Aug 2026· Journal of Animal Science and Biotechnology· Vol 17· 0 citations· 57 references
Medicine
TL;DR
In vivo studies indicated that exogenous supplementation of TLCA significantly ameliorated hepatic glycolipid metabolism and improved overall liver function in LBW neonatal piglets, providing potential nutritional strategies to improve liver health in LBW piglets and a theoretical basis for using BAs as feed additives in pig production.
Abstract
Low-birth-weight (LBW) piglets often exhibit glycolipid metabolic disorders at birth, which severely impair their postnatal growth and survival. Bile acids (BAs) act as signaling molecules that participate in the regulation of glycolipid metabolism. However, whether the hepatic metabolic abnormalities observed in LBW piglets are associated with altered BA metabolism remains largely unclear. Thus, using naturally occurring LBW fetal pigs, neonatal piglets, and hepatic cell lines as models, the present study aimed to elucidate the association between BA homeostasis and hepatic glycolipid metabolism and to further reveal the underlying molecular mechanisms through integrated analyses of BA-targeted metabolomics, 16S rRNA gene sequencing, and molecular docking. Compared with normal-birth-weight (NBW) fetal pigs, LBW fetal pigs exhibited a marked reduction in hepatic glycogen storage accompanied by excessive lipid accumulation. As key nuclear receptors governing glycolipid metabolism, farnesoid X receptor (FXR) and hepatocyte nuclear factor 4α (HNF4α) were significantly down-regulated in the liver of LBW fetal pigs at both the transcriptional and protein levels, which was coupled with impaired glycogen synthetic capacity and lipolytic capacity in these fetal pigs. Targeted BA metabolomic analysis revealed a profound alteration in the hepatic BA profile of LBW fetal pigs, characterized by an increased proportion of secondary BAs. Notably, the hepatic level of taurolithocholic acid (TLCA) was markedly decreased in LBW fetal pigs. Further analyses demonstrated that critical processes of BA metabolism, including synthesis, transport, detoxification and conjugation, were impaired in LBW fetal pigs, along with disrupted endogenous TLCA biosynthesis. Mechanistically, molecular docking results suggested that TLCA might act as a potential agonist of FXR and HNF4α. In vitro assays confirmed that TLCA modulated hepatic glycolipid metabolism by activating FXR and HNF4α. More importantly, in vivo studies indicated that exogenous supplementation of TLCA significantly ameliorated hepatic glycolipid metabolism and improved overall liver function in LBW neonatal piglets. These findings reveal crosstalk between hepatic glucose-lipid and BA metabolism via HNF4α and FXR, providing potential nutritional strategies to improve liver health in LBW piglets and a theoretical basis for using BAs as feed additives in pig production.
ABSTRACT The gut microbiota plays an important role in the occurrence and development of metabolic dysfunction-associated steatotic liver disease (MASLD), but the specific molecular mechanisms involved have not been fully elucidated. In this study, human cohort studies were performed to identify that the relative abundance of Bacteroides cellulosilyticus (B. cellulosilyticus) was significantly decreased in patients with MASLD. Through the integration of metagenomic and metabolomic analyses, it was confirmed that B. cellulosilyticus and its metabolite 2-hydroxyphenylacetic acid (2HPAA) are key factors regulating the occurrence and development of MASLD. Single-cell sequencing and lipidomic analyses revealed that 2HPAA can enter the liver through the enterohepatic circulation to exert regulatory effects. Specifically, 2HPAA inhibits the peroxisome proliferator-activated receptor γ (PPARγ) signaling pathway, thereby suppressing the expression of the fatty acid transporter CD36. Meanwhile, 2HPAA regulates lipid metabolism in hepatocytes by significantly enhancing palmitate conversion efficiency and inhibiting CD36 palmitoylation. This dual regulatory effect on CD36 expression and palmitoylation can reduce lipid accumulation in hepatocytes and ultimately alleviate MASLD progression. These findings reveal the mechanism by which B. cellulosilyticus and 2HPAA alleviate MASLD by targeting the PPARγ-CD36 pathway. This work provides a new perspective for the study of gut microbiota-host interactions in regulating liver diseases.
Kaiwei Chen, Zizhen Yang, Jixing Peng et al.· Gut microbes· 0 citations
BACKGROUND & AIMS
Lactylation has been implicated in the repair and regeneration of multiple organs including skin and heart. The liver serves as a vital organ for lactate metabolism, while the roles of lactate and lactylation during liver regeneration remain unclear.
METHODS
Mice were subjected to 70% partial hepatectomy (PHx), and liver-to-body weight (LW/BW) ratio and proliferative markers were measured. Protein-protein interactions were detected by Co-IP. The pivotal site of GCN5 for catalysis was predicted by theoretical modelling. CUT&Tag and bulk RNA-seq assays were used to identify downstream genes regulated by H3K9 lactylation (H3K9la). Murine hepatocyte organoids and human liver tissues were used to validate the effects of H3K9la.
