Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease and is considered the hepatic manifestation of metabolic syndrome, triggering out adverse outcomes. A stacked multimodal machine learning model is constructed and validated for early identification and prognosis stratification of NAFLD by integrating genetic and clinical data sourced from 36 490 UK Biobank and 9 007 Nanfang Hospital participants and extracted its probabilities as in-silico scores for NAFLD (ISNLD). The efficacy of ISNLD is evaluated for the early prediction of severe liver disease (SeLD) and analyzed its association with metabolism-related outcomes. The multimodal model performs satisfactorily in classifying individuals into low- and high-risk groups for NAFLD, achieving area under curves (AUCs) of 0.843, 0.840, and 0.872 within training, internal, and external test sets, respectively. Among high-risk group, ISNLD is significantly associated with intrahepatic and metabolism-related complications after lifestyle factors adjustment. Further, ISNLD demonstrates notable capability for early prediction of SeLD and further stratifies high-risk subjects into three risk subgroups of elevated risk for adverse outcomes. The findings emphasize the model's ability to integrate multimodal features to generate ISNLD, enabling early detection and prognostic prediction of NAFLD. This facilitates personalized stratification for NAFLD and metabolism-related outcomes based on digital non-invasive markers, enabling preventive interventions.

Patatin-like phospholipase domain-containing 3 (PNPLA3) protein 148M variant is strongly associated with cirrhosis and hepatocellular carcinoma (HCC); however, the underlying mechanisms remain elusive. This study aimed to elucidate the role of the PNPLA3148M variant in alcohol-related HCC development. Control and humanized PNPLA3148M transgenic mice were fed with an ethanol-containing diet for 12 weeks. The animals were examined for liver tumors. After the alcohol feeding, the PNPLA3148M mice had twofold higher liver cancer incidence rates and larger tumor sizes than those in the control mice. Cancer stem cell markers in the PNPLA3148M mouse livers were elevated relative to those in the control mouse livers. Alcohol detoxification was impaired in the PNPLA3148M mouse livers. Hepatic oxidative stress and DNA damage were elevated in the PNPLA3148M mice. Wnt/β-catenin and Yes-associated protein (YAP) and WW domain-containing transcription regulator 1 (TAZ) were activated in the PNPLA3148M mouse livers. The data suggest that the PNPLA3148M variant has a strong interaction with alcohol in HCC development through attenuation of alcohol detoxification and promotion of oncogenic pathways. Targeting the PNPLA3148M variant might be useful for the prevention or treatment of alcohol-associated HCC in patients carrying this variant.

Nonalcoholic fatty liver disease (NAFLD) is a major public health problem and the most common chronic liver disease today. In Korea, the prevalence and incidence of NAFLD are currently very high, causing a serious social burden. Perfluoroalkyl substances (PFAS) have been consistently implicated as a potential cause of NAFLD, but research in Koreans is limited.

Using data from the 4th Korean National Environmental Health Survey (KoNEHS, n = 2859), we investigated the association between PFAS blood levels and NAFLD. Multivariable logistic regression models were used to calculate odds ratios (ORs) for the effects of PFAS. A mediation analysis was also conducted to examine the mediating effect of obesity. Finally, weighted quantile sum (WQS) and G-computation methods were implemented to evaluate the joint effect of PFAS mixtures. Hepatic steatosis index was used as a diagnostic tool for NAFLD.

Through multivariable logistic regression, statistically significant associations with NAFLD were observed for perfluorooctanoic acid (PFOA) (OR 1.09-1.39), perfluorooctansulfonate (PFOS) (1.09-1.40), perfluorohexanesulfonic acid (PFHxS) (1.04-1.22), perfluorononanoic acid (PFNA) (1.12-1.42), and total PFAS (1.21-1.81). We also found that obesity was a significant mediator for PFOA, PFNA, and total PFAS. The ORs for NAFLD obtained by WQS and G-computation methods in the multivariable adjusted model were 1.10-1.46 and 1.08-1.32, respectively.

This study confirmed a significant association between some PFAS and increased odds of NAFLD. Excessive exposure to PFAS might explain the high prevalence and incidence of chronic liver disease in Koreans. Long-term cohort studies are needed to assess geographic and occupational exposures in the Korean population.

This study aimed to investigate the relationship between lung function and metabolic dysfunction-associated steatotic liver disease (MASLD), and the potential mediating role of type 2 diabetes.

Data from the 2007 to 2012 National Health and Nutrition Examination Survey were used. Logistic regression analysis was employed to assess the association between lung function parameters [forced vital capacity (FVC), forced expiratory volume in 1 s (FEV 1 ), FEV 1 /FVC] and MASLD prevalence while exploring type 2 diabetes mediation. Further analyses included linkage disequilibrium score regression, Mendelian randomization, and meta-analysis to examine the causal relationship between lung function and MASLD, considering type 2 diabetes mediation.

The results showed that higher FVC and FEV 1 levels were associated with decreased MASLD risk, with type 2 diabetes partially mediating this relationship. Genetic analyses supported a causal link between lung function and MASLD, with type 2 diabetes acting as an intermediary. However, no significant association was found between FEV 1 /FVC and MASLD.

The study identified a causal relationship between lung function and MASLD, with type 2 diabetes playing a partial mediating role.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the umbrella term that comprises metabolic dysfunction-associated steatotic liver, or isolated hepatic steatosis, through to metabolic dysfunction-associated steatohepatitis, the progressive necroinflammatory disease form that can progress to fibrosis, cirrhosis and hepatocellular carcinoma. MASLD is estimated to affect more than one-third of adults worldwide. MASLD is closely associated with insulin resistance, obesity, gut microbial dysbiosis and genetic risk factors. The obesity epidemic and the growing prevalence of type 2 diabetes mellitus greatly contribute to the increasing burden of MASLD. The treatment and prevention of major metabolic comorbidities such as type 2 diabetes mellitus and obesity will probably slow the growth of MASLD. In 2023, the field decided on a new nomenclature and agreed on a set of research and action priorities, and in 2024, the US FDA approved the first drug, resmetirom, for the treatment of non-cirrhotic metabolic dysfunction-associated steatohepatitis with moderate to advanced fibrosis. Reliable, validated biomarkers that can replace histology for patient selection and primary end points in MASH trials will greatly accelerate the drug development process. Additionally, noninvasive tests that can reliably determine treatment response or predict response to therapy are warranted. Sustained efforts are required to combat the burden of MASLD by tackling metabolic risk factors, improving risk stratification and linkage to care, and increasing access to therapeutic agents and non-pharmaceutical interventions.

Nonalcoholic fatty liver disease (NAFLD) is a metabolic liver disorder with severe complications. Mitochondrial dysfunction due to over-opening of the mitochondrial permeability transition pore (mPTP) in liver cells plays a central role in the development and progression of NAFLD. Restoring mitochondrial function is a promising strategy for NAFLD therapy. Herein, we designed and developed a microenvironment-induced programmable nanotherapeutic to restore mitochondrial function and ameliorate NAFLD. cyclosporine (Cyclosporine capsules) A (CsA), as a highly effective inhibitors of the opening of mPTP, was chosen in the present work. Nanotherapeutics were prepared by assembling two structurally simple multifunctional glucosamine derivatives: dextran-grafted galactose (Dex-Gal) and Dex-triphenylphosphine (Dex-TPP). Galactose units in the nanotherapeutics guide the hepatocyte-specific uptake. Detachment of galactose from acidic lysosomes via Schiff base cleavage exposes the TPP moieties, which subsequently steers the nanotherapeutics to escape from lysosomes and target mitochondria through an enhanced positive charge, enabling precise in situ drug delivery. Simultaneously, the nanotherapeutics improved mitochondrial dysfunction by inhibiting palmitic acid-induced opening of the mitochondrial permeability transition pore in HepG2 cells, maintaining mitochondrial membrane potential, and decreasing reactive oxygen species production. Furthermore, CsA@Dex-Gal/TPP accumulated in the livers of NAFLD mice, restored mitochondrial autophagy, regulated abnormalities in glucose and lipid metabolism, and improved hepatic lipid deposition. This study offers a new cascading strategy for targeting liver cell mitochondria to treat NAFLD and other mitochondria-associated diseases. STATEMENT OF SIGNIFICANCE: We design microenvironment-induced programmable nanotherapeutics for NAFLD Nanotherapeutics has the capabilities of lysosomal escape and mitochondrial targeting Nanotherapeutics improves mitochondrial dysfunction and ameliorates NAFLD This study offers a new cascading strategy for other mitochondria-associated diseases.

