Non-alcoholic Fatty Liver Disease Pathways Research Articles

Unveiling the role of disulfidptosis-related genes in the pathogenesis of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) presents as a common liver disease characterized by an indistinct pathogenesis. Disulfidptosis is a recently identified mode of cell death. This study aimed to investigate the potential role of disulfidptosis-related genes (DRGs) in the pathogenesis of NAFLD. Gene expression profiles were obtained from the bulk RNA dataset GSE126848 and the single-cell RNA dataset GSE136103, both associated with NAFLD. Our study assessed the expression of DRGs in NAFLD and normal tissues. Weighted gene co-expression network analysis (WGCNA) and differential expression analysis were employed to identify the key NAFLD-specific differentially expressed DRGs (DE-DRGs). To explore the biological functions and immune regulatory roles of these key DE-DRGs, we conducted immune infiltration analysis, functional enrichment analysis, consensus clustering analysis, and single-cell differential state analysis. Finally, we validated the expression and biological functions of DRGs in NAFLD patients using histology and RNA-sequencing transcriptomic assays with human liver tissue samples. Through the intersection of WGCNA, differentially expressed genes, and DRGs, two key DE-DRGs (DSTN and MYL6) were identified. Immune infiltration analysis indicated a higher proportion of macrophages, T cells, and resting dendritic cells in NAFLD compared to control liver samples. Based on the key DE-DRGs, Two disulfidptosis clusters were defined in GSE126848. Cluster 1, with higher expression of the key DE-DRGs, exhibited increased immune infiltration abundance and was closely associated with oxidative stress and immune regulation compared to cluster 2. High-resolution analysis of mononuclear phagocytes highlighted the potential role of MYL6 in intrahepatic M1 phenotype Kupffer cells in NAFLD patients. Our transcriptome data revealed that the expression levels of the majority of DRGs were significantly increased in NAFLD patients. NAFLD patients exhibit elevated MYL6 correlating with inflammation, oxidative stress, and disease severity, offering promising diagnostic specificity. This comprehensive study provides evidence for the association between NAFLD and disulfidptosis, identifying potential target genes and pathways in NAFLD. The identification of MYL6 as a possible treatment target for NAFLD provided a novel understanding of the disease's development.

Inhibition of ACOX1 enhances the therapeutic efficacy of obeticholic acid in treating non-alcoholic fatty liver disease and mitigates its lipotoxicity.

High-dose Obeticholic acid exhibits promise for non-alcoholic fatty liver disease (NAFLD) treatment but can induce lipotoxicity. Our study sought to understand this mechanism and propose a solution. In a non-alcoholic fatty liver disease (NAFLD) model induced by a high-fat diet in FXR-/- mice, we pinpointed that FXR regulated the expression of ACOX1 through RNA-Seq analysis. In the livers of FXR-/- mice, both ACOX1 mRNA and protein expression notably decreased. In both HL-7702 and HEP-G2 cells, the silencing of FXR through shRNA plasmids decreased ACOX1 expression, while FXR activation with GW4064 increased it. These effects were reversible with the ACOX1-specific inhibitor, 10,12-Tricosadiynoic acid. In the NAFLD model of FXR-/- mice, The activation of ACOX1 is correlated with elevated serum LDL, triglycerides, and aggravated hepatic steatosis. However, the combination of 10,12-Tricosadiynoic acid with low-dose obeticholic acid effectively treated hepatic steatosis, reducing LDL levels in the NAFLD model of wild-type mice. This combination therapy demonstrated efficacy comparable to high-dose obeticholic acid alone. Notably, the combined drug regimen treats hepatic steatosis by inhibiting the IL-1β and α-SMA pathways in NAFLD. Combining ACOX1-specific inhibitors with low-dose obeticholic acid effectively treats high-fat diet-induced hepatic steatosis and reduces serum LDL. This approach enhances the therapeutic effects of obeticholic acid and mitigates its lipotoxicity by inhibiting the IL-1β and α-SMA pathways.

