Association of systemic immune biomarkers with metabolic dysfunction-associated steatotic liver disease: a cross-sectional study of NHANES 2007-2018.

Objective: Numerous studies emphasize the pivotal role of inflammation in metabolic dysfunction-associated steatotic liver disease (MASLD) development. Some link specific systemic immune biomarkers (e.g., systemic immuno-inflammatory index [SII], neutrophil-to-albumin ratio [NPAR] and neutrophil-to-lymphocyte ratio [NLR]) to hepatic steatosis risk. However, the relevance of other markers like systemic immune-inflammation index [SIRI], platelet-to-lymphocyte ratio [PLR] and lymphocyte/monocyte ratio [LMR] in MASLD remains unclear. Limited literature covers all six markers together. This study aims to investigate the association between SII, SIRI, LMR, NLR, PLR, and NPAR and MASLD, assessing their predictive value. Methods: In this cross-sectional analysis of adults from NHANES (2007-2018), we investigated the relationship between six systemic immune biomarkers, stratified by quartiles: quartile1 (Q1), quartile2 (Q2), quartile3 (Q3) and quartile4 (Q4), and the outcome of MASLD assessed by Fatty Liver Index (FLI) and United States Fatty Liver Index (USFLI). Logistic regression and restricted cubic splines (RCS) were employed to assess the association between systemic immune biomarkers and MASLD risks. Propensity score matching controlled for potential confounders, and receiver operating characteristic (ROC) curve analysis evaluated the biomarkers' predictive performances for MASLD. Subgroup and interaction analysis were conducted to explore the effects of systemic immune biomarkers on MASLD risks. Multicollinearity was quantified using the variance inflation factor. Results: In total, 14,413 participants were included and 6,518 had MASLD. Compared with non-MASLD, participants with MASLD had higher SII, SIRI, NLR, PLR, and NPAR (p < 0.001). SII, SIRI, NLR, and NPAR were further validated in the restricted cubic splines (RCS) regression model and identified as positive linear relationships (p for nonlinear >0.05). The prevalence of MASLD increased with the Q4 of SII [OR = 1.47, 95%CI (1.24, 1.74)], SIRI [OR = 1.30, 95%CI (1.09, 1.54)], NLR [OR = 1.25, 95%CI (1.04, 1.49)], PLR [OR = 1.29, 95%CI (1.09, 1.53)] and NPAR [OR = 1.29, 95%CI (1.09, 1.54)] compared to the Q1 after adjusting for the bias caused by potential confounders. However, the propensity score matching analysis only supported an association between the highest SII, SIRI, NLR NPAR and the risk of MASLD. The results of the subgroup analysis showed considerable robustness in the relationship. Conclusion: Higher SII, SIRI, NLR and NPAR were positively associated with a heightened risk of MASLD. NPAR showed the superior predictive value, followed by SII, SIRI and NLR. This needs to be validated in additional longitudinal studies and clinical trials.

Ultraportable Quantitative Ultrasound for Hepatic Steatosis Assessment.

OBJECTIVE: This study aimed to evaluate the performances of quantitative ultrasound (QUS) for the detection and assessment of hepatic steatosis when implemented using an ultraportable ultrasound scanner. METHODS: Seven established QUS parameters were investigated. Ultrasound signals were acquired using a new ultraportable ultrasound device, the Hepatoscope. The feasibility of QUS using the Hepatoscope was first assessed in vitro. Clinical reliability, accuracy and staging capabilities were evaluated in 60 patients referred to a hepatology consultation for known chronic liver disease and enrolled in a prospective clinical investigation using the controlled attenuation parameter (CAP) as ground truth. RESULTS: QUS parameters showed moderate (intra-class correlation coefficient [ICC] >0.50) to excellent (ICC >0.90) reliability. Two parameters, namely Lizzi-Feleppa mid-band fit and attenuation, were both reliable (ICC = 0.89 and 0.86, respectively) and correlated with the CAP (squared Pearson correlation coefficient of R2 = 0.65 and R2 = 0.6, respectively). For steatosis detection (S0 vs. ≥S1), the two parameters yielded an area under the receiving operating characteristic curve of 0.90 and 0.86, respectively (95% confidence interval: [0.81-0.99] and [0.76-0.96], respectively). CONCLUSION: QUS can be reliably and accurately implemented on ultraportable ultrasound scanners. The combination of ultraportability and quantitative assessment of liver fat is promising for large-scale screening and monitoring of hepatic steatosis.