For characterizing health states, fat distribution is more informative than overall body size. We used population-based whole-body magnetic resonance imaging (MRI) to identify distinct body composition subphenotypes and characterize associations with cardiovascular disease (CVD) risk.

Bone marrow, visceral, subcutaneous, cardiac, renal, hepatic, skeletal muscle and pancreatic adipose tissue were measured by MRI in n = 299 individuals from the population-based KORA cohort. Body composition subphenotypes were identified by data-driven k-means clustering. CVD risk was calculated by established scores.

We identified five body composition subphenotypes, which differed substantially in CVD risk factor distribution and CVD risk. Compared to reference subphenotype I with favorable risk profile, two high-risk phenotypes, III&V, had a 3.8-fold increased CVD risk. High-risk subphenotype III had increased bone marrow and skeletal muscle fat (26.3 % vs 11.4 % in subphenotype I), indicating ageing effects, whereas subphenotype V showed overall high fat contents, and particularly elevated pancreatic fat (25.0 % vs 3.7 % in subphenotype I), indicating metabolic impairment. Subphenotype II had a 2.7-fold increased CVD risk, and an unfavorable fat distribution, probably smoking-related, while BMI was only slightly elevated. Subphenotype IV had a 2.8-fold increased CVD risk with comparably young individuals, who showed high blood pressure and hepatic fat (17.7 % vs 3.0 % in subphenotype I).

Whole-body MRI can identify distinct body composition subphenotypes associated with different degrees of cardiometabolic risk. Body composition profiling may enable a more comprehensive risk assessment than individual fat compartments, with potential benefits for individualized prevention.

Observational studies have reported a bidirectional correlation between nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D), but the shared genetic basis between the two conditions remains unclear. Using genome-wide association study (GWAS) summary data from European-ancestry populations, we examined the cross-trait genetic correlation and identified genomic overlaps and shared risk loci. We employed a latent causal variable model and Mendelian randomization (MR) analysis to infer causal relationships. Colocalization analysis and conditional/conjunctional false discovery rate (condFDR/conjFDR) were used to identify genomic overlaps and shared risk loci. Two-step MR analysis was utilized to identify potential mediators. We observed a strong positive genomic correlation between NAFLD and T2D (rg = 0.652, P = 5.67 × 10-6) and identified tissue-specific transcriptomic correlations in the pancreas, liver, skeletal muscle, subcutaneous adipose, and blood. Genetic enrichment was observed in NAFLD conditional on associations with T2D and vice versa, indicating significant polygenic overlaps. We found robust evidence for the causal effect of NAFLD on T2D, particularly insulin-related T2D, rather than vice versa. Colocalization analysis identified shared genomic regions between NAFLD and T2D, including GCKR, FTO, MAU2-TM6SF2, and PNPLA3-SAMM50. High-density lipoprotein cholesterol and insulin were partly mediated the association between NAFLD and T2D. These findings unveil a close genetic link between NAFLD and T2D, shedding light on the biological mechanisms connecting NAFLD progression to T2D.

Previous studies have emphasized the independent effects of anthropometric indices-including body mass index (BMI), A Body Shape Index (ABSI), waist-to-height ratio (WHtR), body roundness index (BRI), and Conicity Index-on mortality. However, their combined impact, especially in diabetic populations with distinct obesity patterns, has been less frequently explored. This study investigates both the independent and combined effects of these anthropometric indices on mortality in diabetic Americans and compares their individual and combined diagnostic value.

A nationally representative cohort study was conducted using NHANES data (2005-2018), including 6,572 diabetic adults. Weighted Cox proportional hazards models and restricted cubic splines were applied to evaluate the independent and combined associations of anthropometric indices (BMI, ABSI, WHtR, BRI, and Conicity Index) with all-cause mortality. The weighted receiver operating characteristic (ROC) curve was used to assess the diagnostic value of individual anthropometric indices and their combinations in predicting mortality.

Among all the anthropometric indices, ABSI exhibited the strongest independent association with all-cause mortality, outperforming other measures such as BMI, WHtR, BRI, and Conicity Index. A clear linear relationship was identified, with higher ABSI tertiles consistently linked to an increased risk of mortality. Notably, within each BMI tertile, ABSI effectively differentiated mortality risk, particularly in the highest tertile. Furthermore, ABSI demonstrated the highest predictive performance among individual metrics (weighted AUC = 0.653) and showed further improvement when combined with BMI (weighted AUC = 0.669).

BMI and ABSI collectively provide a comprehensive evaluation of mortality risk in diabetic populations, capturing the synergistic effects of general and central obesity. These findings highlight the importance of integrating BMI and ABSI into risk assessments to identify high-risk individuals and guide targeted interventions for reducing mortality.

The link between antioxidants and metabolic dysfunction-associated steatotic liver disease (MASLD) is a topic of considerable discussion in the field of observational studies, with the exact causal connections still being unclear.

In this investigation, a cohort consisting of 17 061 participants from the National Health and Nutrition Examination Surveys was studied. Initially, a cross-sectional analysis was carried out to examine the relationship between the CDAI and MASLD. Further, Mendelian randomization (MR) was utilized to assess the possible causal links between antioxidant levels in the bloodstream and MASLD.

The association between the CDAI and MASLD was found to be significant in the fully adjusted logistic regression model, showing an OR of 0.95 [95% confidence interval (CI): 0.94-0.97; P  < 0.001]. The use of restricted cubic spline regression revealed no significant nonlinear association between the CDAI and the occurrence of MASLD ( Pnonlinearity  = 0.321). Additionally, MR findings did not suggest any causal connections between circulating levels of various antioxidants and MASLD. These antioxidants included vitamin A (retinol) (IVW: OR: 0.67, 95% CI: 0.33-1.36, P  = 0.272), vitamin C (ascorbate) (IVW: OR: 0.61, 95% CI: 0.34-1.09, P  = 0.094), vitamin E (α-tocopherol) (IVW: OR: 0.55, 95% CI: 0.13-2.25, P  = 0.407), vitamin E (γ-tocopherol) (IVW: OR: 0.89, 95% CI: 0.36-2.23, P  = 0.806), zinc (IVW: OR: 0.95, 95% CI: 0.82-1.09, P  = 0.449), selenium (IVW: OR: 0.98, 95% CI: 0.84-1.16, P  = 0.855), and carotene (IVW: OR: 0.80, 95% CI: 0.36-1.81, P  = 0.596).

The findings highlight a significant negative linear relationship between CDAI and MASLD prevalence in the observational component of the study. However, the MR analysis did not indicate any causal effects of circulating antioxidant levels on MASLD.

The prevalence of non-alcoholic fatty liver disease (NAFLD) is gradually increasing among non-obese people and shows a trend of younger age. The objective of this study was to investigate the potential association between serum uric acid (SUA) and NAFLD in a non-obese young population.