Integrated network pharmacology, metabolomics, and transcriptomics of Huanglian-Hongqu herb pair in non-alcoholic fatty liver disease

Ethnopharmacological relevanceThe Huanglian-Hongqu herb pair (HH) is a synergistic drug combination used to treat non-alcoholic fatty liver disease (NAFLD). However, the molecular mechanism underlying the therapeuticeffects of HH requires further elucidation. Aim of the studyThe present study explored the potential mechanism of HH in treating NAFLD. Materials and methodsUPLC-Q-TOF-MS was employed to identify the drug constituents in HH. A NAFLD rat model was induced by a high-fat diet (HFD) and treated with different doses of HH. The functional mechanism of HH in NAFLD rats was predicted using network pharmacology, metabolomics and transcriptomics. Immunohistochemistry, real-time PCR, and Western blot were performed to validate the key mechanisms. ResultsPharmacodynamic assessment demonstrated that HH exhibited improvements in lipid deposition and reduced hepatic oxidative stress in NAFLD rats. Hepatic wide-target metabolomics revealed that HH primarily modulated amino acids and their metabolites, fatty acids, organic acids and their derivatives, bile acids, and other liver metabolites. The enriched pathways included metabolic pathways, primary bile acid biosynthesis, and bile secretion. Network pharmacology analysis indicated that HH regulated the key pathways in NAFLD, notably PPAR, AMPK, NF-κB and other signaling pathways. Furthermore, hepatic transcriptomics, based on Illumina RNA-Seq sequencing analyses, suggested that HH improved NAFLD through metabolic pathways, the PPAR signaling pathway, primary bile acid biosynthesis, and fatty acid metabolism. Further mechanistic studies indicated that HH could regulate the genes and proteins associated with the PPAR signaling pathway. ConclusionOur findings demonstrated that the potential therapeutic benefits of HH in ameliorating NAFLD by targeting the PPAR signaling pathway, thereby facilitating a more extensive use of HH in NAFLD.

106.6: Spatial transcriptomic analysis on the liver of pig-to-NHP islet transplantation recipient reveals increased adipogenesis and non-alcoholic fatty liver disease pathway in early post-transplantation

106.6: Spatial transcriptomic analysis on the liver of pig-to-NHP islet transplantation recipient reveals increased adipogenesis and non-alcoholic fatty liver disease pathway in early post-transplantation

Hepatic transcriptome delineates the therapeutic effects of Sanren Tang on high-fat diet-induced non-alcoholic fatty liver disease.

To evaluate the effects of Sanren Tang (SRT, ) on a high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) in mice and to investigate the hepatic transcriptome regulated by SRT. The primary SRT components were identified using ultra-high-performance liquid chromatography-high-resolution accurate mass spectrometry. The SRT-induced pharmacological effects on HFD-induced NAFLD were evaluated in mice for 16 weeks. Obeticholic acid was used as a control drug. Body weight, food intake, and homeostatic model assessment for insulin resistance (HOMA-IR) index were analysed. Hepatic histological changes were observed in haematoxylin and eosin-stained sections and quantified using the NAFLD activity score (NAS). Serum alanine aminotransferase (ALT) and hepatic triglyceride (TG) levels were measured. Lipids in hepatocytes were visualised by Oil red staining. RNA-sequencing was performed to determine the transcriptome profile of the liver tissue. The differentially expressed genes were validated using real-time polymerase chain reaction and Western blotting. Four principal compounds were identified in the SRT: adenosine, amygdalin, luteoloside, and magnolol. SRT ameliorated hepatic histology and lipid deposition in the NAFLD mice, and decreased HOMA-IR, NAS and ALT, and hepatic TG levels. Hepatic transcriptome analysis revealed 232 HFD-regulated genes that were reversed by SRT simultaneously. Retinol metabolism, cytokine-cytokine receptor interaction, and peroxisome proliferator-activated receptor (PPAR) γ signalling were the top three SRT-regulated pathways in NAFLD. SRT significantly ameliorated HFD-induced NAFLD, which was correlated with the regulation of genes enriched in the retinol metabolism, cytokine-cytokine receptor interaction, and PPARγ signalling pathways.