Improvement of MASLD and MASH by suppression of hepatic N-acetyltransferase 10.

OBJECTIVE: Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are characterized by excessive triglyceride accumulation in the liver. However, due to an incomplete understanding of its pathogenesis, more efforts are needed to identify specific and effective treatments. N4-acetylcytidine (ac4C) is a newly discovered RNA modification to regulate mRNA. N-acetyltransferase 10 (NAT10) has not been fully explored in MASLD and MASH. METHODS: The clinical relevance of NAT10 was evaluated based on its expression in various mouse and human models of MASLD and MASH. Acetylated RNA immunoprecipitation sequencing and mRNA stability assays were used to explore the role of NAT10 in regulating ac4C modification and expression of target genes. Genetically engineered mice were employed to investigate the role of NAT10 in MASLD and MASH progression. RESULTS: Hepatic NAT10 expression was significantly increased in multiple mice and humans of MASLD and MASH. Genetic knockout of NAT10 protected mice from diet-induced hepatic steatosis and steatohepatitis, whereas overexpression of NAT10 exacerbated high-fat-diet-induced liver steatosis. Mechanistically, NAT10 binds to Srebp-1c mRNA, promoting its stability and expression, thereby upregulating lipogenic enzymes. Treatment with Remodelin, a NAT10-specific inhibitor, effectively ameliorates liver steatosis and dyslipidemia in a preclinical mouse model. CONCLUSIONS: Our findings indicate that NAT10 could regulate lipid metabolism in MASLD and MASH by stabilizing Srebp-1c mRNA and upregulating lipogenic enzymes. This study highlights the role of NAT10 and RNA acetylation in the pathogenesis of MASLD and MASH. Thus, our findings suggest a promising new therapeutic approach, such as the use of NAT10 inhibitor, for treating metabolic liver disease.

Missed and Delayed Diagnoses of Chronic Liver Disease in Primary Care Patients with Cirrhosis.

BACKGROUND: Chronic liver diseases (CLD), cirrhosis, and hepatocellular carcinoma (HCC) cause significant morbidity and mortality. Unfortunately, patients with CLD often go undiagnosed until progression to cirrhosis and HCC. We aimed to determine the proportion of primary care patients with severe liver disease outcomes that had missed or delayed CLD diagnoses. METHODS: This retrospective cohort study evaluated primary care patients with a diagnosis of cirrhosis, HCC, or other severe liver disease outcome between 2012 and 2021. The outcomes of interest were missed and delayed diagnoses of CLD, defined as the absence of a CLD diagnosis (missed) or first appearance of CLD on the same day as the cirrhosis diagnosis (delayed). Univariate analyses were performed to describe the cohort. Multivariable logistic regression models analyzed the association of aminotransferase elevations with the outcomes of interest. RESULTS: Of 667 patients with cirrhosis or HCC, 133 (20%) had a missed CLD diagnosis, and 243 (36%) had a delayed CLD diagnosis. Alcohol-related liver disease was the most common etiology among patients with missed/delayed diagnoses. A lower proportion of patients with missed/delayed diagnoses had an elevation in ALT or AST compared to patients with timely diagnoses (61% vs. 77%, p < 0.001). Elevated aminotransferase values were associated with lower odds of a missed/delayed diagnosis (OR 0.47; 95%CI 0.34-0.66). CONCLUSIONS: Most patients with cirrhosis or HCC had missed or delayed diagnoses of CLD in the context of probable overreliance on aminotransferase elevation for CLD detection. Enhanced screening for high prevalence CLD, especially alcohol, in primary care is needed.

