cardiometabolic health.

Manganese (Mn) is involved in hepatic lipoprotein secretion, and dietary Mn supplementation has been proposed as a potential therapeutic strategy for hyperlipidemia. SLC30A10 is a unique transporter responsible for Mn efflux from hepatocytes and regulated by dietary fructose. However, whether direct manipulation of hepatic Mn levels through SLC30A10 can alter plasma lipid levels remains unclear. Here we demonstrate that SLC30A10 regulates hepatic Mn levels without affecting hepatic triglyceride secretion or plasma lipid homeostasis. Adeno-associated virus-mediated overexpression of SLC30A10 significantly decreased hepatic Mn concentrations without compromising VLDL secretion or changing plasma triglyceride or total cholesterol levels in mice on either standard chow or high-fat diet (HFD). Moreover, hepatocyte-specific deletion of Slc30a10 gene in mice led to a marked Mn accumulation in the liver and to a less extent in the plasma, while hepatic lipoprotein secretion or plasma lipid levels were unaffected under either chow or HFD feeding condition. Taken together, these results suggest that manipulation of hepatic manganese levels through the exporter SLC30A10 does not alter plasma lipid homeostasis.

Dietary methionine restriction (MR) improves metabolic health in various animals. Beneficial effects on mice include reduced obesity and improved metabolism associated with the appearance of multilocular uncoupling protein 1 (UCP1) positive adipocytes in white fat. This suggests that MR-induced UCP1 thermogenesis contributes significantly to metabolic health. To test this, we evaluated MR effects using unique UCP1-deficient mice on a hybrid (F1) background that is resistant to developing hypothermia upon acute cold exposure. F1.Ucp1^HET and F1.Ucp1^KO mice were fed high fat control diet (HF-CD) and then switched to a high fat MR diet (HF-MRD). Indirect calorimetry was used to monitor energy metabolism; and, serum hormones, metabolites, tissue gene expression, and histology were evaluated. While both genotypes showed improved metabolic parameters when fed HF-MRD, F1.Ucp1^KO mice exhibited further changes in iWAT morphology and more pronounced metabolic improvements in glucose tolerance, serum metabolic biomarker profiles and hepatic steatosis compared to F1.Ucp1^HET. Strikingly, F1.Ucp1^KO mice showed elevated fatty acid oxidation compared with F1.Ucp1^HET when fed HF-CD that was sustained after the switch to HF-MRD. We posit that F1.Ucp1^KO mice employ fatty acid oxidation for body temperature maintenance as at least a part of a mechanism that protects them from acute exposure to cold temperatures in addition to development of diet-induced obesity. Furthermore, our studies suggest that many of the metabolic benefits of MR in mice do not require functional UCP1 thermogenesis.

Long-chain polyunsaturated fatty acids (LCPUFA) promote immune development and improve obesity-related inflammation. This study determined the effects of LCPUFA-supplemented diets (age Wk3-10) fed to male and female rats on: 1) anthropometrics and glucose tolerance, 2) splenocyte membrane lipid composition, 3) systemic and intestinal immune function, and 4) systemic, subcutaneous (SAT) and visceral (VAT) adipose inflammation. Wistar rats were fed a high-fat diet (20% w/w fat) with 0% docosahexaenoic acid (DHA)+0% arachidonic acid (ARA) (control), 1%DHA+1%ARA (1%DHA), 2%DHA+1%ARA (2%DHA) or 1%DHA+1%ARA+1% eicosapentaenoic acid (EPA) (fish oil). Diets did not alter anthropometrics or glucose tolerance. Compared to control, all diets increased DHA in splenocyte phosphatidylethanolamine, 2%DHA also increased DHA in phosphatidylcholine; fish oil increased EPA in phosphatidylethanolamine and phosphatidylcholine (P<0.01). Experimental diets altered splenocyte phenotypes (P<0.05), including higher % of activated cytotoxic T cells (2%DHA), natural killer T cells (2%DHA, fish oil) and dendritic cells/macrophages expressing MHC-II complex (1%DHA) without altering ex vivo responses to mitogens. In mesenteric lymph nodes, experimental diets lowered IL-10 (1%DHA, 2%DHA, female-only) and increased IL-8 (2%DHA) production after mitogen stimulation (P<0.01). In plasma, experimental diets lowered IL-8 (1%DHA, male-only), CRP (2%DHA) and TGF-β (2%DHA, female-only) (P<0.02). In SAT, 2%DHA increased IL-10 (male-only, P<0.05). In VAT, all diets increased IL-10, 2%DHA also increased leptin (P<0.01). Collectively, compared to high-fat control, LCPUFA diets reduced systemic and adipose inflammation and altered the splenocyte phenotypes and MLN immune response in a sex-specific manner. These effects may indicate improved immune and adipose function and were more pronounced in rats fed the 2%DHA.

Metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis (MASLD/MASH), has emerged as one of the leading causes of cirrhosis and hepatocellular carcinoma. Currently, no specific pharmacological treatment is available for MASLD/MASH patients. Sirtuin 3 (SIRT3) plays a pivotal role in regulating mitochondrial metabolism, antioxidant defenses, and the maintenance of cellular homeostasis.

Objective: To investigate the effects of SIRT3 overexpression on inflammation, oxidative stress, and fibrosis in mice.