Analysis of gut bacteriome of in utero arsenic-exposed mice using 16S rRNA-based metagenomic approach.

Approximately 200 million people worldwide are affected by arsenic toxicity emanating from the consumption of drinking water containing inorganic arsenic above the prescribed maximum contaminant level. The current investigation deals with the role of prenatal arsenic exposure in modulating the gut microbial community and functional pathways of the host. 16S rRNA-based next-generation sequencing was carried out to understand the effects of in utero 0.04 mg/kg (LD) and 0.4 mg/kg (HD) of arsenic exposure. This was carried out from gestational day 15 (GD-15) until the birth of pups to understand the alterations in bacterial diversity. The study focused on gestational exposure to arsenic and the altered gut microbial community at phyla and genus levels, along with diversity indices. A significant decrease in firmicutes was observed in the gut microbiome of mice treated with arsenic. Functional analysis revealed that a shift in genes involved in crucial pathways such as insulin signaling and non-alcoholic fatty liver disease pathways may lead to metabolic diseases in the host. The present investigation may hypothesize that in utero arsenic exposure can perturb the gut bacterial composition significantly as well as the functional pathways of the gestationally treated pups. This research paves the way to further investigate the probable mechanistic insights in the field of maternal exposure environments, which may play a key role in epigenetic modulations in developing various disease endpoints in the progeny.

Hunger & satiety signals: another key mechanism involved in the NAFLD pathway.

Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent metabolic disease, although prevalence could change according to region, nowadays is considered a public health problem whose real impact on the health system is unknown. NAFLD has a multifactorial and complex pathophysiology, due to this, developing a unique and effective pharmacological treatment has not been successful in reverting or avoiding the progression of this liver disease. Even though NAFLD pathophysiology is known, all actual treatments are focused on modifying or regulating the metabolic pathways, some of which interplay with obesity. It has been known that impairments in hunger and satiety signals are associated with obesity, however, abnormalities in these signals in patients with NAFLD and obesity are not fully elucidated. To describe these mechanisms opens an additional option as a therapeutic target sharing metabolic pathways with NAFLD, therefore, this review aims to describe the hormones and peptides implicated in both hunger-satiety in NAFLD. It has been established that NAFLD pharmacological treatment cannot be focused on a single purpose; hence, identifying interplays that lead to adding or modifying current treatment options could also have an impact on another related outcome such as hunger or satiety signals.

Altered splicing factor and alternative splicing events in a mouse model of diet- and polychlorinated biphenyl-induced liver disease

Non-alcoholic fatty liver disease (NAFLD) is associated with human environmental exposure to polychlorinated biphenyls (PCBs). Alternative splicing (AS) is dysregulated in steatotic liver disease and is regulated by splicing factors (SFs) and N-6 methyladenosine (m6A) modification. Here integrated analysis of hepatic mRNA-sequencing data was used to identify differentially expressed SFs and differential AS events (ASEs) in the livers of high fat diet-fed C57BL/6 J male mice exposed to Aroclor1260, PCB126, Aroclor1260 + PCB126, or vehicle control. Aroclor1260 + PCB126 co-exposure altered 100 SFs and replicate multivariate analysis of transcript splicing (rMATS) identified 449 ASEs in 366 genes associated with NAFLD pathways. These ASEs were similar to those resulting from experimental perturbations in m6A writers, readers, and erasers. These results demonstrate specific hepatic SF and AS regulatory mechanisms are disrupted by HFD and PCB exposures, contributing to the expression of altered isoforms that may play a role in NAFLD progression to NASH.

