Occurrence Of Nonalcoholic Fatty Liver Disease Research Articles

Potential mediation effect of insulin resistance on the association between iron metabolism indicators and non-alcoholic fatty liver disease.

Iron metabolism and insulin resistance (IR) are closely related to non-alcoholic fatty liver disease (NAFLD). However, the interplay between them on the occurrence and progression of NAFLD is not fully understood. We aimed to disentangle the crosstalk between iron metabolism and IR and explore its impact on NAFLD. We analyzed data from the National Health and Nutritional Examination Survey (NHANES) 2017-2018 to evaluate the association between serum iron metabolism indicators (ferritin, serum iron, unsaturated iron-binding capacity [UIBC], total iron-binding capacity [TIBC], transferrin saturation, and transferrin receptor) and NAFLD/non-alcoholic steatohepatitis (NASH). Mediation analysis was conducted to explore the role of IR played in these relationship. A total of 4812 participants were included, among whom 43.7% were diagnosed with NAFLD and 13.2% were further diagnosed with NASH. After adjusting the covariates, the risk of NAFLD increases with increasing serum ferritin (adjusted odds ratio [aOR] 1.71, 95% confidence interval [CI] 1.37-2.14), UIBC (aOR 1.45, 95% CI 1.17-1.79), and TIBC (aOR 1.36, 95% CI 1.11-1.68). Higher levels of serum ferritin (aOR 3.70, 95% CI 2.25-6.19) and TIBC (aOR 1.69, 95% CI 1.13-2.56) were also positively associated with NASH. Participants with IR were more likely to have NAFLD/NASH. Moreover, IR-mediated efficacy accounted for 85.85% and 64.51% between ferritin and NAFLD and NASH, respectively. Higher levels ofserum ferritin and TIBC are closely associated with the occurrence of NAFLD and NASH. IR may be considered a possible link between NAFLD or NASH and increased serum ferritin levels.

Association between thyroid function and nonalcoholic fatty liver disease: a dose-response meta-analysis.

Thyroid hormones (THs) have been found that it is closely associated with the onset and progression of non-alcoholic fatty liver disease (NAFLD). However, the current study could not verify the intrinsic relationship between thyroid hormones and NAFLD, which requires further research. The searches of studies reported both TH level in serum and NAFLD were performed in PubMed, Web of Science, Cochrane Library, and Embase databases. We combined an overall meta-analysis with a dose-response meta-analysis to assess the correlation and dose-response relationship between thyroid function levels and the risk of NAFLD. Overall, 10 studies were included with a total of 38,425 individuals. We found that the non-linear dose-response model showed that for every 1 ng/dL increase in FT4, the risk of NAFLD was reduced by 10.56% (p=0.003). The odds ratios (ORs) for NAFLD with high free triiodothyronine (FT3) exposure compared to those with low FT3 were 1.580 (95% CI 1.370 to 1.830, I2=0.0%, p<0.001) in the overall meta-analysis. The continuous variable meta-analysis indicated that individuals with high levels of TSH (SMD=1.32, 95% CI 0.660 to 1.970, p<0.001) had significantly higher levels of liver fibrosis than those with low levels. Our findings only validate that there is a correlation between the occurrence of NAFLD and abnormal levels of THs, and it is expected that more observational studies will still be conducted in the future to further demonstrate the relationship between thyroid hormones and NAFLD. Registered number in PROSPERO: CRD42023405052.

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.

Causal relationship between air pollution, lung function, gastroesophageal reflux disease, and non-alcoholic fatty liver disease: univariate and multivariate Mendelian randomization study.

