Swept up in the tsunami: Pediatric and adolescent steatotic (fatty) liver disease.

The worldwide epidemic of steatotic (fatty) liver disease also affects children and adolescents. The consensus statement by Zhang et al.1 summarizes key evidence on detection, risk factors, manifestations, comorbidities, and potential treatments in children and adolescents. The work emphasizes the need for advancements in managing this threat to the health and longevity of young individuals.

The Beneficial Effect of Brazilian Propolis for Liver Damage through Endoplasmic Reticulum Stress.

There is evidence that propolis exhibits anti-inflammatory, anticancer, and antioxidant properties. We assessed the potential beneficial effects of Brazilian propolis on liver injury in nonalcoholic fatty liver disease (NAFLD). Our findings demonstrate that Brazilian propolis suppresses inflammation and fibrosis in the liver of mice with NAFLD by inhibiting the expression of genes involved in endoplasmic reticulum (ER) stress. Additionally, Brazilian propolis also suppressed the expression of ER stress-related genes in HepG2 cells treated with an excess of free fatty acids, leading to cell apoptosis. A deeper analysis revealed that kaempferol, one of the components present in Brazilian propolis, induces cell proliferation through the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway and protects against oxidative stress. In conclusion, Brazilian propolis exhibits hepatoprotective properties against oxidative stress by inhibiting ER stress in NAFLD-induced model mice.

A PNPLA3-Deficient iPSC-Derived Hepatocyte Screen Identifies Pathways to Potentially Reduce Steatosis in Metabolic Dysfunction-Associated Fatty Liver Disease.

The incidence of nonalcoholic fatty liver disease (NAFLD), or metabolic dysfunction-associated fatty liver disease (MAFLD), is increasing in adults and children. Unfortunately, effective pharmacological treatments remain unavailable. Single nucleotide polymorphisms (SNPs) in the patatin-like phospholipase domain-containing protein (PNPLA3 I148M) have the most significant genetic association with the disease at all stages of its progression. A roadblock to identifying potential treatments for PNPLA3-induced NAFLD is the lack of a human cell platform that recapitulates the PNPLA3 I148M-mediated onset of lipid accumulation. Hepatocyte-like cells were generated from PNPLA3-/- and PNPLA3I148M/M-induced pluripotent stem cells (iPSCs). Lipid levels were measured by staining with BODIPY 493/503 and were found to increase in PNPLA3 variant iPSC-derived hepatocytes. A small-molecule screen identified multiple compounds that target Src/PI3K/Akt signaling and could eradicate lipid accumulation in these cells. We found that drugs currently in clinical trials for cancer treatment that target the same pathways also reduced lipid accumulation in PNPLA3 variant cells.

Depletion of Activated Hepatic Stellate Cells and Capillarized Liver Sinusoidal Endothelial Cells Using a Rationally Designed Protein for Nonalcoholic Steatohepatitis and Alcoholic Hepatitis Treatment.

Nonalcoholic steatohepatitis (NASH) and alcoholic hepatitis (AH) affect a large part of the general population worldwide. Dysregulation of lipid metabolism and alcohol toxicity drive disease progression by the activation of hepatic stellate cells and the capillarization of liver sinusoidal endothelial cells. Collagen deposition, along with sinusoidal remodeling, alters sinusoid structure, resulting in hepatic inflammation, portal hypertension, liver failure, and other complications. Efforts were made to develop treatments for NASH and AH. However, the success of such treatments is limited and unpredictable. We report a strategy for NASH and AH treatment involving the induction of integrin αvß3-mediated cell apoptosis using a rationally designed protein (ProAgio). Integrin αvß3 is highly expressed in activated hepatic stellate cells (αHSCs), the angiogenic endothelium, and capillarized liver sinusoidal endothelial cells (caLSECs). ProAgio induces the apoptosis of these disease-driving cells, therefore decreasing collagen fibril, reversing sinusoid remodeling, and reducing immune cell infiltration. The reversal of sinusoid remodeling reduces the expression of leukocyte adhesion molecules on LSECs, thus decreasing leukocyte infiltration/activation in the diseased liver. Our studies present a novel and effective approach for NASH and AH treatment.

Observational and genetic association of non-alcoholic fatty liver disease and calcific aortic valve disease.