The study recruited 10,938 participants without NAFLD (18 ≤ age < 45,18.5 ≤ BMI < 25) in 2006. After a median follow-up of 9.95 years, 4835 (44.20%) participants were diagnosed with NAFLD. According to the baseline SUA level, the research subjects were divided into 4 groups by the quartile method. The association between SUA and NAFLD was predicted using the Kaplan -Meier survival curve and Cox hazard regression model.

After adjusting for all the confounders, the HRs and 95%CI for NAFLD in the quartile 2, quartile 3 and quartile 4 were 1.095(1.004 ~ 1.193), 1.195(1.095 ~ 1.304) and 1.409(1.289 ~ 1.541). The restrictive cubic spline (RCS) functions confirmed the existence of a non-linear association between the initial SUA and NAFLD (non-linearity association P < 0.05). Kaplan-Meier Survival Curve shows that the risk of NAFLD increased with increasing levels of SUA. The cumulative incidences of the four groups were 46.19, 51.99, 56.52 and 65.87%, respectively (log-rank test P < 0.001).

It has been confirmed through a prospective cohort study that in non-obese young population, SUA can serve as an independent predictor of NAFLD. An increase in SUA within the physiological range, even if it doesn't reach the level of hyperuricemia, can impose a significant burden on the occurrence of NAFLD.

Trial registration number: ChiCTR-TNC-11001489, registration site: http://www.chictr.org.cn/index.aspx .

Metabolic dysfunction-associated steatotic liver disease (MASLD), hepatic fibrosis, and portal hypertension constitute an increasing public health problem due to the growing prevalence of obesity and diabetes. C-type natriuretic peptide (CNP) is an endogenous regulator of cardiovascular homeostasis, immune cell reactivity, and fibrotic disease. Thus, we investigated a role for CNP in the pathogenesis of MASLD. Wild-type (WT), global CNP (gbCNP-/-), and natriuretic peptide receptor-C (NPR-C-/-) knockout mice were fed a choline-deficient defined amino acid diet or administered CCl4. Liver damage was assessed by histological and biochemical analyses, with steatosis and portal vein size determined by ultrasound. Portal vein pressure and reactivity were measured in vivo and ex vivo, respectively. Pharmacological CNP delivery was used to evaluate prospective therapeutic benefit, and plasma CNP concentration was compared in controls and patients with cirrhosis. Circulating CNP concentration was lower in patients with cirrhosis compared with controls. gbCNP-/- mice were more susceptible, versus WT, to advanced steatohepatitis and hepatic fibrosis, characterized by increased immune cell infiltration, fibrosis, ballooning, plasma alanine aminotransferase concentration, and up-regulation of markers driving these processes. gbCNP-/- mice had increased portal vein diameter and pressure, underpinned by CNP insensitivity. NPR-C-/- animals recapitulated, comparatively, the exaggerated pathogenic phenotype in gbCNP-/- mice, whereas CNP reduced hepatic stellate cell proliferation via NPR-B-dependent inhibition of extracellular signal-related kinase 1/2. Administration of CNP reversed many aspects of disease severity. These data define a new intrinsic role for CNP in offsetting the pathogenesis of MASLD, hepatic fibrosis, and portal hypertension and the potential for targeting CNP signaling for treating these disorders.

The incidence of non-alcoholic fatty liver disease (NAFLD) is increasing with obesity, and it is believed that the ongoing low-grade inflammation in obesity and alterations in the enterohepatic axis contributing this process. This study aimed to determine the role of fecal calprotectin (FC) as inflammatory biomarker in obesity and NAFLD.

Between November 2022-August 2023, 31 obese and 10 healthy adolescents aged between 10 and 18 years enrolled in this prospective controlled study. Body mass index higher than 2 standard deviation is considered as obesity. Obese adolescents were divided into two subgroups: obese adolescents (n = 11) and Obese + NAFLD group (n = 20). NAFLD diagnosis was made with biochemical analysis or ultrasonography. FC levels and laboratory parameters analyzed in study group, while only FC samples taken from control group. Anthropometric and laboratory parameters were compared between groups. This study was registered in ClinicalTrials.gov (NCT06229184).

The median (IQR P25-75) FC levels in the obese + NAFLD, obese and the healthy controls were 136.23 (43.36-332.04), 61.77 (29.70-285.92) and 38.95 (27.59-50.52) µg/g feces, respectively (p = 0.018). Subgroup analyses revealed that the significant difference was between the obese + NAFLD group and the control group (p = 0.02), while no significant differences were observed between the control and obese groups, or between the obese and obese + NAFLD groups. FC positivity rates were 20% (n = 2) in the control group, 54.5% (n = 6) in the obese group, and 75% (n = 15) in the Obese + NAFLD group (p = 0.018).

FC is significantly higher in obese adolescents compared to healthy peers, but no significant difference was observed between obese and obese + NAFLD groups. Further studies needed on this subject.

This trial is registered in ClinicalTrials.gov (Trial registration number [ClinicalTrials.gov ID] NCT06229184).

Lipoprotein(a) (Lp(a)) is an emerging biomarker for cardiometabolic factors. We studied the role of Lp(a) in the full spectrum of metabolic dysfunction-associated steatotic liver disease (MASLD).

Three independent analyses were implemented using a multi-center, cross-sectional, liver biopsy-based study (n = 332) (Study 1) and the UK Biobank prospective study (n = 270,004) (Study 2; median follow-up, 12.47 years). In Study 1, we studied the cross-sectional association between Lp(a) mass and MASLD stages (Analysis A). In Study 2, we studied the prospective association between Lp(a) concentration and MASLD, liver cirrhosis, and hepatocellular carcinoma (Analysis B). Finally, these analyses were accompanied by a prospective analysis using LPA Genetic Risk Score (Analysis C).

In Study 1, an inverse association between Lp(a) and at-risk metabolic dysfunction-associated steatohepatitis (odds ratioper 1-SD increase, 0.64; 95% confidence interval [CI], 0.42-0.97) was observed. In contrast, when similar associations were examined prospectively (Study 2), subjects with Lp(a) <10.75 nmol/L had a higher risk for cirrhosis (hazard ratio, 1.49; 95% CI, 1.22-1.81) and HCC (hazard ratio, 1.69; 95% CI, 1.12-2.56) compared with subjects with Lp(a) within the 10.75 to 21.5 nmol/L range. Above these levels, the risk increased significantly and positively. Similarly, genetic analysis showed an L-shaped association with LPA Genetic Risk Score.

The inverse association observed in cross-sectional studies should be attributed to reverse causality (ie, the presence of liver disease may decrease Lp(a) levels). Genetically predicted very low Lp(a) levels are also associated with impaired liver health prospectively. Clinical trials evaluating Lp(a)-lowering agents should thus be monitored carefully for adverse liver effects in subjects attaining extremely low concentrations.

Thyroid hormones play a critical role in brain development. However, the precise causal associations between thyroid function and structural changes in specific brain regions remain uncertain.

We applied the univariate Mendelian randomization (UVMR) method to assess the causal effects of thyroid function on brain structure. Genome-wide association study (GWAS) data on thyroid-related traits from the ThyroidOmics Consortium including free thyroxine (FT4), free tri-iodothyronine (FT3), thyroid-stimulating hormone (TSH), FT3/FT4 ratio, as well as dichotomized high and low TSH levels were used as exposures. GWAS data on cortical thickness, surface area, and volume of subcortical structures served as outcomes. Inverse variance weighted was the main estimate method. Subsequently, multivariable MR (MVMR) was conducted to validate significant causal associations identified in UVMR.

UVMR analysis demonstrated a statistically significant inverse association between genetically predicted FT4 and putamen volume (β = -71.91 mm3, 95% confidence interval: -112.11 mm3 to -31.71 mm3, p = 4.54 × 10-4). The findings were robust in sensitivity analysis. MVMR analysis further confirmed a persistent causal relationship between FT4 and putamen volume after adjusting for FT3, TSH, and neuropsychiatric disorders. Functional enrichment analyses indicated the pathways by which FT4 influences putamen volume may be related to the thyroid hormone signaling pathway, sodium-independent organic anion transport, and Rap1 signaling pathway.