SAT-395 - Risk-stratification of patients with non-alcoholic fatty liver disease (NAFLD) in primary care: lessons from the Calgary NAFLD pathway

SAT-395 - Risk-stratification of patients with non-alcoholic fatty liver disease (NAFLD) in primary care: lessons from the Calgary NAFLD pathway

Dysregulation of Lipid and Glucose Metabolism in Nonalcoholic Fatty Liver Disease.

Non-Alcoholic Fatty Liver Disease (NAFLD) is a highly prevalent condition affecting approximately a quarter of the global population. It is associated with increased morbidity, mortality, economic burden, and healthcare costs. The disease is characterized by the accumulation of lipids in the liver, known as steatosis, which can progress to more severe stages such as steatohepatitis, fibrosis, cirrhosis, and even hepatocellular carcinoma (HCC). This review focuses on the mechanisms that contribute to the development of diet-induced steatosis in an insulin-resistant liver. Specifically, it discusses the existing literature on carbon flux through glycolysis, ketogenesis, TCA (Tricarboxylic Acid Cycle), and fatty acid synthesis pathways in NAFLD, as well as the altered canonical insulin signaling and genetic predispositions that lead to the accumulation of diet-induced hepatic fat. Finally, the review discusses the current therapeutic efforts that aim to ameliorate various pathologies associated with NAFLD.

In silico and in vivo demonstration of the regulatory mechanism of Qi-Ge decoction in treating NAFLD

Background Nonalcoholic fatty liver disease (NAFLD), a chronic and progressive liver disease, often causes steatosis and steatohepatitis. Qi-Ge decoction (QGD) shows a good effect against NAFLD in the clinic. But the molecular mechanism for QGD in improving NAFLD is unknown. Purpose This study explored the molecular mechanism of QGD in NAFLD model rats using comprehensive network pharmacology, molecular docking and in vivo verification strategies. Methods Active components and targets of QGD were obtained from public database. The overlapped genes between QGD and NAFLD targets were analyzed by enrichment analysis. Active components and targets were used to predict molecular docking analysis. Finally, seven key targets were screened out and the gene expression were verified in the NAFLD rat’s liver tissues after QGD treatment. Results Fifty-eight common QGD therapeutic targets were associated with NAFLD. Molecular docking demonstrated that seven targets had strong binding ability for the corresponding active ingredients. GO analysis identified 18 biological process entries, which were mainly related to regulation of lipid storage, lipid localization and peptide transport. KEGG analysis identified multiple signaling pathways, which were mainly associated with tumor necrosis factor signaling and NAFLD. In vivo data confirmed that the effect of QGD in the treatment of NAFLD was mainly exerted through improving liver steatosis and inflammatory cell infiltration. Additionally, QGD upregulated the expression of MAPK8 and ESR1 and downregulated the transcriptional expression of IL6, VEGFA, CASP3, EGFR and MYC. These targets may affect lipid metabolism by regulating lipid storage and inflammation. Conclusion The integration of results obtained in silico and in vivo indicated that QGD regulates multiple targets, biological processes and signaling pathways in NAFLD, which may represent a complex molecular mechanism by which QGD improves NAFLD. Key messages QGD intervention is related to multiple biological processes such as inflammation, oxidation and cell apoptosis in NAFLD. Lipid and atherosclerosis, TNF signaling pathway, IL-17 signaling pathway, non-alcoholic fatty liver disease and AGE-RAGE signaling pathway in diabetic complications are the main pathways for QGD intervention NAFLD. The active components of QGD can form good binding with relevant target proteins through intermolecular forces, exhibiting excellent docking activity.