Links between fecal microplastics and parameters related to metabolic dysfunction-associated steatotic liver disease (MASLD) in humans: An exploratory study.

Microplastics (MPs) can persist in the environment and human body. Murine studies showed that exposure to MPs could cause metabolic dysregulation, contributing metabolic dysfunction-associated steatotic liver disease (MASLD) or steatohepatitis (MASH). However, research on the role of MPs in humans is limited. Thus, we aimed to assess links between human fecal MPs and liver histology, gene expression, immune cells and intestinal microbiota (IM). We included 6 lean healthy liver donors and 6 normal liver (obese) and 11 MASH patients. Overall, pre-BSx, we observed no significant differences in fecal MPs between groups. However, fecal MP fibers and total MPs positively correlated with portal and total macrophages and total killer T cells while total fecal MPs were positively correlated with natural killer cells. Additionally, 19 genes related to immune system and apoptosis correlated with fecal MPs at baseline. Fecal MP fibers correlated positively with fecal Bifidobacterium and negatively with Lachnospiraceae. Patients with MASH (n = 11) were re-assessed 12-months post-bariatric surgery (BSx) and we found that those with persistent disease (n = 4) had higher fecal MP fragments than those with normalized liver histology (n = 7). At 12-month post-BSx, MP fragments positively correlated with helper T cells and total MPs positively correlated with natural killer T cells and B cells. Our study is the first to look at 1) the role of MPs in MASH and its association with IM, immune cells and hepatic gene expression and 2) look at the role of MPs longitudinally in MASH persistence following BSx. Future research should further explore this relationship.

Targeting PYK2 with heterobifunctional T6BP helps mitigate MASLD and MASH-HCC progression.

BACKGROUND & AIMS: The mechanisms underlying the regulation of hepatocyte non-receptor tyrosine kinases in metabolic dysfunction-associated steatohepatitis (MASH) remain largely unclear. METHODS: Hepatocyte-specific overexpression or deletion and anti-protein tyrosine kinase 2 beta (PYK2) or anti-TRAF6-binding protein (T6BP) crosslinking were utilised to study fatty liver protection by T6BP. P-PTC, a peptide-proteolysis targeting chimaera, degrades PYK2 to block MASH progression. RESULTS: Since PYK2 activation is promoter signalling in steatohepatitis development, we find that T6BP is a novel and critical suppressor of PYK2 that reduces hepatic lipid accumulation, pro-inflammatory factor release, and pro-fibrosis production by ubiquitin ligase CBL to degrade PYK2. Mechanistic evidence suggests that T6BP directly targets PYK2 and prevents its N-terminal FERM domain-triggered dimerization, disrupting downstream PYK2-JNK signalling hyperactivation. Additionally, T6BP favourably recruits CBL, a particular E3 ubiquitin ligase targeting PYK2, to form a complex and degrade PYK2. T6BP (F1), a core fragment of T6BP, directly blocks N-terminal FERM domain-associated dimerization of PYK2, followed by T6BP-recruiting CBL-mediated PYK2 degradation in a typical T6BP-dependent manner when the tiny fragment is specifically expressed using thyroxine binding globulin (TBG)-ground vectors. This inhibits the progression of MASH, metabolic dysfunction-associated steatotic liver disease (MASLD)-related HCC (MASH-HCC), and metabolic syndrome in dietary rodent models. First-ever peptide-proteolysis targeting chimaera (P-PTC) based on the core segment of T6BP as a ligand for targeted recruitment of CBL targeting metabolic disorders like MASH has been devised and validated in animal models. CONCLUSIONS: Our study revealed a previously unknown mechanism: identification of T6BP as a key eliminator of fatty liver strongly contributes to the development of promising therapeutic targets, and the discovery of crucial fragments of T6BP-based pharmacon that interrupt PYK2 dimerization are novel and viable treatments for fatty liver and its advanced symptoms and complications. IMPACT AND IMPLICATIONS: Excessive high-energy diet ingestion is critical in driving steatohepatitis via regulation of hepatocyte non-receptor tyrosine kinases. The mechanisms under lying the regulation of hepatocyte PYK2 in metabolic dysfunction-associated steatohepatitis (MASH) remain largely unclear. Here, we found that T6BP as a critical fatty liver eliminator has a significant impact on the development of promising therapeutic targets. Additionally, vital T6BP-based pharmacon fragments that impede PYK2 dimerization have been found, offering new and effective treatments for advanced fatty liver symptoms and complications.