MR analysis provides evidence for causal relationships between thyroid function and brain structural alterations, particularly highlighting the impact of FT4 on putamen volume. Further research is warranted to elucidate the underlying mechanisms by which thyroid hormones modulate brain structure.

Metabolic dysfunction-associated fatty liver disease (MAFLD) and diabesity (diabetes related to obesity) are interrelated since glucose and lipid alterations play a vital role in the development of both disorders. Due to their multi-variant metabolic features, more than one drug or natural product may be required to achieve proper therapeutic effects. This study aimed to evaluate the effectiveness of a formulation containing co-micronized palmitoylethanolamide and rutin (PEA-Rut) associated with hydroxytyrosol (HT), namely NORM3, against hepatic damage and metabolic alterations in high-fat diet (HFD)-induced diabesity in mice. NORM3 decreased the body weight and fat mass of obese mice. The formulation improved HFD-altered insulin sensitivity and hepatic glucose production and metabolism, as shown by glucose, insulin, pyruvate tolerance tests, Western blot, and real-time PCR. In the liver, NORM3 limited macro- and micro-vacuolar steatosis, as revealed by morphological analysis, and reduced the associated hepatic inflammation. NORM3 counteracted lipid dysfunctions of HFD animals, activating AMPK, a key cellular energy sensor, and normalizing the expression of carnitine palmitoyl-transferase (CPT)1, a rate-limiting enzyme of fatty acid β-oxidation, and other genes involved in lipid homeostasis. Relevantly, the hepatic antioxidant activity of NORM3 was proved (reduced ROS and increased detoxifying factors and enzymes). Finally, in vitro synergistic protective effects of the components (PEA-Rut and HT) on H2O2-induced oxidative challenge in HepG2 were determined (ROS production, inflammation, and antioxidant defense). Our results show the beneficial effect of NORM3 and its potential as an innovative phytotherapeutic combination in limiting hepatic damage progression and counteracting glucose and lipid dysmetabolism associated with diabesity.

To establish normative values and identify potential factors influencing pancreatic iodine uptake using dual-energy CT (DECT).

This retrospective study included participants without pancreatic diseases undergoing DECT at two institutions with different platforms. Their protocols both included arterial phase (AP), portal venous phase (PP), and equilibrium phase (EP), defined as 35 s-40 s, 60 s-70 s, and 150 s-180 s after injection of contrast agent, respectively. Both iodine concentration (IC) and normalised IC (NIC) were measured. Demographic features, local measurements of the pancreas and visceral fat area (VFA) were considered as potential factors influencing iodine uptake using multivariate linear regression analyses.

A total of 562 participants (median age 58 years [interquartile range: 47-67], with 282 men) were evaluated. The mean IC differed significantly between two institutions (all p < 0.001) across three contrast-enhanced phases, while the mean NIC showed no significant differences (all p > 0.05). The mean values of NIC were 0.22 at AP, 0.43 at PP and 0.45 at EP. NICAP was independently affected by VFA (β = 0.362, p < 0.001), smoking (β = -0.240, p = 0.001), and type-II diabetes (β = -0.449, p < 0.001); NICPP by VFA (β = -0.301, p = 0.017) and smoking (β = -0.291, p < 0.001); and NICEP by smoking (β = -0.154, p = 0.10) and alcohol consumption (β = -0.350, p < 0.001) with statistical power values over 0.81.

NIC values were consistent across institutions. Abdominal obesity, smoking, alcohol consumption, and diabetes are independent factors influencing pancreatic iodine uptake.

This study has provided reference normative values, influential factors and effective normalisation methods of pancreatic iodine uptake in multiphase dual-energy CT for future studies in this area as a new biological marker.

Evaluation of pancreatic iodine uptake measured by dual-energy CT is a promising method for future studies. Abdominal obesity, smoking, alcohol consumption, diabetes, and sex are independent factors influencing pancreatic iodine uptake. Utility of normalised iodine concentration is necessary to ensure the consistency across different institutions.

Metabolic-dysfunction-associated fatty liver disease (MAFLD) and serum uric acid are closely related to cardiovascular and cerebrovascular diseases. However, the causal association between MAFLD and serum uric acid remains unclear. A total of 3417 patients without hyperuricemia were included in the final analysis. MAFLD was defined as fatty liver index (FLI) ≥ 30. Multivariate Cox regression analysis was used to explore the association between FLI and new-onset hyperuricemia. Restricted cubic splines and threshold saturation effect analysis were used to detect nonlinear associations. The mean age was 62.8 ± 8.3 year, and 68.5% were women. A total of 738 (21.6%) hypertensive patients developed new-onset hyperuricemia, 388 (11.4%) new-onset hyperuricemia10 and 190 (5.6%) new-onset hyperuricemia20 during the 4-year midday follow-up period. In the fully adjusted model, compared with the Q1 (FLI ≤ 8.5) group, the risk of hyperuricemia increased by 56% (HR: 1.56; 95% CI: 1.02, 2.38) in the Q4 (FLI > 39.4) group, new-onset hyperuricemia10 increased by 108% (HR: 2.08; 95% CI: 1.15, 3.78), and new-onset hyperuricemia20 increased by 156% (HR: 2.56; 95% CI: 1.11, 5.94), respectively. Saturation effects showed a nonlinear association between FLI and new-onset hyperuricemia (p for log likelihood ratio test < 0.05). Subgroup analysis and stratified analysis showed that there had a significantly higher risk of new-onset hyperuricemia in the patients with normal body mass index (< 24 kg/m2) (p for interaction: 0.018) and non-central obesity (p for interaction: 0.024). MAFLD is an independent risk factor for hyperuricemia in hypertensive patients, especially in patients with normal body mass index and non-central obesity.

The global burden of metabolic dysfunction-associated steatotic liver disease (MASLD) is growing, but its subsequent health consequences have not been thoroughly examined.

A phenome-wide association study was conducted to map the associations of MASLD with 948 unique clinical outcomes among 361,021 Europeans in the UK Biobank. Disease trajectory and comorbidity analyses were applied to visualize the sequential patterns of multiple comorbidities related to the occurrence of MASLD. The associations jointly verified by observational and polygenic phenome-wide analyses were further replicated by two-sample Mendelian randomization analysis using data from the FinnGen study and international consortia.

The observational and polygenic phenome-wide association study revealed the associations of MASLD with 96 intrahepatic and extrahepatic diseases, including circulatory, metabolic, genitourinary, neurological, gastrointestinal, and hematologic diseases. Sequential patterns of MASLD-related extrahepatic comorbidities were primarily found in circulatory, metabolic, and inflammatory diseases. Mendelian randomization analyses supported the causal associations between MASLD and the risk of several intrahepatic disorders, metabolic diseases, cardio-cerebrovascular disease, and ascites but found no associations with neurological diseases.

This study elucidated multisystem comorbidities and health consequences of MASLD, contributing to the development of combination interventions targeting distinct pathways for health promotion among patients with MASLD.

X.L. was funded by the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001) and the National Nature Science Foundation of China (82204019) and Y.D. was funded by the Key Project of Traditional Chinese Medicine Science and Technology Plan of Zhejiang Province (GZY-ZJ-KJ-24077) and the National Natural Science Foundation of China (82001673 and 82272860).

Liver fibrosis (LF) is a common complication of diabetes mellitus (DM). Studies have found that vitamin D (VD), as a modifiable factor has been reported to be associated with LF. The relationship between serum VD concentration and LF in DM patients has rarely been reported. The aim of this study was to assess the association between serum VD concentration and LF in DM patients.

