Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by severe mitochondrial dysfunction, associated with the production of mitochondrial reactive oxygen species (mROS). The substantial generation of mROS in the MASH liver, resulting from lipid surplus and electron transport chain (ETC) overload, impairs mitochondrial structure and functionality, thereby contributing to the development of severe hepatic steatosis and inflammation. Regular exercise represents an effective strategy for the treatment of MASH. Understanding the effects of exercise on oxidative stress and mitochondrial function is essential for effective treatment of MASH. This article reviews the pathological alterations in mitochondrial β-oxidation, ETC efficiency and mROS production within MASH liver. Additionally, it discusses how exercise influences the redox state and mitochondrial quality control mechanisms-such as biogenesis, mitophagy, fusion, and fission-within the MASH liver. The article emphasizes the importance of in-depth studies on exercise-induced MASH mitigation through the enhancement of mitochondrial redox balance, quality control, and function. Exploring the relationship between exercise and hepatic mitochondria could provide valuable insights into identifying potential therapeutic targets for MASH.

The management of hyperglycemia and lipid metabolism is pivotal for the treatment of type 2 diabetes mellitus (T2DM). Metformin hydrochloride (DMBG) remains the most widely prescribed medication for this condition. This study aimed to elucidate the effects and underlying mechanisms by which DMBG enhances glucolipid metabolism using both in vivo and in vitro experimental models. Animal models were established using high-fat diet (HFD)-fed mice, while cellular models utilized palmitic acid (PA)-induced HepG2 cells. In vivo, the impact of DMBG on glucolipid metabolism was evaluated through measurements of insulin and HbA1c levels, intraperitoneal glucose tolerance tests (ipGTT), intraperitoneal insulin tolerance tests (ipITT), as well as histological assessments with hematoxylin-eosin (HE) and Oil-red O staining. Mitochondrial function was assessed via biochemical assays of TBARS, SOD, ATP, and H2O2 levels in liver tissue, alongside determinations of mitochondrial membrane potential, ROS production, mtDNA content, and SIRT5 mRNA expression. For in vitro analysis, glucose consumption, mitochondrial membrane potential, ROS levels, and protein expressions of AMPK and PGC-1α were quantified in HepG2 cells. Western blotting and co-immunoprecipitation (co-IP) techniques were employed to investigate the mechanistic pathways involved. Treatment with DMBG resulted in reduced levels of free fatty acids, body weight, and fat mass, while also alleviating hyperglycemia and hepatic lipid accumulation in HFD-fed mice. Furthermore, DMBG restored impaired mitochondrial function in these animals and increased SIRT5 expression via AMPK activation. In vitro, DMBG mitigated PA-induced alterations in glucose consumption and mitochondrial dysfunction in HepG2 cells, an effect that was abrogated upon SIRT5 knockdown. Overexpression of SIRT5 led to enhanced trifunctional enzyme subunit-alpha (ECHA) desuccinylation at the K540 site, thereby increasing its activity. Collectively, our findings indicate that DMBG improves hepatic glucolipid metabolism through a mechanism involving SIRT5-mediated ECHA desuccinylation, potentially offering a new therapeutic avenue for T2DM.

The pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear due to the complexity of its etiology. The emerging field of the epitranscriptome has shown significant promise in advancing the understanding of disease pathogenesis and developing new therapeutic approaches. Recent research has demonstrated that N4-acetylcytosine (ac4C), an RNA modification within the epitranscriptome, is implicated in progression of various diseases. However, the role of ac4C modification in MASLD remains unexplored. Herein, we performed acRIP-ac4c-seq and RNA-seq analysis in free fatty acids-induced MASLD model cells, identifying 2128 differentially acetylated ac4C sites, with 1031 hyperacetylated and 1097 hypoacetylated peaks in MASLD model cells. Functional enrichments analysis showed that ac4C differentially modified genes were significantly involved in processes related to MASLD, such as nuclear transport and MAP kinase (MAPK) signaling pathway. We also identified 341 differentially expressed genes (DEGs), including 61 lncRNAs and 280 mRNAs, between control and MASLD model cells. Bioinformatics analysis showed that DEGs were significantly enriched in long-chain fatty acid biosynthetic process. Notably, 118 genes exhibited significant changes in both ac4C modification and expression levels in MASLD model cells. Among these proteins, JUN, caveolin-1 (CAV1), fatty acid synthase (FASN), and heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) were identified as core proteins through protein-protein interaction (PPI) network analysis using cytoscape software. Collectively, our findings establish a positive correlation between ac4C modification and the pathogenesis of MASLD and suggest that ac4C modification may serve as a therapeutic target for MASLD.