Background: Non-alcoholic fatty liver disease (NAFLD) has emerged as a predominant driver of chronic liver disease globally and is associated with increased cardiovascular disease morbidity and mortality. However, the association between NAFLD and calcific aortic valve disease remains unclear. We aimed to prospectively investigate the association between NAFLD and incident aortic valve calcification (AVC), as well as its genetic relationship with incident calcific aortic valve stenosis (CAVS). Methods: A post hoc analysis was conducted on 4226 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) database. We employed the adjusted Cox models to assess the observational association between NAFLD and incident AVC. Additionally, we conducted two-sample Mendelian randomization (MR) analyses to investigate the genetic association between genetically predicted NAFLD and calcific aortic valve stenosis (CAVS), a severe form of CAVD. We repeated the MR analyses by excluding NAFLD susceptibility genes linked to impaired very low-density lipoprotein (VLDL) secretion. Results: After adjustment for potential risk factors, participants with NAFLD had a hazard ratio of 1.58 (95% CI: 1.03-2.43) for incident AVC compared to those without NAFLD. After excluding genes associated with impaired VLDL secretion, the MR analyses consistently showed the significant associations between genetically predicted NAFLD and CAVS for 3 traits: chronic elevation of alanine aminotransferase (odds ratio = 1.13 [95% CI: 1.01-1.25]), imaging-based NAFLD (odds ratio = 2.81 [95% CI: 1.66-4.76]), and biopsy-confirmed NAFLD (odds ratio = 1.12 [95% CI: 1.01-1.24]). However, the association became non-significant when considering all NAFLD susceptibility genes. Conclusions: NAFLD was independently associated with an elevated risk of incident AVC. Genetically predicted NAFLD was also associated with CAVS after excluding genetic variants related to impaired VLDL secretion.

Unveiling the role of ferroptosis in the progression from NAFLD to NASH: recent advances in mechanistic understanding.

Non-alcoholic fatty liver disease (NAFLD) is a prevalent and significant global public health issue. Nonalcoholic steatohepatitis (NASH) represents an advanced stage of NAFLD in terms of pathology. However, the intricate mechanisms underlying the progression from NAFLD to NASH remain elusive. Ferroptosis, characterized by iron-dependent cell death and distinguished from other forms of cell death based on morphological, biochemical, and genetic criteria, has emerged as a potential participant with a pivotal role in driving NAFLD progression. Nevertheless, its precise mechanism remains poorly elucidated. In this review article, we comprehensively summarize the pathogenesis of NAFLD/NASH and ferroptosis while highlighting recent advances in understanding the mechanistic involvement of ferroptosis in NAFLD/NASH.

Roles of lipid droplets and related proteins in metabolic diseases.

Lipid droplets (LDs), which are active organelles, derive from the monolayer membrane of the endoplasmic reticulum and encapsulate neutral lipids internally. LD-associated proteins like RAB, those in the PLIN family, and those in the CIDE family participate in LD formation and development, and they are active players in various diseases, organelles, and metabolic processes (i.e., obesity, non-alcoholic fatty liver disease, and autophagy). Our synthesis on existing research includes insights from the formation of LDs to their mechanisms of action, to provide an overview needed for advancing research into metabolic diseases and lipid metabolism.

USP13 ameliorates nonalcoholic fatty liver disease through inhibiting the activation of TAK1.

BACKGROUND: The molecular mechanisms underlying nonalcoholic fatty liver disease (NAFLD) remain to be fully elucidated. Ubiquitin specific protease 13 (USP13) is a critical participant in inflammation-related signaling pathways, which are linked to NAFLD. Herein, the roles of USP13 in NAFLD and the underlying mechanisms were investigated. METHODS: L02 cells and mouse primary hepatocytes were subjected to free fatty acid (FFA) to establish an in vitro model reflective of NAFLD. To prepare in vivo model of NAFLD, mice fed a high-fat diet (HFD) for 16 weeks and leptin-deficient (ob/ob) mice were used. USP13 overexpression and knockout (KO) strategies were employed to study the function of USP13 in NAFLD in mice. RESULTS: The expression of USP13 was markedly decreased in both in vitro and in vivo models of NAFLD. USP13 overexpression evidently inhibited lipid accumulation and inflammation in FFA-treated L02 cells in vitro. Consistently, the in vivo experiments showed that USP13 overexpression ameliorated hepatic steatosis and metabolic disorders in HFD-fed mice, while its deficiency led to contrary outcomes. Additionally, inflammation was similarly attenuated by USP13 overexpression and aggravated by its deficiency in HFD-fed mice. Notably, overexpressing of USP13 also markedly alleviated hepatic steatosis and inflammation in ob/ob mice. Mechanistically, USP13 bound to transforming growth factor ß-activated kinase 1 (TAK1) and inhibited K63 ubiquitination and phosphorylation of TAK1, thereby dampening downstream inflammatory pathways and promoting insulin signaling pathways. Inhibition of TAK1 activation reversed the exacerbation of NAFLD caused by USP13 deficiency in mice. CONCLUSIONS: Our findings indicate the protective role of USP13 in NAFLD progression through its interaction with TAK1 and inhibition the ubiquitination and phosphorylation of TAK1. Targeting the USP13-TAK1 axis emerges as a promising therapeutic strategy for NAFLD treatment.