The association between air pollution, lung function, gastroesophageal reflux disease, and Non-alcoholic fatty liver disease (NAFLD) remains inconclusive. Previous studies were not convincing due to confounding factors and reverse causality. We aim to investigate the causal relationship between air pollution, lung function, gastroesophageal reflux disease, and NAFLD using Mendelian randomization analysis. In this study, univariate Mendelian randomization analysis was conducted first. Subsequently, Steiger testing was performed to exclude the possibility of reverse association. Finally, significant risk factors identified from the univariate Mendelian analysis, as well as important factors affecting NAFLD from previous observational studies (type 2 diabetes and body mass index), were included in the multivariable Mendelian randomization analysis. The results of the univariable Mendelian randomization analysis showed a positive correlation between particulate matter 2.5, gastroesophageal reflux disease, and NAFLD. There was a negative correlation between forced expiratory volume in 1 s, forced vital capacity, and NAFLD. The multivariable Mendelian randomization analysis indicated a direct causal relationship between gastroesophageal reflux disease (OR = 1.537, p = 0.011), type 2 diabetes (OR = 1.261, p < 0.001), and NAFLD. This Mendelian randomization study confirmed the causal relationships between air pollution, lung function, gastroesophageal reflux, and NAFLD. Furthermore, gastroesophageal reflux and type 2 diabetes were identified as independent risk factors for NAFLD, having a direct causal connection with the occurrence of NAFLD.

Gallic Acid Can Promote Low-Density Lipoprotein Uptake in HepG2 Cells via Increasing Low-Density Lipoprotein Receptor Accumulation.

Gallic acid (GA) is a type of polyphenolic compound that can be found in a range of fruits, vegetables, and tea. Although it has been confirmed it improves non-alcoholic fatty liver disease (NAFLD), it is still unknown whether GA can improve the occurrence of NAFLD by increasing the low-density lipoprotein receptor (LDLR) accumulation and alleviating cholesterol metabolism disorders. Therefore, the present study explored the effect of GA on LDLR and its mechanism of action. The findings indicated that the increase in LDLR accumulation in HepG2 cells induced by GA was associated with the stimulation of the epidermal growth factor receptor-extracellular regulated protein kinase (EGFR-ERK1/2) signaling pathway. When the pathway was inhibited by EGFR mab cetuximab, it was observed that the activation of the EGFR-ERK1/2 signaling pathway induced by GA was also blocked. At the same time, the accumulation of LDLR protein and the uptake of LDL were also suppressed. Additionally, GA can also promote the accumulation of forkhead box O3 (FOXO3) and suppress the accumulation of hepatocyte nuclear factor-1α (HNF1α), leading to the inhibition of proprotein convertase subtilisin/kexin 9 (PCSK9) mRNA expression and protein accumulation. This ultimately results in increased LDLR protein accumulation and enhanced uptake of LDL in cells. In summary, the present study revealed the potential mechanism of GA's role in ameliorating NAFLD, with a view of providing a theoretical basis for the dietary supplementation of GA.

Association between Baltic sea diet and healthy Nordic diet index with risk of non-alcoholic fatty liver disease: a case–control study

Recent evidence shows the beneficial effects of Baltic Sea diet score (BSDS) and healthy Nordic diet index (HNDI) on chronic diseases, however, there is no evidence to investigate them on the risk of non-alcoholic fatty liver disease (NAFLD). The purpose of this study was to investigate the associations between BSDS and HNDI with the risk of NAFLD. In this case–control study, 552 people in good health and 340 people with NAFLD over the age of 18 took part. The evaluation of BSDS and HNDI employed a validated 168-item semi-quantitative food frequency questionnaire (FFQ). Binary logistic regression was used to determine how OBS and NAFLD are related. The mean BSDS and HNDI were 16.00 ± 2.49 and 11.99 ± 2.61, respectively. The final model's confounder adjustment revealed that greater HNDI adherence scores gave protection against the occurrence of NAFLD (odds ratio [OR]: 0.42; 95% confidence interval [CI] 0.18–0.98; P for trend = 0.043). In addition, those with the highest BSDS scores had significantly lower risks of developing NAFLD compared to subjects with the lowest scores (OR = 0.48, 95% CI 0.32–0.89; p for trend = 0.003). Our findings showed that following a healthy Nordic diet can significantly prevent the risk of developing NAFLD, and suggest that the highly nutritious components of the Nordic diet are beneficial for the prevention of NAFLD.