Sex-specific effects of PNPLA3 I148M.

Metabolic dysfunction-associated steatotic liver disease (MASLD, previously termed NAFLD, nonalcoholic fatty liver disease) is a complex multifactorial disease showing generally higher prevalence and severity in men than in women. With respect to women, men are also more prone to develop metabolic dysfunction-associated steatohepatitis, fibrosis and liver-related complications. Several genetic, hormonal, environmental and lifestyle factors may contribute to sex differences in MASLD development, progression and outcomes. However, after menopause, the sex-specific prevalence of MASLD shows an opposite trend between men and women, pointing to the relevance of oestrogen signalling in the sexual dimorphism of MASLD. The patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene, that encodes a triacylglycerol lipase that plays a crucial role in lipid metabolism, has emerged as a key player in the pathogenesis of MASLD, with the I148M variant being strongly associated with increased liver fat content and disease severity. Recent advances indicate that carrying the PNPLA3 I148M variant can be a risk factor for MASLD especially for women. To elucidate the molecular mechanisms underlying the sex-specific role of PNPLA3 I148M in the development of MASLD, several in vitro, ex vivo and in vivo models have been developed.

Association between MASLD and increased risk of serious bacterial infections requiring hospital admission: A meta-analysis.

BACKGROUND: Previous studies have reported an association between metabolic dysfunction-associated steatotic liver disease (MASLD) and the risk of serious bacterial infections. However, the magnitude of the risk and whether this risk varies with the severity of MASLD remains uncertain. We performed a meta-analysis of observational studies to quantify the association between MASLD and serious bacterial infections requiring hospital admission. METHODS: We systematically searched PubMed, Scopus, Web of Science and Embase from database inception to 1 April 2024, using predefined keywords to identify studies examining the risk of serious bacterial infections among individuals with and without MASLD. MASLD was diagnosed using liver biopsy, imaging or International Classification of Diseases codes. Meta-analysis was performed using random-effects modelling. RESULTS: We identified six cross-sectional and two prospective cohort studies with aggregate data on ~26.6 million individuals. MASLD was significantly associated with higher odds of serious bacterial infections (pooled random-effects odds ratio 1.93, 95% confidence interval [CI] 1.44-2.58; I2 = 93%). Meta-analysis of prospective cohort studies showed that MAFLD was associated with an increased risk of developing serious bacterial infections (pooled random-effects hazard ratio 1.80, 95% CI 1.62-2.0; I2 = 89%). This risk further increased across the severity of MASLD, especially the severity of fibrosis (pooled random-effects hazard ratio 2.42, 95% CI 1.89-2.29; I2 = 92%). These results remained significant after adjusting for age, sex, obesity, diabetes and other potential confounders. Sensitivity analyses did not modify these findings. The funnel plot did not reveal any significant publication bias. CONCLUSIONS: This meta-analysis shows a significant association between MASLD and an increased risk of serious bacterial infections requiring hospital admission.

Waitlist and transplant outcomes in patients with metabolic dysfunction-associated steatotic liver disease and autoimmune hepatitis.