Usefulness of Body Fat and Visceral Fat Determined by Bioimpedanciometry versus Body Mass Index and Waist Circumference in Predicting Elevated Values of Different Risk Scales for Non-Alcoholic Fatty Liver Disease.

BACKGROUND: Obesity constitutes a public health problem worldwide and causes non-alcoholic fatty liver disease (MALFD), the leading cause of liver disease in developed countries, which progresses to liver cirrhosis and liver cancer. MAFLD is associated with obesity and can be evaluated by validated formulas to assess MAFLD risk using different parameters such as the body mass index (BMI) and waist circumference (WC). However, these parameters do not accurately measure body fat. As MAFLD is strongly associated with obesity, we hypothesize that measuring body and visceral fat by electrical bioimpedance is an efficient method to predict the risk of MAFLD. The objective of our work was to demonstrate that electrical bioimpedance is a more efficient method than the BMI or WC to predict an elevated risk of MAFLD. METHODS: A cross-sectional, descriptive study involving 8590 Spanish workers in the Balearic Islands was carried out. The study's sample of employees was drawn from those who underwent occupational medicine examinations between January 2019 and December 2020. Five MAFLD risk scales were determined for evaluating very high levels of body fat and visceral fat. The determination of body and visceral fat was performed using bioimpedanciometry. Student's t-test was employed to ascertain the mean and standard deviation of quantitative data. The chi-square test was used to find prevalences for qualitative variables, while ROC curves were used to define the cut-off points for body and visceral fat. The calculations included the area under the curve (AUC), the cut-off points along with their Youden index, sensitivity, and specificity. Correlation and concordance between the various scales were determined using Pearson's correlation index and Cohen's kappa, respectively. RESULTS: As both total body fat and visceral fat increase, the risk of MAFLD increases with a statistically significant result (p < 0.001), presenting a higher risk in men. The areas under the curve (AUC) of the five scales that assess overweight and obesity to determine the occurrence of high values of the different MAFLD risk scales were very high, most of them exceeding 0.9. These AUC values were higher for visceral and body fat than for the BMI or waist circumference. FLD-high presented the best results in men and women with the AUC at around 0.97, both for visceral fat and total body fat, with a high Youden index in all cases (women body fat = 0.830, visceral fat = 0.892; men body fat = 0.780, visceral fat = 0.881). CONCLUSIONS: In our study, all the overweight and obesity scales show a very good association with the scales assessing the risk of MAFLD. These values are higher for visceral and body fat than for waist circumference and the BMI. Both visceral fat and body fat are better associated than the BMI and waist circumference with MAFLD risk scales.

The Role of CD4+T Cells in Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) has become the fourth leading cause of cancer-related deaths worldwide; annually, approximately 830,000 deaths related to liver cancer are diagnosed globally. Since early-stage HCC is clinically asymptomatic, traditional treatment modalities, including surgical ablation, are usually not applicable or result in recurrence. Immunotherapy, particularly immune checkpoint blockade (ICB), provides new hope for cancer therapy; however, immune evasion mechanisms counteract its efficiency. In addition to viral exposure and alcohol addiction, nonalcoholic steatohepatitis (NASH) has become a major cause of HCC. Owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance, NASH-associated HCC patients respond much less efficiently to ICB treatment than do patients with other etiologies. In addition, abnormal inflammation contributes to NASH progression and NASH-HCC transition, as well as to HCC immune evasion. Therefore, uncovering the detailed mechanism governing how NASH-associated immune cells contribute to NASH progression would benefit HCC prevention and improve HCC immunotherapy efficiency. In the following review, we focused our attention on summarizing the current knowledge of the role of CD4+T cells in NASH and HCC progression, and discuss potential therapeutic strategies involving the targeting of CD4+T cells for the treatment of NASH and HCC.