Association between per- and poly-fluoroalkyl substances and nonalcoholic fatty liver disease: A nested case-control study in northwest China

Per- and poly-fluoroalkyl substances (PFAS) have been reported to have hepatotoxic effects. However, it is unclear whether they are linked to non-alcoholic fatty liver disease (NAFLD). This nested case-control study focused on the epidemiological links between PFAS and the prevalence of NAFLD. We selected 476 new cases of NAFLD and 952 age- and sex-matched controls from the Jinchang cohort population between 2014 and 2019. Serum concentrations of PFAS were measured using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Only PFAS with a detection rate of ≥90 % were included for analysis, which included PFPeA, PFOA, PFNA, PFHxS, PFOS, and 9Cl-PF3ONS. The relationship between single and co-exposure to PFAS and the occurrence of NAFLD was evaluated using conditional logistic regression, Quantile g-computation (QgC), and Bayesian kernel machine regression (BKMR) model. Logistic regression indicated that PFPeA, PFOA, and 9Cl-PF3ONS were positive correlation with the incidence of NAFLD after adjusting for confounders, with odds ratios (OR) and 95 % confidence interval (CI) of 3.13 (95 % CI: 2.53, 3.86), 1.39 (95 % CI: 1.12, 1.73), and 1.41 (95 % CI: 1.20, 1.66), respectively. PFNA, PFHxS, and PFOS were nonlinearly and negatively associated with the incidence of NAFLD, with OR (95 % CI) of 0.53 (0.46, 0.62), 0.83 (0.73, 0.95), and 0.52 (0.44, 0.61), respectively. QgC showed a significant joint effect of PFAS mixture on NAFLD onset (OR: 1.52, 95 % CI: 1.24, 1.88). BKMR showed a weak positive trend between PFAS mixtures and NAFLD incidence. Positive correlations were primarily driven by PFPeA and 9Cl-PF3ONS, while negative correlations were mainly influenced by PFNA and PFOS. The BKMR model also suggested that there was an interaction between PFOS and PFNA and other four PFAS compounds. In conclusion, our findings suggest that individual and co-exposure to PFAS is associated with a risk of NAFLD onset.

Necroptosis contributes to non-alcoholic fatty liver disease pathoetiology with promising diagnostic and therapeutic functions.

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent type of chronic liver disease. However, the disease is underappreciated as a remarkable chronic disorder as there are rare managing strategies. Several studies have focused on determining NAFLD-caused hepatocyte death to elucidate the disease pathoetiology and suggest functional therapeutic and diagnostic options. Pyroptosis, ferroptosis, and necroptosis are the main subtypes of non-apoptotic regulated cell deaths (RCDs), each of which represents particular characteristics. Considering the complexity of the findings, the present study aimed to review these types of RCDs and their contribution to NAFLD progression, and subsequently discuss in detail the role of necroptosis in the pathoetiology, diagnosis, and treatment of the disease. The study revealed that necroptosis is involved in the occurrence of NAFLD and its progression towards steatohepatitis and cancer, hence it has potential in diagnostic and therapeutic approaches. Nevertheless, further studies are necessary.

Type 1 diabetes mellitus and non-alcoholic fatty liver disease: a two-sample Mendelian randomization study.

NAFLD (Nonalcoholic fatty liver disease) is becoming an increasingly common cause of chronic liver disease. Metabolic dysfunction, overweight/obesity, and diabetes are thought to be closely associated with increased NAFLD risk. However, few studies have focused on the mechanisms of NAFLD occurrence in T1DM. We conducted a two-sample Mendelian randomization (MR) analysis to assess the causal association between T1DM and NAFLD with/without complications, such as coma, renal complications, ketoacidosis, neurological complications, and ophthalmic complications. Multiple Mendelian randomization methods, such as the inverse variance weighted (IVW) method, weighted median method, and MR-Egger test were performed to evaluate the causal association of T1DM and NAFLD using genome-wide association study summary data from different consortia, such as Finngen and UK biobank. We selected 37 SNPs strongly associated with NAFLD/LFC (at a significance level of p < 5 × 10-8) as instrumental variables from the Finnish database based on the T1DM phenotype (8,967 cases and 308,373 controls). We also selected 14/16 SNPs based on with or without complications. The results suggest that the genetic susceptibility of T1DM does not increase the risk of NAFLD (OR=1.005 [0.99, 1.02], IVW p=0.516, MR Egger p=0.344, Weighted median p=0.959, Weighted mode p=0.791), regardless of whether complications are present. A slight causal effect of T1DM without complications on LFC was observed (OR=1.025 [1.00, 1.03], MR Egger p=0.045). However, none of the causal relationships were significant in the IVW (p=0.317), Weighted median (p=0.076), and Weighted mode (p=0.163) methods. Our study did not find conclusive evidence for a causal association between T1DM and NAFLD, although clinical observations indicate increasing abnormal transaminase prevalence and NAFLD progression in T1DM patients.