In this cross-sectional study, data of DM patients aged ≥ 45 years were extracted from the National Health and Nutrition Examination Survey (NHANES 2017-2018). Serum VD concentration was measured by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Vibration controlled transient elastography (VCTE) was used to measure liver stiffness. Covariates included sociodemographic information, lifestyles, laboratory data, diseases history were extracted from the database. The weighted univariable and multivariable logistic regression models were utilized to explore the association between serum VD concentration and LF in DM patients, and were described as odds ratio (ORs) and 95% confidence intervals (CIs). Subgroup analyses based on BMI, liver steatosis, hypertension and dyslipidemia were further assessed the association.

A total of 799 patients were included, of which 188 (23.53%) had LF. Higher serum VD concentration was associated with the lower odds of LF (OR = 0.33, 95% CI 0.19-0.59) and advanced LF (OR = 0.31, 95% CI 0.17-0.55) in DM patients after adjustment for race, liver steatosis, BMI, smoking, drinking, AST, ALT and physical activity, especially in patients with liver steatosis (OR = 0.28, 95% CI 0.13-0.59) and dyslipidemia (OR = 0.31, 95% CI 0.14-0.66), respectively.

High serum VD concentration may have a potential benefit for maintain the liver health in DM patients.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide. If left untreated, MASLD can progress from simple hepatic steatosis to metabolic dysfunction-associated steatohepatitis, which is characterized by inflammation and fibrosis. Current treatment options for MASLD remain limited, leaving substantial unmet medical needs for innovative therapeutic approaches. Here, we show that PLIN2, a lipid droplet protein inhibiting hepatic lipolysis, serves as a promising therapeutic target for MASLD. Hepatic PLIN2 levels were markedly elevated in multiple MASLD mouse models induced by diverse nutritional and genetic factors. The liver-specific deletion of Plin2 exhibited significant anti-MASLD effects in these models. To translate this discovery into a therapeutic application, we developed a GalNAc-siRNA conjugate with enhanced stabilization chemistry and validated its potent and sustained efficacy in suppressing Plin2 expression in mouse livers. This siRNA therapeutic, named GalNAc-siPlin2, was shown to be biosafe in mice. Treatment with GalNAc-siPlin2 for 6-8 weeks led to a decrease in hepatic triglyceride levels by approximately 60% in high-fat diet- and obesity-induced MASLD mouse models, accompanied with increased hepatic secretion of VLDL-triglyceride and enhanced thermogenesis in brown adipose tissues. Eight-week treatment with GalNAc-siPlin2 significantly improved hepatic steatosis, inflammation, and fibrosis in high-fat/high fructose-induced metabolic dysfunction-associated steatohepatitis models compared to control group. As a proof of concept, we developed a GalNAc-siRNA therapeutic targeting human PLIN2, which effectively suppressed hepatic PLIN2 expression and ameliorated MASLD in humanized PLIN2 knockin mice. Together, our results highlight the potential of GalNAc-siPLIN2 as a candidate MASLD therapeutic for clinical trials.

Background Obesity is a global healthcare problem, and nonalcoholic fatty liver disease (NAFLD) is a commonly observed comorbid disease in the bariatric population. This study evaluated the relationship between NAFLD and various risk factors, including demographic, biochemical, and comorbid conditions in patients undergoing laparoscopic sleeve gastrectomy (LSG). Material and methods This retrospective data analysis study included patients who underwent LSG between August 2023 and 2024. Patient demographic data were collected, such as age, gender, weight, and body mass index (BMI), and NAFLD grade was determined by ultrasonography. Biochemical markers were recorded, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol, triglyceride (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), fasting blood glucose (FBG), HbA1c, and vitamin D. The presence of type II diabetes mellitus (T2DM) and hypertension (HT) was evaluated and compared with the grade of hepatosteatosis. Results The study included 436 patients, of whom 73.6% (n = 321) were female. The mean age was 37.23 ± 10.49 years, and the mean BMI value was 41.25 ± 6.11 kg/m2. Patients were classified and compared according to their NAFLD grade, revealing statistically significant differences in weight, BMI, ALT, AST, HDL, LDL, TG, total cholesterol, HbA1c, FBG, vitamin D, obesity class, DM, and HT (p < 0.05). HDL and vitamin D showed an inverse correlation with NAFLD. We observed no significant difference in the relationship of NAFLD with age and the presence of gallstone. Logistic regression analysis revealed that ALT, AST, LDL, total cholesterol, and FBG were statistically significantly associated with NAFLD in the multivariate model. Conclusion Hepatosteatosis, T2DM, and HT are frequent comorbid diseases that are common in bariatric patients. Our study shows that ALT, AST, LDL, FBG, and total cholesterol may be used as predictors of NAFLD.

2,4-dinitroaniline (2,4-D), a widely used dye intermediate, is one of the typical pollutants, and its potential health risks and toxicity are still largely unknown. To explore its subchronic oral toxicity, Wistar rats (equal numbers of males and females) were used as test animals, and a 90-day oral dosing experiment was conducted, divided into control group, low-dose group (0.055 mg/kg), medium-dose group (0.22 mg/kg), medium-high dose group (0.89 mg/kg), and high-dose group (3.56 mg/kg). The body weight data, clinical appearance, and drug reactions of each test rat within 90 days of dosing were recorded; morning urine samples were collected four times to test for eight urinary indicators; blood samples were collected to test for nineteen hematological indicators and sixteen biochemical indicators; tissue samples were collected for pathological analysis; moreover, the no-observed-adverse-effect level (NOAEL) was determined, and the benchmark dose method was used to support this determination and provide a statistical estimate of the dose corresponding. The results indicated that the chronic toxicity of 2,4-dinitroaniline showed certain gender differences, with the eyes, liver, and kidneys being the main potential target organs of toxicity. Moreover, the subchronic oral NOAEL for 2,4-dinitroaniline was determined to be 0.22 mg/kg body weight (0.22 mg/kg for males and 0.89 mg/kg for females), and a preliminary calculation of the safe exposure limit for human was 0.136 mg/kg. The research results greatly enriched the safety evaluation data of 2,4-dinitroaniline, contributing to a robust scientific foundation for the development of informed safety regulations and public health precautions.

Observational studies have reported significant association between non-alcoholic fatty liver disease (NAFLD) and bone mineral density (BMD), a critical indicator of bone health. We aimed to investigate whether NAFLD is a cause for changes in BMD.

We selected 29 independent SNPs as instrumental variables for NAFLD. A range of Mendelian randomization (MR) methods, namely the inverse variance-weighted (IVW) method, weighted-median, weighted-mode, and MR-Egger regression, were utilized to determine the causal effects of NAFLD on BMD. Two-step MR analysis was conducted to determine the mediating effect of fasting glucose, insulin, glycosylated hemoglobin, low-density cholesterol, and body-mass index on the association between NAFLD and BMD. False-discovery-rate (FDR) was used to correct for multiple testing bias.

The IVW-method indicated a significantly inverse association between genetically predicted NAFLD and total body BMD (β = -0.04, 95 % CI -0.07 to -0.02, FDR = 0.010). Notably, the relationship was more pronounced in participants over 60 years of age (β = -0.06, 95 % CI -0.11 to -0.02, FDR = 0.030). Inverse associations were observed in other subpopulations and in site-specific BMD, though they were not statistically significant after correcting for multiple testing. We observed a significantly positive association between NAFLD and the risk of osteoporosis. Consistency in results was observed across multiple MR methods and in the repeated analysis. Fasting glucose, insulin, and glycosylated hemoglobin mediated 25.4 % (95 % CI 17.6-31.5 %), 18.9 % (12.0-24.9 %), and 27.9 % (19.9-36.7 %) of the effect of NAFLD on BMD, respectively.

Our findings underscore a probable causal negative link between NAFLD and BMD, indicating that NAFLD might detrimentally affect bone health, especially in older individuals.