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD), in the context of autoimmune hepatitis (AIH) among liver transplantation (LT) candidates or recipients remains poorly understood. This study compares waitlist and post-LT outcomes in patients with MASLD/AIH to MASLD and AIH alone. METHODS: Using the united network organ sharing database (2002-2022), we compared waitlist outcomes and post-LT survival among patients with MASLD/AIH (n = 282), AIH (n = 5812), and MASLD (n = 33 331). Competing risk, Kaplan Meier estimates and Cox proportional hazard analyses were performed. RESULTS: MASLD/AIH group had the highest rates of encephalopathy and ascites, and highest MELD scores. MASLD/AIH patients had higher transplantation incidence (adjusted subdistribution hazard ratio [aSHR] 1.64, 95% CI 1.44-1.85; p < .001) and lower waitlist removal risk (aSHR .30, 95% CI .20-.44; p < .001) compared to MASLD alone. One-year post-LT survival favoured MASLD compared to AIH (patient: 92% vs. 91%, p < .001; graft: 89% vs. 88%, p < .001) and MASLD/AIH (patient: 92% vs. 90%, p = .008; graft: 89% vs. 88%, p = .023). Recipients with MASLD/AIH showed no significant difference in survival at 10-year post-LT compared to MASLD (patient: 63% vs. 61%, p = .68; graft 60% vs. 59%, p = .83) and AIH (patient: 63% vs. 70%, p = .07; graft: 60% vs. 64%, p = .42). CONCLUSIONS: Our study showed that MASLD/AIH patients demonstrate higher LT incidence and lower dropout rates. Long-term post-LT outcomes did not significantly differ between groups. Further prospective multicenter studies are needed to validate these findings.

Association of healthy lifestyles with risk of all-cause and cause-specific mortality among individuals with metabolic dysfunction-associated steatotic liver disease: results from the DFTJ cohort.

AIM: To examine the associations of healthy lifestyles with risk of all-cause and cause-specific mortality among adults with metabolic dysfunction-associated steatotic liver disease (MASLD), and whether the association was mediated by systemic immune-inflammatory biomarkers (SIIBs). METHODS: The study included 10,347 subjects with MASLD, who were enrolled in the Dongfeng-Tongji cohort study. The healthy lifestyles referred to non-smoking, being physically active (≥7.5 metabolic equivalents-hours/week), low-risk alcohol consumption (1-14 g/day for women and 1-28 g/day for men), and optimal sleep duration (≥6 to ≤8 h/day). Cox proportional hazard models were used to examine the relationship between each lifestyle and SIIBs with the risk of all-cause and cause-specific mortality. A mediation analysis was conducted to investigate the role of SIIBs on the association between healthy lifestyles and mortality. RESULTS: There were 418 MASLD subjects dead till the follow-up of 2018, including 259 deaths from cardiovascular disease (CVD). Compared to MASLD participants with 0-1 healthy lifestyle score (HLS), those with 3-4 HLS had the lowest risk of all-cause mortality [hazard ratio (HR), 0.46; 95% CI, (0.36-0.60)], and CVD mortality [HR (95%CI), 0.41 (0.29-0.58)]. Mediation analyses indicated that SIIBs mediated the association between healthy lifestyles and mortality, with proportions ranging from 2.5% to 6.1%. CONCLUSIONS: These findings suggest that adherence to healthy lifestyles can significantly reduce mortality for MASLD patients, and the decreased SIIBs may partially explain the protection mechanism of healthy lifestyles.

Combination of Waist Circumference and Circulating Levels of IGFBP-2 as a Simple Screening Tool for Early Detection of Metabolic Dysfunction-Associated Steatotic Liver Disease.

Optimal non-invasive biomarkers for metabolic dysfunction-associated steatotic liver disease (MASLD) remain elusive, especially in the detection of early stages. This study tested in an asymptomatic cohort of 171 men (49.2 ± 8.6 years) and 131 women (51.8 ± 8.5 years) whether waist circumference (WC) and circulating levels of insulin-like growth factor-binding protein 2 (IGFBP-2) could identify individuals with liver fat >5% as assessed by magnetic resonance spectroscopy. Participants with high WC (> 85 or 90 cm for women and men, respectively) and low IGFBP-2 (< 260 or 230 ng/mL for women and men, respectively) were characterized by a higher risk of having MASLD (46.3%, p < 0.0001). Among the 68 individuals with MASLD, 73.5% fell into the subgroup with high WC and low IGFBP-2 concentrations (p < 0.0001). When combined, these markers reached a sensitivity of 73.5% and specificity of 75.2% for MASLD. Thus, WC and plasma IGFBP-2 levels might be useful as a novel, simple, and non-invasive index to support existing tools in the identification of individuals at risk of early-stage MASLD.