Relationship between non-alcoholic fatty liver and progressive fibrosis and serum 25-hydroxy vitamin D in patients with type 2 diabetes mellitus.

OBJECTIVE: We aimed to analyze the relationship between non-alcoholic fatty liver and progressive fibrosis and serum 25-hydroxy vitamin D (25(OH)D) in patients with type 2 diabetes mellitus. METHODS: A total of 184 patients with T2DM who were hospitalized in the Department of Endocrinology of the ShiDong Clinical Hospital between January 2023 and June 2023 were selected. We compared review of anthropometric, biochemical, and inflammatory parameters and non-invasive scores between groups defined by ultrasound NAFLD severity grades.We determine the correlation between 25(OH)D and FLI and FIB-4 scores, respectively. RESULTS: Statistically significant differences were seen between BMI, WC, C-peptide levels, FPG, ALT, serum 25(OH)D, TC, HDL, lumbar spine bone density, FLI, and FIB-4 in different degrees of NAFLD. Multivariate logistic regression analysis showed that 25(OH)D (OR = 1.26, p = 0.001), age (OR = 0.93, P < 0.001) and BMI (OR = 1.04, p = 0.007) were independent predictors of NAFLD in patients with T2DM. CONCLUSIONS: This study revealed the correlation between serum 25(OH)D levels and NAFLD in patients with T2DM. We also demonstrated that serum 25(OH)D levels were negatively correlated with FLI/FIB-4 levels in patients with T2DM with NAFLD, suggesting that vitamin D deficiency may promote hepatic fibrosis progression in T2DM with NAFLD.

Exploring Fibrosis Pathophysiology in Lean and Obese Metabolic-Associated Fatty Liver Disease: An In-Depth Comparison.

While obesity-related nonalcoholic fatty liver disease (NAFLD) is linked with metabolic dysfunctions such as insulin resistance and adipose tissue inflammation, lean NAFLD more often progresses to liver fibrosis even in the absence of metabolic syndrome. This review aims to summarize the current knowledge regarding the mechanisms of liver fibrosis in lean NAFLD. The most commonly used lean NAFLD models include a methionine/choline-deficient (MCD) diet, a high-fat diet with carbon tetrachloride (CCl4), and a high-fructose and high-cholesterol diet. The major pro-fibrogenic mechanisms in lean NAFLD models include increased activation of the extracellular signal-regulated kinase (ERK) pathway, elevated expression of α-smooth muscle actin (α-SMA), collagen type I, and TGF-ß, and modulation of fibrogenic markers such as tenascin-X and metalloproteinase inhibitors. Additionally, activation of macrophage signaling pathways promoting hepatic stellate cell (HSC) activation further contributes to fibrosis development. Animal models cannot cover all clinical features that are evident in patients with lean or obese NAFLD, implicating the need for novel models, as well as for deeper comparisons of clinical and experimental studies. Having in mind the prevalence of fibrosis in lean NAFLD patients, by addressing specific pathways, clinical studies can reveal new targeted therapies along with novel biomarkers for early detection and enhancement of clinical management for lean NAFLD patients.

Decrease in UCP1 by sustained high lipid promotes NK cell necroptosis to exacerbate nonalcoholic liver fibrosis.

Uncoupling protein 1 (UCP1) catalyzes the leak of protons across the mitochondrial inner membrane for thermogenesis. Compromised NK cell activity is involved in the occurrence of nonalcoholic liver fibrosis. Here, decreased UCP1 in NK cells was identified in patients with advanced nonalcoholic fatty liver disease. Although no obvious changes were observed in the NK cells of physiologic UCP1-/- mice (8-10 weeks old), impaired NK cell bioactivity was shown in methionine-choline-diet (MCD)-fed UCP1-/- mice and involved in the acerbation of nonalcoholic steatohepatitis (NASH) progress to liver fibrosis. Moreover, UCP1-deficient NK cells were responsible for the aggravation of liver fibrosis, as confirmed in MCD-fed UCP1flox/flox-NCR1cre mice. Acerbation of liver fibrosis was also seen in wild-type mice when their endogenous NK cells were replaced with UCP1-/- NK cells. Transcriptions of mitophagy-associated molecules in UCP1-/- NK cells were enhanced according to RNA-seq. Electron microscopic results showed mitochondrial injuries and autophagic vesicles in MCD-fed NKWT cells, PA-treated NKWT cells, or physiologic NKKO cells. However, the co-existence of UCP1 deficiency and high lipid can synergistically induce NK cell necroptosis via DRP1S616 accompanied with reduced mitophagy. Finally, The UCP1 in NK cells was downregulated when treated by sustained high PA (600 µM) via the PPARγ/ATF2 axis. Thus, persistent high-lipid treatment not only decreases UCP1 expression but also combines with reduced UCP1 to promote NK cell necroptosis, and it is involved in NASH progression to fibrosis.