This study explored the mediating effect of diabetes on the relationship between nonalcoholic fatty liver disease (NAFLD) and atherosclerotic cardiovascular disease (ASCVD).

In this prospective community cohort study, 82 975 participants were enrolled, with the primary outcome being the incidence of new-onset ASCVD. Using the Cox proportional hazards model, the hazard ratio (HR) and 95% confidence interval (CI) for ASCVD occurrence were computed between NAFLD and non-NAFLD groups. The correlation between NAFLD and diabetes was assessed using a binary logistic regression model, and that between NAFLD, diabetes and ASCVD using a mediation model.

During follow-up, 9471 ASCVD cases were observed. Compared with individuals without NAFLD, those with NAFLD showed an increased ASCVD risk (HR: 1.424; 95% CI: 1.363-1.488; P < 0.001). Stratifying NAFLD based on metabolic subphenotypes revealed a higher ASCVD risk in the NAFLD combined with diabetes subgroup than in the non-NAFLD subgroup (HR: 1.960; 95% CI: 1.817-2.115; P < 0.001). NAFLD was positively associated with baseline diabetes (odds ratio: 2.983; 95% CI: 2.813-3.163; P < 0.001). Furthermore, NAFLD severity was positively correlated with diabetes risk. Mediation analysis indicated that diabetes partially mediated the effect of NAFLD on ASCVD incidence, accounting for 20.33% of the total effect.

NAFLD is an independent predictor of increased ASCVD risk, which may be slightly mediated by diabetes in patients with NAFLD. Evaluating NAFLD and diabetes may be crucial in the early screening and prevention of ASCVD.

Observational studies have associated nonalcoholic fatty liver disease (NAFLD) with adverse pregnancy events, but findings show heterogeneity, leaving the causal direction and mediating pathways unclear. We aimed to investigate the causal relation between NAFLD and various pregnancy events, and to elucidate the underlying mediating pathways while determining the proportion of this correlation that is mediated through these pathways.

A genome-wide association study involving over 6 million participants employing Mendelian randomization (MR) and mediation analysis was performed. The study used genetically predicted NAFLD as exposures and cardiometabolic traits as mediators, with various adverse pregnancy events as outcomes. The main analysis was performed using the inverse variance weighted (IVW) approach, while sensitivity analyses included the weighted median, weighted mode, MR-Egger, and MR-PRESSO methods. Mediation analyses were performed using a two-step MR framework.

In this MR cohort study, NAFLD was found to be strongly associated with elevated risks of GDM (P = 0.019 for the discovery dataset, P < 0.001 for the discovery dataset) and HDPs, including any HDP (P < 0.001 for the both datasets), gestational hypertension (P = 0.007 for the discovery dataset, P < 0.001 for the discovery dataset), and pre-eclampsia or eclampsia (P = 0.040 for the discovery dataset, P < 0.001 for the discovery dataset). However, no significant associations were found with hemorrhage in early pregnancy, postpartum hemorrhage, preterm birth, or offspring birthweight for both datasets. Cardiometabolic traits played a significant mediating role in these associations, rather than solely acting as confounding factors.

This study provided evidence supporting a correlation between NAFLD and a higher risk of adverse pregnancy events and introduces some new insights. These findings may inform preventions and interventions for remediating adverse pregnancy outcomes attributable to NAFLD.

Type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) are prevalent metabolic disorders with overlapping pathophysiological mechanisms. A comprehensive understanding of the shared molecular pathways involved in these conditions can advance the development of effective therapeutic interventions.

We used two datasets sourced from the Gene Expression Omnibus (GEO) database to identify common differentially expressed genes (DEGs) between T2D and NAFLD. Subsequently, we conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses to identify the enriched biological processes and signaling pathways. In addition, we performed a protein-protein interaction (PPI) network analysis to identify hub genes with pivotal roles. To validate our findings, we established a type 2 diabetic mouse model with NAFLD.

Our analysis identified 53 DEGs shared between T2D and NAFLD. Enrichment analysis revealed their involvement in signal transduction, transcriptional regulation, and cell proliferation as well as in the ferroptosis signaling pathways. PPI network analysis identified ten hub genes, namely CD44, CASP3, FYN, KLF4, HNRNPM, HNRNPU, FUBP1, RUNX1, NOTCH3, and ANXA2. We validated the differential expression of FYN, HNRNPU, and FUBP1 in liver tissues of a type 2 diabetic mouse model with NAFLD.

Our study offers valuable insights into the shared molecular mechanisms underlying T2D and NAFLD. The identified hub genes and pathways present promising prospects as therapeutic targets to address these prevalent metabolic disorders.

It is unclear to what extent lifestyle and genetic factors affect the incidence of chronic liver disease (CLD) in the general population and if lifestyle affects CLD independently of underlying cardiometabolic perturbations and genetic predisposition.

We examined 27,991 men and women aged 44-73 years from the Malmö Diet and Cancer Study recruited between 1991-1996 and followed until the end of 2020 using registry linkage (median follow-up time 25.1 years; 382 incident first-time CLD events). Associations between cardiometabolic factors, polygenic risk scores (PRSs), and lifestyle factors in relation to CLD were examined using multivariable Cox proportional hazards regression models.

The incidence of CLD increased with number of cardiometabolic risk factors (the hazard ratio per each additional cardiometabolic risk factor was 1.33; 95% CI 1.21-1.45; p = 5.1 x 10-10). Two novel PRSs for metabolic dysfunction-associated steatotic liver disease and a PRS for cirrhosis were associated with higher risk of CLD but provided marginal predictive utility on top of other risk factors and compared to the PNPLA3 rs738409 genetic variant. An unhealthy lifestyle (high alcohol intake, current smoking, physical inactivity and unhealthy diet) markedly increased the risk of CLD (hazard ratio 3.97, 95% CI 2.59-6.10). Observed associations between examined lifestyle factors and CLD were largely independent of cardiometabolic perturbations and polygenic risk.

We confirmed the importance of cardiometabolic dysfunction in relation to risk of CLD in the general population. Lifestyle risk factors were shown to be independently associated with CLD and added predictive information on top of cardiometabolic risk factors. Information on the polygenic risk of liver disease does not currently improve the prediction of CLD in the general population.

This large population-based prospective study suggests largely independent roles of cardiometabolic, lifestyle, and genetic risk factors in the development of chronic liver disease. Findings strengthen the evidence base for a beneficial effect of modification of high-risk lifestyle behaviors in the primary prevention of chronic liver disease in the general population.

The prevalence of metabolic-associated steatotic liver disease (MASLD) is rising precipitously among children, particularly in regions or countries burdened with high prevalence of obesity. However, identifying those at high risk remains a significant challenge, as the majority do not exhibit distinct symptoms of MASLD. There is an urgent need for a widely accepted non-invasive predictor to facilitate early disease diagnosis and management of the disease. Our study aims to 1) evaluate and compare existing predictors of MASLD, and 2) develop a practical screening strategy for children, tailored to local prevalence of obesity.

We utilized a school-based cross-sectional survey in Beijing as the training dataset to establish predictive models for screening MASLD in children. An independent school-based study in Ningbo was used to validate the models. We selected the optimal non-invasive MASLD predictor by comparing logistic regression model, random forest model, decision tree model, and support vector machine model using both the Beijing and Ningbo datasets. This was followed by serial testing using the best performance index we identified and indices from previous studies. Finally, we calculated the potential MASLD screening recommendation categories and corresponding profits based on national and subnational obesity prevalence, and applied those three categories to 200 countries according to their obesity prevalence from 1990 to 2022.