ONOO–-activatable and LD-traced NIR fluorescent probe for mechanism study and early diagnosis of NAFLD and diabetes induced liver injury

Lipid metabolism disorder and oxidative stress play an essential role in the occurrence and development of metabolic diseases such as nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM). Here, we constructed an ONOO-activatable and lipid drops (LDs) traced near-infrared (NIR) fluorescent probe BDP-NIR-Py+ through structural modification, and evaluated oxidative stress and lipid metabolism disorders in relevant disease by monitoring changes in ONOO and LDs levels in cells and mice. With the dual monitoring of ONOO and LDs, BDP-NIR-Py+ realized real-time visualization of the occurrence and development of NAFLD and T2DM, and early diagnosis of liver injury, which is faster and more sensitive than tissue analysis and blood detection. Collectively, the ability of BDP-NIR-Py+ to simultaneously monitor ONOO and LDs makes it has unlimited potential in the early diagnosis and mechanism research of diseases such as NAFLD and T2DM in which oxidative stress and lipid metabolism disorder interact.

A Review: Cytochrome P450 in Alcoholic and Non-Alcoholic Fatty Liver Disease.

Alcoholic fatty liver disease (FALD) and non-alcoholic fatty liver disease (NAFLD) have similar pathological spectra, both of which are associated with a series of symptoms, including steatosis, inflammation, and fibrosis. These clinical manifestations are caused by hepatic lipid synthesis and metabolism dysregulation and affect human health. Despite having been studied extensively, targeted therapies remain elusive. The Cytochrome P450 (CYP450) family is the most important drug-metabolising enzyme in the body, primarily in the liver. It is responsible for the metabolism of endogenous and exogenous compounds, completing biological transformation. This process is relevant to the occurrence and development of AFLD and NAFLD. In this review, the correlation between CYP450 and liver lipid metabolic diseases is summarised, providing new insights for the treatment of AFLD and NAFLD.

Lian-Mei-Yin formula alleviates diet-induced hepatic steatosis by suppressing Yap1/FOXM1 pathway-dependent lipid synthesis.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, with a global prevalence of 25%. Patients with NAFLD are more likely to suffer from advanced liver disease, cardiovascular disease, or type II diabetes. However, unfortunately, there is still a shortage of FDA-approved therapeutic agents for NAFLD. Lian-Mei-Yin (LMY) is a traditional Chinese medicine formula used for decades to treat liver disorders. It has recently been applied to type II diabetes which is closely related to insulin resistance. Given that NAFLD is another disease involved in insulin resistance, we hypothesize that LMY might be a promising formula for NAFLD therapy. Herein, we verify that the LMY formula effectively reduces hepatic steatosis in diet-induced zebrafish and NAFLD model mice in a time- and dose-dependent manner. Mechanistically, LMY suppresses Yap1-mediated Foxm1 activation, which is crucial for the occurrence and development of NAFLD. Consequently, lipogenesis is ameliorated by LMY administration. In summary, the LMY formula alleviates diet-induced NAFLD in zebrafish and mice by inhibiting Yap1/Foxm1 signaling-mediated NAFLD pathology.

Liver-derived Exosomal miRNA in NAFLD: Mechanisms of Action, Biomarkers, and Therapeutic Applications.