RANK-RANKL-OPG Axis in MASLD: Current Evidence Linking Bone and Liver Diseases and Future Perspectives.

Metabolic dysfunction-associated steatotic liver disease (MASLD)-and its worse form, metabolic-associated steatohepatitis (MASH), characterised by inflammation and liver damage-corresponds to the liver's involvement in metabolic syndrome, which constitutes an economic burden for healthcare systems. However, the biomolecular pathways that contribute to steatotic liver disease are not completely clear. Abnormalities of bone metabolism are frequent in people affected by metabolic liver disease, with reduced bone density and an increased risk of fracture. Receptor activator of NF-κB (RANK), receptor activator of NF-κB ligand (RANKL), and osteoprotegerin(OPG) are critical regulators of bone metabolism, performing pleiotropic effects, and may have potential involvement in metabolic disorders like MASLD, resulting in a topic of great interest and intrigue. This narrative review aims to investigate this potential role and its implications in MASLD development and progression and in hepatocellular carcinoma, which represents its worst complication.

Multi-echo three-dimensional (3D) Dixon sequence combined with disodium gadolinium for risk stratification of advanced fibrosis in metabolic dysfunction-associated steatotic liver disease.

Background: The hepatic steatosis and fibrosis related to metabolic dysfunction-associated steatotic liver disease (MASLD) are important factors in the progression. The Multi echo three-dimensional (3D) Dixon sequence can obtain a single breath hold scan for a fat fraction map and an R2* map. The R2* value is usually used to evaluate iron deposition. Whether the change in R2* value is related to liver fibrosis after injection of gadolinium disulfide (Gd) should be noted. This study evaluates the value of enhanced magnetic relaxation time in the risk stratification of liver fibrosis by analyzing the changes in R2* before and after Gd enhancement, and explores the potential application of Multi echo 3D Dixon sequence in one-stop evaluation of MASLD. Methods: This retrospective study included 138 MASLD patients who underwent Gadolinum ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA) magnetic resonance imaging (MRI) examination in The First Affiliated Hospital of Chongqing Medical University from June 2020 to December 2021. Finally, 90 subjects were divided into moderate and high-risk fibrosis group and low-risk fibrosis group by two-step assessment of liver fibrosis. Multi-echo 3D chemical shift imaging sequence (Q-Dixon) sequences and gradient-echo T1WI (Vibe-Dixon) sequence were performed during the non-enhanced phase and hepatobiliary phase, respectively, and then the signal-intensity enhancement (SE) and magnetic relaxation-time enhancement (RE) values were calculated. The interobserver correlation coefficient was used to evaluate the consistency between observers. Univariate t-test was used to analyze the differences in RE and SE of liver fibrosis among different risk levels. Delong analysis was performed on receiver operating characteristic (ROC) curve to evaluate the difference in diagnostic efficacy between RE and SE in differentiating the risk level of liver fibrosis. Results: Among the 90 patients, 55 (61.1%) belonged to the low-risk group and 35 (38.9%) belonged to the medium-to-high-risk group. The average RE and SE values were 1.23±0.15 and 1.57±0.23 in the low-risk group and 0.99±0.09 and 1.38±0.21 in both the medium-to-high-risk group (P<0.01). The ROC curve showed that the area under the curve (AUC) value of RE was 0.922, with a corresponding optimal threshold of 0.713, sensitivity of 0.852, and specificity of 0.861. The AUC value of SE was 0.724, with a corresponding optimal threshold of 0.352, sensitivity of 0.519, and specificity of 0.833. The AUC difference between RE and SE for the predictive value of different risk assessments was 0.198, and the 95% confidence interval of the difference was 0.084-0.312. The Delong test showed that the difference was significant (P<0.01). Conclusions: Magnetic RE had high effectiveness for distinguishing between liver-fibrosis risk levels. The combination of the Q-Dixon sequence and Gd-EOB-DTPA has the potential of one-stop evaluation of MASLD.