Increase in bile acids after sleeve gastrectomy improves metabolism by activating GPBAR1 to increase cAMP in mice with nonalcoholic fatty liver disease.

BACKGROUND: Bile acids (BAs) concentration can affect metabolic improvement caused by bariatric surgery and BA concentrations increase in patients after sleeve gastrectomy (SG). Here, how BAs after SG affect metabolism in nonalcoholic fatty liver disease (NAFLD) was studied. METHODS: Mice were given high-fat diet (HFD) to induce NAFLD and received SG surgery. Hepatic and fecal BA concentrations in mice were detected by liquid chromatography-tandem mass spectrometry method. BA-related genes were detected by quantitative real-time polymerase chain reaction. G protein BA receptor 1 (GPBAR1) expression was identified using western blot analysis. NAFLD mice after SG received GPBAR1 inhibitor Triamterene. The weight of mice and mice liver was detected. Mouse liver tissue was observed by hematoxylin-eosin and Oil Red O staining. Triglyceride (TG), nonesterified fatty acid (NEFA), and cyclic adenosine monophosphate (cAMP) levels in mouse liver tissue were analyzed by metabolic assay and enzyme-linked immune sorbent assay. RESULTS: SG boosted increase in hepatic total/conjugated BAs and related genes and GPBAR1 expression, and attenuated increase in fecal total BAs/muricholic acid in HFD-induced mice and increased fecal taurine-BAs in HFD-induced mice. Triamterene (72 mg/kg) reversed the inhibitory role of SG in HFD-induced increase of body weight, lipid accumulation, inflammatory cell infiltration, and increase of hepatic weight and TG/NEFA content, and counteracted the positive role of SG in HFD-induced increase of hepatic cAMP concentration in mice. CONCLUSIONS: BAs improve metabolism via activating GPBAR1 to increase cAMP in NAFLD mice after SG.

CXCL9, IL2RB, and SPP1, potential diagnostic biomarkers in the co-morbidity pattern of atherosclerosis and non-alcoholic steatohepatitis.

Non-alcoholic steatohepatitis (NASH) is a hepatocyte inflammation based on hepatocellular steatosis, yet there is no effective drug treatment. Atherosclerosis (AS) is caused by lipid deposition in the endothelium, which can lead to various cardiovascular diseases. NASH and AS share common risk factors, and NASH can also elevate the risk of AS, causing a higher morbidity and mortality rate for atherosclerotic heart disease. Therefore, timely detection and diagnosis of NASH and AS are particularly important. In this study, differential gene expression analysis and weighted gene co-expression network analysis were performed on the AS (GSE100927) and NASH (GSE89632) datasets to obtain common crosstalk genes, respectively. Then, candidate Hub genes were screened using four topological algorithms and externally validated in the GSE43292 and GSE63067 datasets to obtain Hub genes. Furthermore, immune infiltration analysis and gene set variation analysis were performed on the Hub genes to explore the underlying mechanisms. The DGIbd database was used to screen candidate drugs for AS and NASH. Finally, a NASH model was constructed using free fatty acid-induced human L02 cells, an AS model was constructed using lipopolysaccharide-induced HUVECs, and a co-morbidity model was constructed using L02 cells and HUVECs to verify Hub gene expression. The result showed that a total of 113 genes common to both AS and NASH were identified as crosstalk genes, and enrichment analysis indicated that these genes were mainly involved in the regulation of immune and metabolism-related pathways. 28 candidate Hub genes were screened according to four topological algorithms, and CXCL9, IL2RB, and SPP1 were identified as Hub genes after in vitro experiments and external dataset validation. The ROC curves and SVM modeling demonstrated the good diagnostic efficacy of these three Hub genes. In addition, the Hub genes are strongly associated with immune cell infiltration, especially macrophages and γ-δ T cell infiltration. Finally, five potential therapeutic drugs were identified. has-miR-185 and hsa-miR-335 were closely related to AS and NASH. This study demonstrates that CXCL9, IL2RB, and SPP1 may serve as potential biomarkers for the diagnosis of the co-morbidity patterns of AS and NASH and as potential targets for drug therapy.