P018 Non-alcoholic fatty liver disease in spondyloarthritis: identifying patients on therapy at high risk of serious liver disease

Abstract Background/Aims People with Spondyloarthritis (SpA), especially those with psoriatic disease (PsD) [psoriasis (PsO) and psoriatic arthritis (PsA)], are at higher risk of non-alcoholic fatty liver disease (NAFLD) due to increased prevalence of metabolic syndrome, obesity, hypertension, dyslipidaemia and disease-specific factors such as duration/ severity of psoriasis. There is significant concern that both synthetic and biological DMARDs (including methotrexate) may worsen liver function in PsD patients with NAFLD. The Leeds Teaching Hospitals Trust (LTHT) NAFLD pathway uses three screening tools (ELF, FIB-4 and fibroscanning) to identify those needing further investigation/ treatment by hepatology. However, the pathway is not validated in PsD. Our aim was to survey the prevalence of liver disease in our PsD population and explore the performance of our hepatology referral pathway. Methods We audited consecutive patients referred from the Leeds Specialist SpA service at LTHT with persistently abnormal ALT, whom the consultant Rheumatologist felt required Hepatology referral for suspected NAFLD. Data collected were: age, sex, BMI, history of diabetes, ALT, AST, platelets, albumin, hepatitis B and C, ELF score, FIB-4 score, fibroscan score, abdominal ultrasound, liver biopsy result and final hepatology diagnosis (NAFLD, fibrosis/cirrhosis or other). Results 72 patients were included; 84.2% had PsD (61/72), and 15.8% (11/62) had ‘Other’ forms of SpA (including axial spondyloarthritis, enteropathic arthritis, etc). Baseline characteristics, drug treatment and liver biochemistry/virology were similar between PsD and Other arthritis groups (Table 1) except for age which was lower in the Other. The average ELF scores were similar between PsD and Other, however FIB-4 scores were higher in PsD, and was associated with higher rates of fibrosis/cirrhosis (Table 1). FIB-4 >1.3, but not ELF>9.5, was statistically significantly associated with a high fibroscan score (p = 0.038 and p = 0.443 respectively). Conclusion PsD patients had higher rates of significant fibrosis/cirrhosis compared with patients with Other SpAs. FIB-4 was better than ELF for identifying which PsD patients required fibroscan and further investigation to exclude significant fibrosis/ cirrhosis. These findings will now be validated in a larger prospective study. Disclosure S.R. Harrison: None. U. Nandasoma: None. R. Parker: None. C. Chimakurthi: None. P. Laws: None. A. Barr: None. C. Vandevelde: None. H. Marzo-Ortega: None. J. Freeston: None.

Network Pharmacology and Molecular Docking Analysis of the Mechanisms of Combined Radix Bupleuri (Chai-Hu) and Radix Paeoniae Alba (Bai-Shao) Treatment in the Prevention and Treatment of Alzheimer’s Disease

Abstract Objective: Radix Bupleuri and Radix Paeoniae Alba are referred to as Chai-Hu and Bai-Shao, respectively, in Chinese. We used molecular docking and network pharmacological approaches to explore the active components of this Chinese herb combination which is commonly used for treating Alzheimer’s disease (AD), the Chai-Hu and Bai-Shao pair (CBP). Materials and Methods: The active compounds and action targets of Chai-Hu and Bai-Shao were identified in the Traditional Chinese Medicine Systems Pharmacology database, and the Therapeutic Target Database, DrugBank, GenCards, DisGeNET, and Online Mendelian Inheritance in Man databases were used to identify therapeutic targets in patients with AD. To identify a common target of CBP in the treatment of AD, we used the Metascape tool to perform Gene Ontology function enrichment and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. In addition, CBP-AD protein–protein interaction (PPI) and herb-component-target networks were created using Cytoscape 3.8.2. Molecular docking was verified using AutoDock tools. Results We identified 20 active compounds of CBP, 202 active targets, 1,323 disease targets, and 117 active compound disease intersection targets; the PPI network showed that the top eight key targets were AKT1, interleukin (IL) 6, JUN, MAPK1, tumor necrosis factor, TP53, vascular endothelial growth factor, and epidermal growth factor. These act mainly on the fluid shear stress, atherosclerosis, IL-17, hypoxia-inducible factor-1, and nonalcoholic fatty liver disease pathways, among others, which control immune inflammation, cell proliferation, and apoptosis. Based on molecular docking results, the active components of CBP bind well to its key targets. Conclusion Our results indicated that CBP was effective for treating AD by reducing the expression of inflammatory factors, promoting cell proliferation and differentiation, and preventing nerve cell death and anti-neuronal cell apoptosis.