RESULTS
Lactate supplementation notably improved LW/BW ratio and upregulated hepatic levels of Ki-67, PCNA and EdU incorporation at 48 h after PHx, while hepatocyte-specific Ldha knockout mice showed impaired liver regenerative capacity. In vitro experiments indicated that increased intracellular lactate upregulated H3 lactylation and promoted hepatocyte proliferation. Mechanistically, GCN5, rather than P300 or MOF, was identified as the pivotal enzyme catalyzing H3K9la. Furthermore, lactate treatment promoted the interaction between GCN5 and H3K9 during liver regeneration. Glu639 was identified as the critical amino acid residue in GCN5 for catalyzing H3K9la. CUT&Tag and bulk RNA-seq results further revealed that H3K9la upregulated the expression of Lipin1 and its mediated transcription of fatty acid oxidation (FAO)-related genes. The pro-regenerative effects of lactate and H3K9la were validated using murine hepatocyte organoids and human liver tissues.
CONCLUSIONS
Lactate facilitates liver regeneration through promoting GCN5-mediated H3K9la, which upregulates Lipin1 transcription and subsequent Lipin1-mediated FAO in hepatocytes.
Xun Qiu, Hanzhi Xu, Lijun Meng et al.· Cellular and Molecular Gastr...· 0 citations
BACKGROUND AND PURPOSE
Lobeglitazone is a thiazolidinedione and PPARγ agonist that improves metabolic parameters and hepatic steatosis, but its mechanisms are not fully understood. This study investigated the effects of lobeglitazone on hepatic transcriptomic and metabolic profiles in a rat model of obesity and Type 2 diabetes mellitus.
EXPERIMENTAL APPROACH
Male Otsuka Long-Evans Tokushima fatty rats were fed a high-fat, high-carbohydrate (HF/HC) diet for 15 weeks and treated with lobeglitazone or vehicle. Metabolic parameters, liver function and histology were assessed. RNA sequencing was conducted to identify changes in hepatic gene expression, and metabolomic profiling was performed on liver and plasma samples. Mechanistic validation was conducted in HepG2 cells using siRNA-mediated PPARγ knockdown.
KEY RESULTS
Lobeglitazone treatment improved glucose tolerance and decreased plasma triglyceride and total cholesterol levels. Histological analyses indicated reduced hepatic steatosis, ballooning and lobular inflammation, reflecting protection against hepatic steatosis. RNA sequencing revealed 334 DEGs between the HF/HC-lobeglitazone and HF/HC groups, with pathway enrichment analyses indicating modulation of pathways related to central carbon metabolism. Five pyruvate metabolism-associated genes were down-regulated by lobeglitazone. Quantitative PCR confirmed selected transcriptomic changes, although mitochondrial pyruvate carrier (MPC) 1 and 2 mRNA levels were not significantly altered. In contrast, MPC1 and MPC2 protein levels were markedly reduced. Metabolomics showed increased hepatic and plasma pyruvate, amino acids involved in pyruvate production and hydroxybutyrates, suggesting reduced mitochondrial pyruvate flux. Functional assays demonstrated decreased mitochondrial pyruvate levels following lobeglitazone treatment. PPARγ knockdown abolished lobeglitazone-induced down-regulation of MPC proteins.
CONCLUSIONS AND IMPLICATIONS
Lobeglitazone treatment was associated with improved hepatic steatosis and liver-associated metabolic parameters, accompanied by transcriptional and metabolomic changes related to mitochondrial pyruvate metabolism. These findings are correlative and provide new insights into the hepatic actions of lobeglitazone in metabolic disease.