A total of 1018 children were included (NBeijing = 596, NNingbo = 422). The logistic regression model demonstrated the best performance, identifying the waist-to-height ratio (WHtR, cutoff value ≥0.48) as the optimal noninvasive index for predicting MASLD, with strong performance in both training and validation set. Additionally, the combination of WHtR and lipid accumulation product (LAP) was selected as an optimal serial test to improve the positive predictive value, with a LAP cutoff value of ≥668.22 cm × mg/dL. Based on the obesity prevalence among 30 provinces, three MASLD screening recommendations were proposed: 1) "Population-screening-recommended": For regions with an obesity prevalence ≥12.0%, where MASLD prevalence ranged from 5.0% to 21.5%; 2) "Resources-permitted": For regions with an obesity prevalence between 8.4% and 12.0%, where MASLD prevalence ranged from 2.3% to 4.4%; 3) "Population-screening-not-recommended": For regions with an obesity prevalence <8.4%, where MASLD prevalence is difficult to detect using our tool. Using our proposed cutoff for screening MASLD, the number of countries classified into the "Population-screening-recommended" and "Resources-permitted" categories increased from one and 11 in 1990 to 95 and 28 in 2022, respectively.

WHtR might serve as a practical and accessible index for predicting pediatric MASLD. A WHtR value ≥0.48 could facilitate early identification and management of MASLD in areas with obesity prevalence ≥12.0%. Furthermore, combining WHtR ≥0.48 with LAP ≥668.22 cm × mg/dL is recommended for individual MASLD screening. Moreover, linking these measures with population obesity prevalence not only helps estimate MASLD prevalence but also indicates potential screening profits in regions at varying levels of obesity risk.

This study was supported by grants from Capital's Funds for Health Improvement and Research (Grant No. 2022-1G-4251), National Natural Science Foundation of China (Grant No. 82273654), Major Science and Technology Projects for Health of Zhejiang Province (Grant No. WKJ-ZJ-2216), Cyrus Tang Foundation for Young Scholar 2022 (2022-B126) and Sino-German Mobility Programme (M-0015).

Abdominal obesity increases the risk for non-alcoholic fatty liver disease (NAFLD), now known as metabolic dysfunction-associated steatotic liver disease (MASLD).

To elucidate the directional cell-type level biological mechanisms underlying the association between abdominal obesity and MASLD, we integrated adipose and liver single nucleus RNA-sequencing and bulk cis-expression quantitative trait locus (eQTL) data with the UK Biobank genome-wide association study (GWAS) data using colocalization. Then we used colocalized cis-eQTL variants as instrumental variables in Mendelian randomization (MR) analyses, followed by functional validation experiments on the target genes of the cis-eQTL variants.

We identified 17 colocalized abdominal obesity GWAS variants, regulating 17 adipose cell-type marker genes. Incorporating these 17 variants into MR discovers a putative tissue-of-origin, cell-type-aware causal effect of abdominal obesity on MASLD consistently with multiple MR methods without significant evidence for pleiotropy or heterogeneity. Single cell data confirm the adipocyte-enriched mean expression of the 17 genes. Our cellular experiments across human adipogenesis identify risk variant -specific epigenetic and transcriptional mechanisms. Knocking down two of the 17 genes, PPP2R5A and SH3PXD2B, shows a marked decrease in adipocyte lipidation and significantly alters adipocyte function and adipogenesis regulator genes, including DGAT2, LPL, ADIPOQ, PPARG, and SREBF1. Furthermore, the 17 genes capture a characteristic MASLD expression signature in subcutaneous adipose tissue.

Overall, we discover a significant cell-type level effect of abdominal obesity on MASLD and trace its biological effect to adipogenesis.

NIH grants R01HG010505, R01DK132775, and R01HL170604; the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (Grant No. 802825), Academy of Finland (Grants Nos. 333021), the Finnish Foundation for Cardiovascular Research the Sigrid Jusélius Foundation and the Jane and Aatos Erkko Foundation; American Association for the Study of Liver Diseases (AASLD) Advanced Transplant Hepatology award and NIH/NIDDK (P30DK41301) Pilot and Feasibility award; NIH/NIEHS F32 award (F32ES034668); Finnish Diabetes Research Foundation, Kuopio University Hospital Project grant (EVO/VTR grants 2005-2021), the Academy of Finland grant (Contract no. 138006); Academy of Finland (Grant Nos 335443, 314383, 272376 and 266286), Sigrid Jusélius Foundation, Finnish Medical Foundation, Finnish Diabetes Research Foundation, Novo Nordisk Foundation (#NNF20OC0060547, NNF17OC0027232, NNF10OC1013354) and Government Research Funds to Helsinki University Hospital; Orion Research Foundation, Maud Kuistila Foundation, Finish Medical Foundation, and University of Helsinki.

The link between nonalcoholic fatty liver disease and type 2 diabetes has not been fully established. We investigated the temporal relationship between nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D), quantitatively assessed the impact, and evaluated the related mediation effect.

This study involved participants from the China Multi-Ethnic Cohort Study and the UK Biobank. We performed cross-lagged path analysis to compare the relative magnitude of the effects between NAFLD and T2D using two-period biochemical data. Hepatic steatosis and fasting blood glucose elevation (FBG) represented NAFLD and T2D respectively. We fitted two separate Cox proportional-hazards models to evaluate the influence of hepatic steatosis on T2D. Furthermore, we applied the difference method to assess mediation effects.

In cross-lagged path analyses, the path coefficients from baseline hepatic steatosis to first repeat FBG (βCMEC = 0.068, βUK-Biobank = 0.033) were significantly greater than the path coefficients from baseline FBG to first repeat hepatic steatosis (βCMEC = 0.027, βUK-Biobank = -0.01). Individuals with hepatic steatosis have a risk of T2D that is roughly three times higher than those without the condition (HR = 3.478 [3.314, 3.650]). Hepatic steatosis mediated approximately 69.514% of the total effect between obesity and follow-up T2D.

Our findings contribute to determining the sequential relationship between NAFLD and T2D in the causal pathway, highlighting that the dominant pathway in the relationship between these two early stages of diseases was the one from hepatic steatosis to fasting blood glucose elevation. Individuals having NAFLD face a significantly increased risk of T2D and require long-term monitoring of their glucose status as well.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is highly prevalent in people with obesity. We aimed to study the association of body mass index (BMI) with clinical outcomes in patients with MASLD.

A retrospective cohort of 32,900 patients with MASLD, identified through the International Classification of Diseases-9 and 10 codes within the electronic health records of a large US-based health system, with a mean follow-up of 5.5 years (range: 1-15 y), was stratified into 6 BMI categories, <25, 25-<30, 30-<40, 40-<50, and ≥50 kg/m2.

The risk of liver decompensation and extrahepatic obesity-associated cancers had a J-shaped profile (both ps for linear and quadratic terms <0.05). Compared to patients with BMI 25-<30 kg/m2, the adjusted HRs (95% CIs) for liver decompensation of patients with BMI <25 and BMI ≥50 kg/m2 were 1.44 (1.17-1.77) and 2.27 (1.66-3.00), respectively. The corresponding figures for obesity-associated extrahepatic cancer were 1.15 (0.97-1.36) and 1.29 (1.00-1.76). There was an inverse association for BMI with liver transplantation and non-obesity-associated cancer (both ps for linear terms <0.05), but no association with HCC or all types of cancers combined. A similar J-shaped association between BMI and all-cause mortality was observed; adjusted HRs (95% CIs) for BMI <25 and ≥50 kg/m2 were 1.51 (1.32-1.72) and 3.24 (2.67-3.83), respectively, compared with BMI 25-<30 kg/m2 (both ps for linear and quadratic terms <0.001).

Patients with MASLD and very severe obesity (BMI ≥50 kg/m2) had the highest risk, exceeding that of patients with lean MASLD, for developing liver decompensation, obesity-associated extrahepatic cancers, or dying from any cause.