Nonalcoholic fatty liver disease (NAFLD) is of global concern due to its high prevalence worldwide. NAFLD, as one of the most common causes of liver function abnormalities, is associated with obesity, insulin resistance, and type 2 diabetes mellitus, and there are no medications available to treat NAFLD. Extracellular vesicles (EVs) are nanosized, membrane-bound vesicles that deliver biomolecules between cells. Exosomes are a subtype of EVs that mediate intercellular communication by delivering proteins and RNAs. MicroRNAs (miRNAs) are a highly conserved class of small tissue-specific non-coding RNAs that influence the expression of many functionally interacting genes. Hepatic-derived exosomal miRNAs are tightly associated with NAFLD occurrence and progression through multiple mechanisms. In addition, the characterization of miRNAs suggests that they may serve as multifunctional biomarkers for NAFLD, be used as clinical therapeutic targets for NAFLD, and be significant predictors of patient prognosis. Here, we review recent advances in the regulation and function of exosome-derived miRNAs in NAFLD, focusing on miRNAs specifically expressed or enriched in hepatocytes (HCs), hepatic macrophages, hepatic stellate cells (HSCs), and other immune cells in the liver. Finally, we discuss future research directions on exosomal miRNAs as biomarkers for NAFLD's diagnosis and clinical therapeutic targets.

The role of gut microbiota in the occurrence and progression of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent cause of chronic liver disease worldwide, and gut microbes are associated with the development and progression of NAFLD. Despite numerous studies exploring the changes in gut microbes associated with NAFLD, there was no consistent pattern of changes. We retrieved studies on the human fecal microbiota sequenced by 16S rRNA gene amplification associated with NAFLD from the NCBI database up to April 2023, and re-analyzed them using bioinformatic methods. We finally screened 12 relevant studies related to NAFLD, which included a total of 1,189 study subjects (NAFLD, n = 654; healthy control, n = 398; obesity, n = 137). Our results revealed a significant decrease in gut microbial diversity with the occurrence and progression of NAFLD (SMD = -0.32; 95% CI -0.42 to -0.21; p < 0.001). Alpha diversity and the increased abundance of several crucial genera, including Desulfovibrio, Negativibacillus, and Prevotella, can serve as an indication of their predictive risk ability for the occurrence and progression of NAFLD (all AUC > 0.7). The occurrence and progression of NAFLD are significantly associated with higher levels of LPS biosynthesis, tryptophan metabolism, glutathione metabolism, and lipid metabolism. This study elucidated gut microbes relevance to disease development and identified potential risk-associated microbes and functional pathways associated with NAFLD occurrence and progression.

Chronic exposure to parabens promotes non-alcoholic fatty liver disease in association with the changes of the gut microbiota and lipid metabolism.

Non-alcoholic fatty liver disease (NAFLD) has become a serious public health issue due to changing dietary patterns and composition. However, the relationship between NAFLD occurrence and food additives, such as preservatives, remains unknown. This study aimed to evaluate the toxicity of parabens, namely methylparaben (MeP) and ethylparaben (EtP), in relation to NAFLD occurrence in mice under different dietary conditions. Exposure to MeP and EtP exacerbated high-fat diet (HFD)-induced obesity, glucose intolerance, higher serum lipid concentrations, and fat accumulation by upregulating genes involved in lipid metabolism. Untargeted metabolomics revealed that arachidonic acid (AA) metabolism was the top enriched pathway upon MeP and EtP exposure in the presence of HFD. 11,12-Epoxyeicosatrienoic acid (11,12-EET) was the most abundant AA metabolite and was significantly reduced upon exposure to MeP or EtP. Moreover, an integrative analysis of differential fecal taxa at the genus level and serum AA metabolites revealed significant associations. In addition, MeP and EtP enhanced lipid accumulation in AML12 cells and HepG2 cells cultured with oleic acid. 11,12-EET supplementation could significantly alleviate lipid accumulation by suppressing the expression of lipid metabolism-related genes and proteins. The present study suggests that chronic exposure to MeP and EtP promoted NAFLD via gut microbiota-dependent AA metabolism. These results highlight the need for reducing oral exposure to synthetic preservatives to improve metabolic disturbance under HFD conditions.