Hyekyung Yang, S. Son, Youngmi Song et al.· British Journal of Pharmacol...· 0 citations
Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) currently lacks effective targeted therapeutic approaches. Although isoliquiritigenin (ISL) exhibits hepatoprotective effects, its precise molecular target remains unclear. This study aims to identify the potential molecular target and mechanism of ISL in MASLD. Methods: HFD-induced MASLD mice were treated with ISL, while palmitic acid (PA)-challenged HepG2 cells were used as an in vitro lipotoxicity model. RNA sequencing (RNA-seq), molecular docking, cellular thermal shift assay (CETSA), and S100A8 overexpression plasmids were employed to investigate the underlying molecular mechanism. Results: In vivo , ISL significantly reduced serum transaminases, hepatic lipid accumulation, and fibrosis. RNA-seq showed that ISL mainly regulated ferroptosis and the mitogen-activated protein kinase (MAPK) pathway, with S100A8 identified as an important candidate regulatory target. Molecular docking and CETSA assays point toward a possible direct interaction between ISL and S100A8, implying that ISL could improve the thermal stability of S100A8. In vitro , ISL reversed PA-triggered lipid accumulation, reduced lipid peroxidation as indicated by MDA levels, restored glutathione peroxidase 4 (GPX4) expression, inhibited acyl-CoA synthetase long-chain family member 4 (ACSL4) expression, and suppressed phosphorylation of p38 and p44/42 MAPK. ISL interacted with S100A8 and modulated S100A8-associated MAPK signaling and ferroptosis, thereby alleviating lipotoxic liver injury and fibrosis. Conclusion: These findings support S100A8 as an important mediator of ISL's protective effects and provide a mechanistic basis for its potential application in MASLD
Ying Zhang, Bing-Qian Li, Ying-Nan Song et al.· Traditional Medicine Researc...· 0 citations
Metabolic dysfunction-associated steatotic liver disease (MASLD) develops through systemic metabolic dysregulation and gut-liver axis-mediated inflammation; however, effective preventive strategies remain limited. Probiotics such as Lactiplantibacillus plantarum have emerged as potential modulators of intestinal barrier integrity and hepatic inflammation; however, preventive efficacy during early MASLD progression has not been fully elucidated. The present study evaluated whether L. plantarum Q180 attenuates early high-fat diet (HFD)-induced MASLD in a murine model. Male C57BL/6J mice were fed a normal diet or 60% HFD for 12 weeks, and Q180 was orally administered at 1.0 × 109 CFU/day from weeks 5 to 12. HFD feeding induced obesity, hepatic lipid accumulation, and an elevated nonalcoholic fatty liver disease activity score (NAS), confirming early-stage MASLD. Although Q180 did not significantly reduce body weight gain or adipose tissue mass, Q180 did significantly decrease hepatic triglyceride levels and NAS, accompanied by improvements in steatosis, hepatocellular ballooning, and inflammatory infiltration. Hepatic expressions of Dgat1 and Sod were significantly upregulated, whereas Ldlr expression was downregulated. In the colon, Q180 markedly suppressed Tnf-α and Il-6 expression and partially restored Zo-1, Occludin, and Muc2 expressions. Serum endotoxin levels were significantly reduced, and a decreasing trend was observed in fecal endotoxin levels. Overall, Q180 exerted metabolic and immunological benefits during early MASLD progression by reducing hepatic lipid accumulation, enhancing antioxidant defenses, attenuating intestinal inflammation, reinforcing intestinal barrier integrity, and lowering endotoxin exposure. The results support Q180 as a promising probiotic candidate for the prevention and early management of MASLD through gut-liver axis modulation.
Yeon-Woo Kim, Hyunchae Joung, Hyunsoo Jang et al.· Journal of Medicinal Food· 0 citations
BACKGROUND
Neuraminidase 1 (Neu1) plays a crucial role in the removal of sialic acid from glycoproteins and glycolipids, significantly influencing hepatic glycolipid metabolism. However, its precise contributions to liver gluconeogenesis and bile acid metabolism are not well defined. Although the sialylation of the hepatic glucagon receptor (GCGR) has been linked to the regulation of hepatic glucose homeostasis, the impact of Neu1 on hepatic gluconeogenesis through the desialylation of GCGR remains to be elucidated.
METHODS
To explore the physiological function of Neu1 in liver glycolipid metabolism, we constructed liver-specific Neu1 knockout mice. Glucagon induced HepG2 cells were used to assess the role of Neu1 in gluconeogenesis.
RESULTS
Phenotypic analysis indicated that these knockout mice exhibited a late-onset glycolipid metabolism disorder. Mechanistically, Neu1 deficiency caused the upregulation of key gluconeogenic genes, with cAMP-PKA signaling and the sialylation mediated activation of GCGR influencing the Akt-FoxO1 pathway, contributing to the disruption of hepatic glucose metabolism in 21-month-old Neu1 deficient mice. Transcriptomic analysis revealed an increase in lipogenesis and bile acid synthesis pathways in the livers of aged Neu1 knockout mice. Notably, there were significant alterations in steroid hormone biosynthesis, with elevated levels of lithocholic acid and allolithocholic acid detected in the Neu1 deficient mice. Additionally, the activation of inflammatory responses and reduced lipolysis seemed to correlate with the observed abnormalities in glycolipid metabolism.
CONCLUSION
These results indicate that Neu1 is essential for GCGR-dependent gluconeogenesis, suggesting that Neu1 could be a potential therapeutic target for addressing hepatic glycolipid metabolism disorders associated with aging.
Shiran Mei, Huiqin Hu, Guoxue Zhu et al.· Molecular and Cellular Endoc...· 0 citations
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