Methods: Mice were injected an SIRT3 overexpressed adeno-associated virus (AAV-SIRT3) vector or a control vector (AAV-GFP) by intravenous tail vein injection.6-week-old mice were randomly assigned to four groups: CD-GFP, CD-SIRT3, HFD-GFP, and HFD-SIRT3. Mice received tail vein injections according to the group assignment, followed by a 12-week feeding regimen with either a chow diet (CD) or a high-fat diet (HFD). 11-week-old mice were randomly divided into four groups: MCS-GFP, MCS-SIRT3, MCD-GFP, and MCD-SIRT3 groups. Tail vein injections were administered prior to a 4-week dietary intervention using either a methionine-choline-sufficient diet (MCS) or a methionine-choline-deficient diet (MCD).

Results: In both HFD-and MCD diet-fed mice, SIRT3 overexpression improved serum ALT and AST levels, decreased hepatic TG levels, reduced macrophage infiltration, and decreased inflammatory signals and cytokines. In addition, hepatic SIRT3 overexpression reduced ROS production and increased antioxidative protein levels, such as HO-1, NQO1, and NRF2, as well as increased Mitochondrial SOD2 deacetylation. Furthermore, SIRT3 overexpression decreased the levels of fibrogenic genes including Col1α1, Col3α1, and α-SMA.

Conclusion: SIRT3 overexpression significantly reduced hepatic lipid accumulation, inflammation, oxidative stress, and fibrosis in HFD-and MCD diet-fed mice.

Against the backdrop of generally reduced fluoride exposure levels in the current environment, the immune barrier function, as the core of the body's defense system, has attracted significant attention for its role in immune regulation under fluoride exposure. The kidneys, serving as a key target organ for Tregs-mediated immune homeostasis, rely on Foxp3 acetylation as a core regulatory mechanism. However, the role of Tregs in fluoride-induced renal injury remains unclear. In this cross-sectional study, we collected data from 336 residents in areas with low-to-moderate fluoride exposure (water fluoride concentration: 0.89-2.66 mg/L). We measured the following parameters: urinary fluoride, urinary creatinine (Ucr), microalbumin (MALB), and N-acetyl-β-D-glucosaminidase (NAG) levels. In addition, we assessed the proportions of CD3⁺, CD3⁺CD4⁺, CD3⁺CD8⁺ T cells and regulatory T cells (Tregs) in peripheral blood mononuclear cells, and measured the expression of silent information regulator 1 (SIRT1) in Tregs. Furthermore, a rat model of fluorosis was established by administering fluoride in drinking water at concentrations of 5, 10, 25, and 50 mg/L for 12 weeks. We measured urinary fluoride levels, examined the changes in Tregs within peripheral blood and kidney tissues, and quantified the expression of SIRT1 and histone acetyltransferase (P300) in Tregs. Subsequently, in vitro-prepared rat Tregs were administered via tail vein injection to evaluate their therapeutic effect on renal injury induced by low-dose fluoride exposure. Multivariate logistic regression analysis indicated that among the population with low water fluoride exposure (<1.5 mg/L), elevated urinary fluoride levels were associated with an increased risk of abnormal MALB and NAG levels. Multivariate linear regression demonstrated that elevated urinary fluoride levels led to decreased proportions of CD3⁺, CD3⁺CD4⁺, and CD3⁺CD8⁺ cells, while increasing the proportion of Tregs. Tregs adoptive transfer effectively alleviated fluoride-induced renal inflammation and improved pathological damage in both glomeruli and tubules. Simultaneously, low fluoride exposure reduced IL-2 expression levels in Tregs in both peripheral blood and kidney tissues. Furthermore, low fluoride exposure inhibited SIRT1 in human peripheral Tregs and decreased SIRT1 and P300 levels in rat peripheral and renal Tregs. These findings demonstrate that Tregs mediate renal dysfunction induced by low-level fluoride exposure, potentially through acetylation-mediated regulation. The suppression of IL-2 levels may thereby affect Tregs activation.

Interesterified fat (IF) has replaced partially hydrogenated fats because it does not generate trans isomers, but it may affect lipid metabolism due to structural changes in triacylglycerols (TAGs). Since chemical interesterification alters TAG configuration and influences digestion and absorption, methodological approaches capable of tracking lipid metabolites are needed. In this study, we investigated the absorption kinetics and systemic distribution of IF metabolites using a radiolabeling strategy. Eight-week-old Swiss mice received via gavage: PA group - 3.7 MBq of ^99mTc-palmitic acid (^99mTc-PA); 2-PG group - 3.7 MBq of ^99mTc-2-palmitoylglycerol (^99mTc-2PG); and TC group - 3.7 MBq of free technetium (^99mTcO₄-). Scintigraphic imaging was performed in vivo at 1-, 3-, and 6-hours post-administration to verify complex stability, while ex vivo imaging assessed absorption kinetics and biodistribution. The data indicated that radiolabeling was sTable and efficient. Compared with PA, 2-PG exhibited shorter digestion time, faster intestinal transit until fecal excretion, and more efficient absorption. Once absorbed, 2-PG reached the systemic circulation and was preferentially detected in organs such as mesenteric lymph nodes, spleen, heart, liver, kidneys, and the brain, where it remained detecTable throughout the experimental period. Beyond these findings, the use of technetium radiolabeling represents a methodological innovation, providing a powerful tool to track the metabolic fate of lipid molecules. This approach adds a new dimension to the study of lipid bioavailability and supports future investigations into the biological relevance of sn-2 monoacylglycerols.