Metabolic-associated fatty liver disease (MAFLD) includes several metabolic dysfunctions caused by dysregulation in the brain-gut-liver axis and, consequently, increases cardiovascular risks and fatty liver dysfunction. In MAFLD, type 2 diabetes mellitus, obesity, and metabolic syndrome are frequently present; these conditions are related to liver lipogenesis and systemic inflammation. This study aimed to review the connection between the brain-gut-liver axis and MAFLD. The inflammatory process, cellular alterations in hepatocytes and stellate cells, hypercaloric diet, and sedentarism aggravate the prognosis of patients with MAFLD. Thus, to understand the modulation of the physiopathology of MAFLD, it is necessary to include the organokines involved in this process (adipokines, myokines, osteokines, and hepatokines) and their clinical relevance to project future perspectives of this condition and bring to light new possibilities in therapeutic approaches. Adipokines are responsible for the activation of distinct cellular signaling in different tissues, such as insulin and pro-inflammatory cytokines, which is important for balancing substances to avoid MAFLD and its progression. Myokines improve the quantity and quality of adipose tissues, contributing to avoiding the development of MAFLD. Finally, hepatokines are decisive in improving or not improving the progression of this disease through the regulation of pro-inflammatory and anti-inflammatory organokines.

Erectile dysfunction (ED) is a common condition affecting middle-aged and elderly men.

The study sought to investigate differentially expressed fatty acid metabolism-related genes and the molecular mechanisms of ED.

The expression profiles of GSE2457 and GSE31247 were downloaded from the Gene Expression Omnibus database and merged. Differentially expressed genes (DEGs) between ED and normal samples were obtained using the R package limma. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses of DEGs were conducted using the R package clusterProfiler. Fatty acid metabolism-related DEGs (FAMDEGs) were further identified and analyzed. Machine learning algorithms, including Lasso (least absolute shrinkage and selection operator), support vector machine, and random forest algorithms, were utilized to identify hub FAMDEGs with the ability to predict ED occurrence. Coexpression analysis and gene set enrichment analysis of hub FAMDEGs were performed.

Fatty acid metabolism-related functions (such as fatty acid metabolism and degradation) may play a vital role in ED.

In total, 5 hub FAMDEGs (Aldh2, Eci2, Acat1, Acadl, and Hadha) were identified and found to be differentially expressed between ED and normal samples. Gene set enrichment analysis identified key pathways associated with these genes. The area under the curve values of the 5 hub FAMDEGs for predicting ED occurrence were all >0.8.

Our results suggest that these 5 key FAMDEGs may serve as biomarkers for the diagnosis and treatment of ED.

The strengths of our study include the use of multiple datasets and machine learning algorithms to identify key FAMDEGs. However, limitations include the lack of validation in animal models and human tissues, as well as research on the mechanisms of these FAMDEGs.

Five hub FAMDEGs were identified as potential biomarkers for ED progression. Our work may prove that fatty acid metabolism-related genes are worth further investigation in ED.

Non-alcoholic fatty liver disease (NAFLD) is a major chronic liver disease worldwide. Cuproptosis has recently been reported as a form of cell death that appears to drive the progression of a variety of diseases. This study aimed to explore cuproptosis-related molecular clusters and construct a prediction model. The gene expression profiles were obtained from the Gene Expression Omnibus (GEO) database. The associations between molecular clusters of cuproptosis-related genes and immune cell infiltration were investigated using 50 NAFLD samples. Furthermore, cluster-specific differentially expressed genes were identified by the WGCNA algorithm. External datasets were used to verify and screen feature genes, and nomograms, calibration curves and decision curve analysis (DCA) were performed to verify the performance of the prediction model. Finally, a NAFLD-diet mouse model was constructed to further verify the predictive analysis, thus providing new insights into the prediction of NAFLD clusters and risks. The role of cuproptosis in the development of non-alcoholic fatty liver disease and immune cell infiltration was explored. Non-alcoholic fatty liver disease was divided into two cuproptosis-related molecular clusters by unsupervised clustering. Three characteristic genes (ENO3, SLC16A1 and LEPR) were selected by machine learning and external data set validation. In addition, the accuracy of the nomogram, calibration curve and decision curve analysis in predicting NAFLD clusters was also verified. Further animal and cell experiments confirmed the difference in their expression in the NAFLD mouse model and Mouse hepatocyte cell line. The present study explored the relationship between non-alcoholic fatty liver disease and cuproptosis, providing new ideas and targets for individual treatment of the disease.