Correlation between controlled attenuation parameter values with SYNTAX score in patients with significant coronary artery disease.

Non-alcoholic fatty liver disease (NAFLD) is an emerging cause of chronic liver disease, with coronary artery disease (CAD) as the main cause of death in NAFLD patients. However, correlation between the severity of liver steatosis and coronary atherosclerosis is yet to be understood. Here we aim to explore the correlation between controlled attenuation parameter (CAP) values and SYNTAX (Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery) score in adult patients with significant CAD, defined as ≥ 50% stenosis of the left main coronary artery, or ≥ 70% stenosis of the other major coronary arteries. A cross-sectional study was conducted on 124 adult patients with significant CAD who underwent coronary angiography. Transient elastography with CAP was used to assess liver steatosis severity, resulting in a mean CAP value of 256.5 ± 47.3 dB/m, with 52.5% subjects had significant steatosis (CAP value of ≥ 248 dB/m). Median SYNTAX score was 22. A statistically significant correlation was observed between CAP value and SYNTAX score (r = 0.245, p < 0.0001). The correlation was more pronounced in patients with prior history of PCI (r = 0.389, p = 0.037). Patients with high-risk SYNTAX score (> 32) had the highest CAP value (285.4 ± 42.6 dB/m), and it was significantly higher than those with low-risk SYNTAX score (0-22), with a mean difference of 38.76 dB/m (p = 0.006). Patients with significant liver steatosis should undergo periodic CAD assessment and lifestyle modification, especially those with severe liver steatosis.

TXNDC5 Plays a Crucial Role in Regulating Endoplasmic Reticulum Activity through Different ER Stress Signaling Pathways in Hepatic Cells.

The pathogenesis of non-alcoholic fatty liver disease (NAFLD) is influenced by a number of variables, including endoplasmic reticulum stress (ER). Thioredoxin domain-containing 5 (TXNDC5) is a member of the protein disulfide isomerase family and acts as an endoplasmic reticulum (ER) chaperone. Nevertheless, the function of TXNDC5 in hepatocytes under ER stress remains largely uncharacterized. In order to identify the role of TXNDC5 in hepatic wild-type (WT) and TXNDC5-deficient (KO) AML12 cell lines, tunicamycin, palmitic acid, and thapsigargin were employed as stressors. Cell viability, mRNA, protein levels, and mRNA splicing were then assayed. The protein expression results of prominent ER stress markers indicated that the ERN1 and EIF2AK3 proteins were downregulated, while the HSPA5 protein was upregulated. Furthermore, the ATF6 protein demonstrated no significant alterations in the absence of TXNDC5 at the protein level. The knockout of TXNDC5 has been demonstrated to increase cellular ROS production and its activity is required to maintain normal mitochondrial function during tunicamycin-induced ER stress. Tunicamycin has been observed to disrupt the protein levels of HSPA5, ERN1, and EIF2AK3 in TXNDC5-deficient cells. However, palmitic acid has been observed to disrupt the protein levels of ATF6, HSPA5, and EIF2AK3. In conclusion, TXNDC5 can selectively activate distinct ER stress pathways via HSPA5, contingent on the origin of ER stress. Conversely, the absence of TXNDC5 can disrupt the EIF2AK3 cascade.

Synergistic Steatosis Induction in Mice: Exploring the Interactions and Underlying Mechanisms between PFOA and Tributyltin.

This study explores the impact of environmental pollutants on nuclear receptors (CAR, PXR, PPARα, PPARγ, FXR, and LXR) and their heterodimerization partner, the Retinoid X Receptor (RXR). Such interaction may contribute to the onset of non-alcoholic fatty liver disease (NAFLD), which is initially characterized by steatosis and potentially progresses to steatohepatitis and fibrosis. Epidemiological studies have linked NAFLD occurrence to the exposure to environmental contaminants like PFAS. This study aims to assess the simultaneous activation of nuclear receptors via perfluorooctanoic acid (PFOA) and RXR coactivation via Tributyltin (TBT), examining their combined effects on steatogenic mechanisms. Mice were exposed to PFOA (10 mg/kg/day), TBT (5 mg/kg/day) or a combination of them for three days. Mechanisms underlying hepatic steatosis were explored by measuring nuclear receptor target gene and lipid metabolism key gene expressions, by quantifying plasma lipids and hepatic damage markers. This study elucidated the involvement of the Liver X Receptor (LXR) in the combined effect on steatosis and highlighted the permissive nature of the LXR/RXR heterodimer. Antagonistic effects of TBT on the PFOA-induced activation of the Pregnane X Receptor (PXR) and Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) were also observed. Overall, this study revealed complex interactions between PFOA and TBT, shedding light on their combined impact on liver health.