Mechanical Study of Jian-Gan-Xiao-Zhi Decoction on Nonalcoholic Fatty Liver Disease Based on Integrated Network Pharmacology and Untargeted Metabolomics.

Jian-Gan-Xiao-Zhi decoction (JGXZ) has demonstrated beneficial effects on nonalcoholic fatty liver disease (NAFLD). However, the mechanisms by which JGXZ improve NAFLD are still unclear. Methods. In this study, we first used a high-fat diet (HFD) to establish a NAFLD rat model to clarify the therapeutic effect of JGXZ on NAFLD. Secondly, we used network pharmacology to predict the potential targets of JGXZ on NAFLD, and then the key targets obtained from network pharmacology were verified. Finally, we used untargeted metabolomics to study the metabolic regulatory mechanism of JGXZ. Results. JGXZ treatment could decrease body weight and ameliorate dyslipidemia in NAFLD model rats. H&E and oil red O staining indicated that JGXZ reduced steatosis and infiltration of inflammatory cells in the liver. In addition, network pharmacology research found that the potential targets of JGXZ on NAFLD pathway were mainly associated with improving oxidative stress, apoptosis, inflammation, lipid metabolism disorders, and insulin resistance. Further experimental verification confirmed that JGXZ could inhibit inflammation and improve oxidative stress, insulin resistance, and lipid metabolism disorders. Serum untargeted metabolomics analyses indicated that the JGXZ in the treatment of NAFLD may work through the linoleic acid metabolism, alpha-linolenic acid metabolism, tryptophan metabolism, and glycerophospholipid metabolism pathways. Conclusions. In conclusion, this study found that JGXZ has an ameliorative effect on NAFLD, and JGXZ alleviates the inflammatory response and oxidative stress and lipid metabolism disorders in NAFLD rats. The mechanism of action of JGXZ in the treatment of NAFLD may be related to the regulation of linoleic acid metabolism, tryptophan metabolism, alpha-linolenic acid metabolism, and glycerophospholipid metabolism.

A novel method for investigating the mechanism of the anti-rheumatoid arthritis activity of Angelicae pubescentis radix by integrating UHPLC-QTOF/MS and network pharmacology.

The study aimed to establish a strategy to elucidate the in vivo constituents of Angelicae Pubescentis Radix (APR, also known as Duhuo) and reveal the probable mechanisms underlying its anti-rheumatoid arthritis activity. First recorded by Shennong Bencao Jing, APR is mainly used to treat Bi syndrome. Eleven absorbed components of APR were successfully identified using the rheumatoid arthritis (RA) rat model and the UHPLC-QTOF/MS technique. Two active ingredients (osthole and columbianadin) and five corresponding targets (PTGS1, PTGS2, RXRA, CCNA2 and ACHE) were found to construct a compound-protein interaction network in RA. In addition, a non-alcoholic fatty liver disease pathway, which was related to anti-RA activity, was eventually identified by KEGG analysis. Subsequently, molecular docking was performed by establishing a mixed matrix network, including the absorbed component, corresponding target and signaling pathway with two key compounds (osthole and columbianadin) and two important targets (PTGS2 and PTGS1). The result of molecular docking is in agreement with the network pharmacology.

Nonalcoholic Fatty Liver Disease and Endocrine Axes-A Scoping Review.