One of the most typical abnormal cleavage patterns during early embryonic development is uneven division, but the first uneven division of pig zygote is common. Uneven division results in different daughter cell sizes and an uneven distribution of organelles such as lipid droplet, mitochondria, but the developmental capacity of daughter cells and proteomic changes of daughter cells are still unclear. Therefore, the developmental ability and proteomic quantification were investigated on blastomeres from even division (ED) or uneven division (UD) embryos at 2-cell stage in the present study. Firstly, the developmental ability was affected by the blastomeric size, when compared with medium blastomeres (MBs), the large blastomeres (LBs) with the higher cleavage rate but the small blastomeres (SBs) with the lower rate was observed. Subsequently, proteomic analysis was performed on blastomeres of LBs, MBs and SBs, a total of 109 DEPs were detected, which were involved in protein metabolism and processing, energy metabolism and ribosome. In particular, DEPs in LBs vs. SBs were focused on RNA binding and actin cytoskeletal tissue. Two protein-dense networks associated with RNA binding and cytoskeleton were revealed by further protein-protein interaction (PPI) analysis of DEPs in LBs vs. SBs, that DDX1 related to RNA binding and ACTB related to cytoskeleton were confirmed in UD embryos. Therefore, a briefly information of DEPs in blastomeres of 2-cell stage pig embryos was described in the present study, and it further confirmed that the formation of uneven division of the first cell cycle of pig embryos might be controlled by the cytoskeleton; the developmental capacity of daughter cells might be affected by the energy metabolism, RNA binding and ribosome, and further account for the developmental potential of the whole embryo.

Non-alcoholic fatty liver disease (NAFLD) is a major health burden with an increasing global incidence. Unfortunately, the unavailability of knowledge underlying NAFLD pathogenesis inhibits effective preventive and therapeutic measures.

To explore the molecular mechanism of NAFLD.

Whole genome sequencing (WGS) analysis was performed on liver tissues from patients with NAFLD (n = 6) and patients with normal metabolic conditions (n = 6) to identify the target genes. A NAFLD C57BL6/J mouse model induced by 16 wk of high-fat diet feeding and a hepatocyte-specific F-box only protein 2 (FBXO2) overexpression mouse model were used for in vivo studies. Plasmid transfection, co-immunoprecipitation-based mass spectrometry assays, and ubiquitination in HepG2 cells and HEK293T cells were used for in vitro studies.

A total of 30982 genes were detected in WGS analysis, with 649 up-regulated and 178 down-regulated. Expression of FBXO2, an E3 ligase, was upregulated in the liver tissues of patients with NAFLD. Hepatocyte-specific FBXO2 overexpression facilitated NAFLD-associated phenotypes in mice. Overexpression of FBXO2 aggravated odium oleate (OA)-induced lipid accumulation in HepG2 cells, resulting in an abnormal expression of genes related to lipid metabolism, such as fatty acid synthase, peroxisome proliferator-activated receptor alpha, and so on. In contrast, knocking down FBXO2 in HepG2 cells significantly alleviated the OA-induced lipid accumulation and aberrant expression of lipid metabolism genes. The hydroxyl CoA dehydrogenase alpha subunit (HADHA), a protein involved in oxidative stress, was a target of FBXO2-mediated ubiquitination. FBXO2 directly bound to HADHA and facilitated its proteasomal degradation in HepG2 and HEK293T cells. Supplementation with HADHA alleviated lipid accumulation caused by FBXO2 overexpression in HepG2 cells.

FBXO2 exacerbates lipid accumulation by targeting HADHA and is a potential therapeutic target for NAFLD.