Association of GCKR and MBOAT7 genetic polymorphisms with non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is one of the most important causes of chronic liver disease (CLD) in both Western and Asian populations. There is wide inter-individual variability in the occurrence of NAFLD and progression to non-alcoholic steatohepatitis (NASH) even after correcting environmental factors, and its true explanation can be provided by heritability. Two such genetic variations, the glucokinase regulator (GCKR) and membrane bound O-acyltransferase domain containing 7 (MBOAT7) genes, in NAFLD patients were studied in the Indian population. A cross sectional analytical study was conducted in the Department of Gastroenterology at a tertiary care centre. In total 100 subjects in the age range of 18-65 years were included in the study; 50 were patients with NAFLD including fatty liver, NASH and NASH related cirrhosis, and 50 were healthy subjects (No NAFLD). The polymorphisms rs780094 and rs1260326 for GCKR and rs641738 for MBOAT7 were determined using PCR followed by the PCR-RFLP. GCKR rs780094 minor allele A was more common in NAFLD patients (p = 0.00001). Within the spectrum of NAFLD, the A allele was present frequently among cirrhotics as compared to NASH and fatty liver (p = 0.00001). Morbidly obese individuals showed significant association with the homozygous A allele (p = 0.028). These results were not seen with GCKR rs1260326 across all alleles. In MBOAT7 (rs641738) the frequency of the minor allele T for NAFLD was 84% vs. 80% in healthy subjects (p = 0.79). The association of the T allele among the spectrum of NAFLD was not statistically significant (p = 0.79). GCKR genetic variant rs780094 was found to be significantly associated with NAFLD. The MBOAT7 (rs641738) genetic variant was not found to be significantly associated with NAFLD.

Bioinformatics analysis of ferroptosis-related genes and immune cell infiltration in non-alcoholic fatty liver disease

BackgroundThe morbidity and mortality rates of patients with non-alcoholic fatty liver disease (NAFLD) have been steadily increasing in recent years. Previous studies have confirmed the important role of ferroptosis in NAFLD development; however, the precise mechanism through which ferroptosis influences NAFLD occurrence remains unclear. The present study aimed to identify and validate ferroptosis-related genes involved in NAFLD pathogenesis and to investigate the underlying molecular mechanisms of NAFLD.MethodsWe downloaded microarray datasets GSE72756 and GSE24807 to identify differentially expressed genes (DEGs) between samples from healthy individuals and patients with NAFLD. From these DEGs, we extracted ferroptosis-related DEGs. GSE89632, another microarray dataset, was used to validate the expression of ferroptosis-related genes. A protein–protein interaction (PPI) network of ferroptosis-related genes was then constructed. The target genes were also subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Finally, competing endogenous RNA networks were constructed. We used the CIBERSORT package to evaluate the infiltration of immune cells infiltration in NAFLD.ResultsFive ferroptosis-related genes (SCP2, MUC1, DPP4, SLC1A4, and TF) were identified as promising diagnostic biomarkers for NAFLD. Enrichment analyses revealed that these genes are mainly involved in metabolic processes. NEAT1-miR-1224-5p-SCP2, NEAT1-miR-485-5p-MUC1, MALAT1-miR-485-5p-MUC1, and CNOT6-miR-145-5p-SLC1A4 are likely to be the potential RNA regulatory pathways that affect NAFLD development. Principal component analysis indicated significant differences in immune cell infiltration between the two groups.ConclusionsThis study identified five ferroptosis-related genes as potential biomarkers for diagnosing NAFLD. The correlations between the expression of ferroptosis-related genes and immune cell infiltration might shed light on the study of the molecular mechanism underlying NAFLD development.

Identification of Predictors of Non-alcoholic Steatohepatitis and Its Severity in Individuals Undergoing Bariatric Surgery.

As obesity reached epidemic proportions, non-alcoholic fatty liver disease (NAFLD) also had a worrisome parallel increase. The non-invasive differentiation of non-alcoholic steatohepatitis (NASH) from uncomplicated NAFLD remains an important challenge in current clinical practice. To identify predictors of the occurrence and severity of NAFLD and NASH. This is an analytical cross-sectional study which included individuals undergoing bariatric surgery. Participants were histologically classified according to the presence NASH and severity of NAFLD. Demographic, clinical, anthropometric, and biochemical aspects were analyzed and compared. Out of 171 individuals, 87.7% were female and the mean age was 38.4±9.3 years. The average BMI was 38±3.0 kg/m2. NAFLD was histologically confirmed in 74.9%; the commonest histopathological abnormalities were macrovesicular steatosis (74.9%) and ballooning (40.4%). Simple steatosis occurred in 30.4%, 44.4% presented with NASH, and 31% had severe NAFLD. NASH associated with higher levels of ALT (0.03), ALP (0.02), and glucose (0.02). Cutoff values were, respectively, 23 U/L, 67 U/L, and 81 mg/dL. Their concomitant use provided an 83.1% specificity for NASH. Severe NAFLD associated with diabetes (p=0.02), higher BMI (p=0.01), AST (p=0.04), ALT (p<0.01), ALP (p=0.01), glucose (p=0.02), and ferritin (p<0.01). BMI over 39.3 kg/m2 and ferritin over 178 ng/mL concomitantly provided a 70.5% accuracy for severe NAFLD. NASH and severe NAFLD associated with higher levels of ALT, ALP, and glucose. Severe NAFLD associated with higher BMI and higher ferritin levels in this group. The concomitant evaluation of these laboratory tests could help ruling out NASH and safely screening severe NAFLD.