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease. NAFLD often occurs associated with endocrinopathies. Evidence suggests that endocrine dysfunction may play an important role in NAFLD development, progression, and severity. Our work aimed to explore and summarize the crosstalk between the liver and different endocrine organs, their hormones, and dysfunctions. For instance, our results show that hyperprolactinemia, hypercortisolemia, and polycystic ovary syndrome seem to worsen NAFLD’s pathway. Hypothyroidism and low growth hormone levels also may contribute to NAFLD’s progression, and a bidirectional association between hypercortisolism and hypogonadism and the NAFLD pathway looks likely, given the current evidence. Therefore, we concluded that it appears likely that there is a link between several endocrine disorders and NAFLD other than the typically known type 2 diabetes mellitus and metabolic syndrome (MS). Nevertheless, there is controversial and insufficient evidence in this area of knowledge.

Hesperidin suppresses ERS-induced inflammation in the pathogenesis of non-alcoholic fatty liver disease.

Objective: The current study aimed to establish a non-alcoholic fatty liver disease (NAFLD) model using HFD-fed SD rats and FFA-stimulated human THP-1 cells to examine whether hesperidin (HSP) plays a role in endoplasmic reticulum stress (ERS)-induced inflammation in the pathogenesis of NAFLD.Methods: Oil red O staining was used to determine the effect of HSP on hepatic steatosis in rat liver tissues. Differentially expressed genes (DEGs) were subjected to functional enrichment analysis by bioinformatics. Western blotting was used to detect the protein expression of GRP94, ATF6, ATF4, p-PERK, p-IRE1α, IL-1β, IL-6, and TNF-α in liver tissues and THP-1 cell lines, and the expression of GRP94 and p-PERK in vitro was detected through immunofluorescence staining.Results: HSP significantly decreased the weight gain, hepatic steatosis but not serum lipid profile and suppressed the serum levels of inflammatory factors in HFD-fed rats. It was revealed by bioinformatics analysis that the inflammatory response and IRE1α activation were enriched signaling pathways in NAFLD. The expression of ERS-related biomarkers, GRP94, ATF6, ATF4, p-PERK and p- IRE1α, was significantly suppressed by HSP in vivo and in vitro. Moreover, the inflammatory markers, including IL-1β, IL-6, and TNF-α, were also decreased by HSP in vivo and in vitro. Immunofluorescence staining exposed that the expression of GRP94 and p-PERK was decreased by HSP in vitro.Conclusion: HSP may suppress ERS-induced inflammation in the pathogenesis of NAFLD.

An exploration of barriers and facilitators to implementing a nonalcoholic fatty liver disease pathway for people with type 2 diabetes in primary care.

AimsWe explored barriers and facilitators to the implementation of nonalcoholic fatty liver disease (NAFLD) pathway for people with diabetes to identify determinants of behaviour surrounding the diagnosis, assessment and management of NAFLD.MethodsHealth practitioners (n = 24) recruited from multidisciplinary diabetes clinics in primary care (n = 3) and hospital (n = 1) settings participated in four focus group discussions, and common themes were identified using thematic analysis.ResultsLack of knowledge and access to resources were key factors that underpinned an inconsistent approach by clinicians to NAFLD diagnosis and risk stratification and impacted their confidence to discuss the diagnosis with patients. Participants often prioritised other medical issues above NAFLD due to lack of concern about liver‐related consequences, reluctance to overburden patients with information, lack of time and perceived absence of accessible fibrosis tests. All participants agreed that implementation of a NAFLD pathway would improve patient care and the general practitioners proposed that screening for NAFLD could be incorporated into routine review cycles for type 2 diabetes. A consistent message from participants was that educating patients about their liver disease needs to be implemented in an integrated care pathway.ConclusionsFrom the perspectives of health practitioners, there is a gap in clinical practice for the implementation of clear, evidence‐based guidelines for NAFLD in people with T2D. By focusing on comorbidity prevention and integrating NAFLD as a diabetes complication to be addressed during established cycles of care, many barriers to implementing a NAFLD pathway in primary care could be overcome.