Diagnostic role of SPP1 and collagen IV in a rat model of type 2 diabetes mellitus with MASLD.

Type 2 diabetes mellitus combined with metabolic dysfunction-associated steatotic liver disease (MASLD) leads to an increasing incidence of liver injury year by year, and patients are at a significantly higher risk of developing cirrhosis or even liver failure. No drugs have emerged to specifically treat this disease. The aim of this study is to investigate the mechanisms and causative hub genes of type 2 diabetes combined with MASLD. The data were obtained through the GEO platform for bioinformatics analysis and validated by in vitro experiments to find the causative targets of type 2 diabetes mellitus combined with MASLD, which will provide some theoretical basis for the development of future therapeutic drugs. GSE23343 and GSE49541 were downloaded from the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs) in type 2 diabetes mellitus combined with MASLD for functional enrichment analysis. And STRING database and Cytoscape software were used to construct Protein-Protein Interaction (PPI) and hub gene networks. And GO (gene ontology, GO) analysis and KEGG (Kyoto encyclopedia of genes and genomes, KEGG) enrichment analysis were performed on target genes. A total of 185 co-expressed DEGs were obtained by differential analysis, and 20 key genes involved in the development and progression of type 2 diabetes were finally screened. These 20 key genes were involved in 529 GO enrichment results and 20 KEGG enrichment results, and were mainly associated with ECM-receptor interaction, Focal adhesion, Human papillomavirus infection, PI3K-Akt signaling pathway, and the Toll-like receptor signaling pathway. A total of two target genes (SPP1, collagen IV) were found to be highly correlated with type 2 diabetes mellitus combined with MASLD. Real time PCR results showed that there was a significant difference in SPP1 and collagen IV mRNA expression among the three groups (P < 0.05). SPP1 and Collagen IV may be candidate biomarkers for type 2 diabetes mellitus combined with MASLD, as verified by bioinformatics screening and in vitro experiments. Our findings provide new targets for the treatment of type 2 diabetes combined with MASLD.

Oleuropein, a Component of Extra Virgin Olive Oil, Improves Liver Steatosis and Lobular Inflammation by Lipopolysaccharides-TLR4 Axis Downregulation.

Gut-dysbiosis-induced lipopolysaccharides (LPS) translocation into systemic circulation has been suggested to be implicated in nonalcoholic fatty liver disease (NAFLD) pathogenesis. This study aimed to assess if oleuropein (OLE), a component of extra virgin olive oil, lowers high-fat-diet (HFD)-induced endotoxemia and, eventually, liver steatosis. An immunohistochemistry analysis of the intestine and liver was performed in (i) control mice (CTR; n = 15), (ii) high-fat-diet fed (HFD) mice (HFD; n = 16), and (iii) HFD mice treated with 6 µg/day of OLE for 30 days (HFD + OLE, n = 13). The HFD mice developed significant liver steatosis compared to the controls, an effect that was significantly reduced in the HFD + OLE-treated mice. The amount of hepatocyte LPS localization and the number of TLR4+ macrophages were higher in the HFD mice in the than controls and were lowered in the HFD + OLE-treated mice. The number of CD42b+ platelets was increased in the liver sinusoids of the HFD mice compared to the controls and decreased in the HFD + OLE-treated mice. Compared to the controls, the HFD-treated mice showed a high percentage of intestine PAS+ goblet cells, an increased length of intestinal crypts, LPS localization and TLR4+ expression, and occludin downregulation, an effect counteracted in the HFD + OLE-treated mice. The HFD-fed animals displayed increased systemic levels of LPS and zonulin, but they were reduced in the HFD + OLE-treated animals. It can be seen that OLE administration improves liver steatosis and inflammation in association with decreased LPS translocation into the systemic circulation, hepatocyte localization of LPS and TLR4 downregulation in HFD-induced mouse model of NAFLD.