Association between hypoglycemic agent use and the risk of occurrence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus.

Nonalcoholic fatty liver disease (NAFLD) is a growing health concern with increasing prevalence and associated health impacts. Although no approved drugs are available for the NAFLD treatment, several hypoglycemic agents have been investigated as promising therapeutic agents. We aimed to compare the risk of occurrence of NAFLD with respect to the use of different hypoglycemic agents in patients with type 2 diabetes. This retrospective cohort study used data from the National Health Insurance Service-National Sample Cohort of South Korea. Participants newly diagnosed with type 2 diabetes (2003-2019) were included in this study. Two new user-active comparator cohorts were assembled: Cohort 1, new users of thiazolidinediones (TZD) and dipeptidyl peptidase-4 inhibitors (DPP-4i), and Cohort 2, new users of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and DPP-4i. The occurrence of NAFLD was defined based claims that include diagnostic codes. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard models in 1:3 propensity score (PS)-matched cohorts. For 65,224 patients newly diagnosed with type 2 diabetes, the overall prevalence of NAFLD was 42.6%. The PS-matched Cohort 1 included 6,351 and 2,117 new users of DPP-4i and TZD, respectively. Compared to DPP-4i, TZD use was associated with the decreased risk of NAFLD (HR, 0.66; 95% CI: 0.55-0.78). Cohort 2 consisted of 6,783 and 2,261 new users of DPP-4i and SGLT-2i, respectively; SGLT-2i use was associated with a decreased risk of NAFLD (HR, 0.93; 95% CI: 0.80-1.08). This population-based cohort study supports the clinical implications of prioritizing TZD and SGLT-2i over DPP-4i in reducing the risk of occurrence of NAFLD in patients with type 2 diabetes. However, the findings lacked statistical significance, highlighting the need for further verification studies.

The causal effect of mTORC1-dependent circulating protein levels on nonalcoholic fatty liver disease: A Mendelian randomization study

BackgroundThe mechanistic target of rapamycin (mTOR) signal pathway plays a crucial role in the development of nonalcoholic fatty liver disease (NAFLD). However, the causal effect of mTOR downstream proteins on NAFLD remains unknown. AimsWe conducted a two-sample Mendelian randomization (MR) study to investigate whether the mTOR-dependent circulating proteins, including Eukaryotic Initiation Factor 4E Binding Proteins (eIF4EBPs), Ribosomal Protein S6K kinase 1 (RP-S6K), Eukaryotic Initiation Factor 4E (eIF4E), Eukaryotic Initiation Factor 4A (eIF4A) and Eukaryotic Initiation Factor 4 G (eIF4G), have causal effects on the risk of NAFLD. MethodsThe causal estimate was evaluated with the inverse-variance weighted (IVW) method in discovery stage and validation stage. The single-nucleotide polymorphisms (SNPs) were selected to genetically predict exposures from Genome-Wide Association Studies (GWAS). Exposures with statistically significant effects in the discovery dataset would be further validated in the validation dataset. ResultsMR study revealed that eIF4E had a causal effect on NAFLD in both discovery stage (OR = 1.339, P = 0.037) and validation stage (OR = 1.0007, P = 0.022). Sensitivity analyses confirmed robustness of the results. ConclusionThe genetically predicted higher level of mTOR-dependent eIF4E in plasma might have a causal effect on the occurrence of NAFLD.