Associations between metabolic risk factors and lung cancer remain elusive, and evidence on the linkage between non-alcoholic fatty liver disease (NAFLD) and pulmonary nodules is limited. This study sought to examine the independent association between NAFLD and the risk of pulmonary nodules.

Cross-sectional analyses of 1,119 patients with intestinal polyps hospitalized at the Department of Gastroenterology, Minhang District Central Hospital of Shanghai, China, were conducted. NAFLD was diagnosed based on hepatic ultrasonography or computed tomography (CT) findings of hepatic steatosis, with exclusion criteria ensuring patients had no history of significant alcohol consumption, viral infections, or hepatic autoimmune diseases. The currently accepted definition of a pulmonary nodule is a solid or sub-solid shadow ≤3 cm in diameter that appears as a solid or semi-solid pattern on a chest CT scan (our specific treatment is pulmonary nodule size: 5 mm to 3 cm). Adjusted 95% confidence intervals (CIs) and odds ratios (ORs) for NAFLD and the clinical features connected with pulmonary nodule risk were determined using a multivariable logistic regression analysis.

Among the 979 intestinal polyp patients, the prevalence rates of NAFLD and pulmonary nodules were 25.9% and 32.8%, respectively. Patients with pulmonary nodules exhibited higher rates of NAFLD (31.5% vs. 23.3%, P=0.006) and obesity (41.4% vs. 32.5%, P=0.006) compared to those without pulmonary nodules. After removing all the possible confounding variables, the adjusted ORs for NAFLD, an older age, smoking, and obesity were 1.370 (95% CI: 1.006-1.867, P=0.04), 1.022 (95% CI: 1.010-1.033), 1.599 (95% CI: 1.033-2.475), and 1.410 (95% CI: 1.057-1.880), respectively (all P values <0.05). NAFLD showed a significant association with an increased risk of pulmonary nodules.

NAFLD was independently linked to an increased incidence of pulmonary nodules in intestinal polyp patients, which emphasizes the importance of screening and managing these conditions in lung cancer prevention.

Previous studies, including Mendelian randomization (MR), have demonstrated type 2 diabetes (T2D) and glycemic traits are associated with increased risk of metabolic dysfunction-associated steatotic liver disease (MASLD). However, few studies have explored the underlying pathway, such as the role of iron homeostasis.

We used a two-step MR approach to investigate the associations of genetic liability to T2D, glycemic traits, iron biomarkers, and liver diseases. We analyzed summary statistics from various genome-wide association studies of T2D (n = 933,970), glycemic traits (n ≤ 209,605), iron biomarkers (n ≤ 246,139), MASLD (n ≤ 972,707), and related biomarkers (alanine aminotransferase (ALT) and proton density fat fraction (PDFF)). Our primary analysis was based on inverse-variance weighting, followed by several sensitivity analyses. We also conducted mediation analyses and explored the role of liver iron in post hoc analysis.

Genetic liability to T2D and elevated fasting insulin (FI) likely increased risk of liver steatosis (ORliability to T2D: 1.14 per doubling in the prevalence, 95% CI: 1.10, 1.19; ORFI: 3.31 per log pmol/l, 95% CI: 1.92, 5.72) and related biomarkers. Liability to T2D also likely increased the risk of developing liver cirrhosis. Genetically elevated ferritin, serum iron, and liver iron were associated with higher risk of liver steatosis (ORferritin: 1.25 per SD, 95% CI 1.07, 1.46; ORliver iron: 1.15 per SD, 95% CI: 1.05, 1.26) and liver cirrhosis (ORserum iron: 1.31, 95% CI: 1.06, 1.63; ORliver iron: 1.34, 95% CI: 1.07, 1.68). Ferritin partially mediated the association between FI and liver steatosis (proportion mediated: 7%, 95% CI: 2-12%).

Our study provides credible evidence on the causal role of T2D and elevated insulin in liver steatosis and cirrhosis risk and indicates ferritin may play a mediating role in this association.

Plant-based diet (PDI) as resource of antioxidants and anti-inflammatory phytochemicals, that was considered to protect against onset and development of Non-alcoholic fatty liver disease (NAFLD).

To investigate the association between plant-based diet and NAFLD in adults.

The present case control study was conducted on 240 individuals (120 with NAFLD and 120 control) aged 20-69 years. Provided recommendations by the American College of Gastroenterology and the American Gastroenterological Association were used for NAFLD diagnosis. Dietary intake was assessed using 178-food item food frequency questionnaire (FFQ). Also, plant-based diet score was evaluated based on 18 food groups classified into animal foods, healthy and unhealthy plant foods. A multiple logistic regression model was used to examine the relationship between fatty liver disease and tertiles of PDI.

The results of this study showed that we did not observe any association between tertiles of PDI and NAFLD in crude model (OR: 1.29, 95%CI:0.66-2.52, P:0.44) and after adjustment for confounders including age, energy intake, physical activity, body mass index (OR:0.76, 95%CI: 0.31-1.86, P:0.52). Also, there were not any association of tertiles of healthy PDI (hPDI) (OR:1.14, 95%CI: 0.50-2.60, P:0.74) and unhealthy PDI (uhPDI) (OR:0.89, 95%CI:0.36-2.18, P: 0.79) with NAFLD after full adjustment for potential confounders.

There was not any association of PDI, hPDI, and uPDI with NAFLD in adults. More research needs to examine whether this specific diet may impact and improve NAFLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become one of the most prevalent liver diseases worldwide, and its occurrence is strongly associated with obesity, insulin resistance (IR), genetics, and metabolic stress. Ranging from simple fatty liver to metabolic dysfunction-associated steatohepatitis (MASH), even to severe complications such as liver fibrosis and advanced cirrhosis or hepatocellular carcinoma, the underlying mechanisms of MASLD progression are complex and involve multiple cellular mediators and related signaling pathways. Pattern recognition receptors (PRRs) from the innate immune system, including Toll-like receptors (TLRs), C-type lectin receptors (CLRs), NOD-like receptors (NLRs), RIG-like receptors (RLRs), and DNA receptors, have been demonstrated to potentially contribute to the pathogenesis for MASLD. Their signaling pathways can induce inflammation, mediate oxidative stress, and affect the gut microbiota balance, ultimately resulting in hepatic steatosis, inflammatory injury and fibrosis. Here we review the available literature regarding the involvement of PRR-associated signals in the pathogenic and clinical features of MASLD, in vitro and in animal models of MASLD. We also discuss the emerging targets from PRRs for drug developments that involved agent therapies intended to arrest or reverse disease progression, thus enabling the refinement of therapeutic targets that can accelerate drug development.

The interaction between endoplasmic reticulum (ER) and mitochondria has been shown to play a key role in hepatic steatosis during chronic obesity. β-nicotinamide mononucleotide (NMN) has been reported to regulate obesity, however, its molecular mechanism at the subcellular level remains unclear. Here, NMN improved liver steatosis and insulin resistance in chronic high-fat diet (HFD) mice. RNA-seq showed that compared with the liver of HFD mice, NMN intervention enhanced fat digestion and absorption and stimulated the cholesterol metabolism signaling pathways, while impaired insulin resistance and the fatty acid biosynthesis signaling pathways. Mechanistically, NMN ameliorated mitochondrial dysfunction and ER oxidative stress in the liver of HFD mice by increasing hepatic nicotinamide adenine dinucleotide (NAD+) (P < 0.01) levels. This effect increased the contact sites (mitochondria-associated membranes [MAMs]) between ER and mitochondria, thereby promoting intracellular ATP (P < 0.05) production and mitigating lipid metabolic disturbances in the liver of HFD mice. Taken together, this study provided a theoretical basis for restoring metabolic dynamic equilibrium in the liver of HFD mice by increasing MAMs via the nutritional strategy of NMN supplementation.