Hepatopancreas transcriptomic and lipidomic analyses reveal the molecular responses of mud crab (Scylla paramamosain) to dietary ratio of docosahexaenoic acid to eicosapentaenoic acid

To investigate the metabolic response of mud crab Scylla paramamosain to dietary ratio of docosahexaenoic acid (DHA) to eicosapentaenoic acid (EPA), transcriptomic and lipidomic analyses were conducted on the hepatopancreas of crabs (initial weight 20.92 ± 0.56 g) fed for 8-week with diets having suboptimum (0.6) and optimal (2.3) DHA/EPA ratios. The analyses identified 358 up-regulated and 432 down-regulated differentially expressed genes, and 48 up-regulated and 30 down-regulated differential lipid molecules with 53% phosphatidylcholine, 14% phosphatidylethanolamine and 13% phosphatidylinositol. GO analysis, KEGG pathway enrichment and network of interaction analysis identified pathways of glycerophospholipid metabolism, PPAR signaling, oxidative phosphorylation, ribosome and thermogenesis as being significantly affected by dietary DHA/EPA ratio. Specifically, dietary DHA/EPA ratio regulated the expression of genes in lipid metabolism and PPAR signaling pathways such as fas, fabp-1/3, fatp, cptI and aco. Compared to the suboptimum ratio, the optimum dietary DHA/EPA ratio down regulated the gene experssion of phospholipase D1/2 and glycerol-3-phosphate O-acyltransferase in glycerophospholipid metabolism pathway, akt and s6 in mTOR pathway, ask1 in thermogenesis and non-alcoholic fatty liver disease pathway, and up regulated the pepck experssion in PPAR signaling pathway. Thus, dietary DHA/EPA ratio influence the lipid, protien and carbohydrate metabolism, immune response, and even the cell member structure. The findings improved our understanding of the impacts and molecular mechanisms of a nutritional challenge, in this case the dietary DHA/EPA ratio, increased basic knowledge of multi-omics analysis of in a commercially important crustacian species, the mud crab S. paramamosain, and provided the framework for further in-depth functional studies to promote sustainable aquaculture.

Elemicin exposure induced aberrant lipid metabolism via modulation of gut microbiota in mice

Elemicin (Ele) is a constituent of natural alkenylbenzene present in many foods and herbs. Ele exposure could induce hepatomegaly and hepatosteatosis. However, the role of gut microbiota in Ele-induced hepatotoxicity remains unclear. Here, the mice were treated with 200 mg/kg/day of Ele for 4 weeks with or without depletion of gut microbiota by antibiotics cocktail treatment. The mice treated with Ele showed enlargement of liver and slight hepatosteatosis, accompanied by higher levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG). Ele could also shift the structure of fecal microbiota and increase the richness. Functional prediction of the microbiota revealed the enrichment of non-alcoholic fatty liver disease pathway upon Ele exposure. Compared with control group, Patescibacteria and Epsilonbacteraeota were significantly enriched at the phylum level upon Ele treatment. A total of 20 genera were significant with respect specifically to Ele exposure, including decreased Alistipes and elevated Ruminiclostridium_9 and Gordonibacter. Among them, 13 retained significant associations with ALT and TG by Spearman correlation test, 4 were correlated with AST. Further MaAsLin analysis revealed that ALT was associated with 4 differentially abundant genera, such as Alistipes and Ruminiclostridium_9 and Gordonibacter. In addition, only Alistipes was significantly correlated with serum TG. Intriguingly, depletion of the microbiota significantly attenuated hepatosteatosis, restore increased ALT, AST and TG and inhibit the expression of genes involved in de novo lipogenesis and adipocyte differentiation, such as Fasn, ADIPOQ and leptin. Collectively, depletion of gut microbiota protected against Ele induced aberrant lipid metabolism in mice.