Hepatocyte MMP14 mediates liver and inter-organ inflammatory responses to diet-induced liver injury.

The matrix metalloproteinase MMP14 is a ubiquitously expressed, membrane-bound, secreted endopeptidase that proteolyzes substrates to regulate development, signaling, and metabolism. However, the spatial and contextual events inciting MMP14 activation and its metabolic sequelae are not fully understood. Here, we introduce an inducible, hepatocyte-specific MMP14-deficient model (MMP14LKO mice) to elucidate cell-intrinsic and systemic MMP14 function. We show that hepatocyte MMP14 mediates diet-induced body weight gain, peripheral adiposity, and impaired glucose homeostasis and drives diet-induced liver triglyceride accumulation and induction of hepatic inflammatory and fibrotic gene expression. Single-nucleus RNA sequencing revealed that hepatocyte MMP14 mediates Kupffer cell and T-cell accumulation and promotes diet-induced hepatocellular subpopulation shifts toward protection against lipid absorption. MMP14 co-immunoprecipitation and proteomic analyses revealed MMP14 substrate binding across both inflammatory and cytokine signaling, as well as metabolic pathways. Strikingly, hepatocyte MMP14 loss-of-function suppressed skeletal muscle and adipose inflammation in vivo, and in a reductionist adipose-hepatocyte co-culture model. Finally, we reveal that trehalose-type glucose transporter inhibitors decrease hepatocyte MMP14 gene expression and nominate these inhibitors as translatable therapeutic metabolic agents. We conclude that hepatocyte MMP14 drives liver and inter-organ inflammatory and metabolic sequelae of obesogenic dietary insult. Modulating MMP14 activation and blockade thus represents a targetable node in the pathogenesis of hepatic inflammation.

External Validation of Serologic Scores for the Detection of Liver Steatosis Among People With HIV.

Background: Fatty liver index (FLI) and hepatic steatosis index (HSI) are serologic scores used to detect liver steatosis. However, their diagnostic performance in people with HIV (PWH) remains unclear. We performed an external validation of FLI and HSI in the Swiss HIV Cohort Study. Methods: We systematically performed vibration-controlled transient elastography (VCTE) among Swiss HIV Cohort Study participants at Bern University Hospital between November 2019 and August 2021. Individuals with viral hepatitis and pregnant women were excluded. We defined liver steatosis as controlled attenuation parameter ≥248 dB/m using VCTE. Model discrimination was assessed with the C-index and model calibration with calibration plots. A decision curve analysis was performed to compare the clinical usefulness of both scores. Results: Of 321 participants, 91 (28.4%) were female, the median age was 51.4 years (IQR, 42-59), 230 (71.7%) were Caucasian, and 164 (51.1%) had a body mass index >25 kg/m2. VCTE-confirmed liver steatosis was present in 158 (49.2%). Overall, 125 (38.9%) had an FLI ≥60, and 128 (39.9%) had an HSI ≥36. At these cutoffs, the C-index to diagnose liver steatosis was 0.85 for FLI (95% CI, .80-.89) and 0.78 for HSI (95% CI, .73-.83). Whereas FLI was well calibrated, HSI overestimated the risk for steatosis. Both models showed a positive net benefit, with FLI having a greater net benefit when compared with HSI. Conclusions: FLI and HSI are valid tools to detect liver steatosis in PWH. FLI should be the preferred score, given its better performance and greater clinical usefulness.

Projected Healthcare System Cost Burden of Metabolic Dysfunction-Associated Steatotic Liver Disease in Canada.

Background and Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of chronic liver disease worldwide. The current and projected cost of treating individuals with MASLD in Canada remains unknown. Our objective was to calculate the projected liver-specific and total health-care costs for people living with MASLD in Canada from 2020 to 2050. Methods: The health-care usage of a cohort of patients diagnosed with MASLD in Calgary, Alberta was calculated using administrative data. Liver-specific encounters were identified and the average costs per year per patient were calculated. Projected costs were calculated by multiplying the average cost per patient within each health state by the projected prevalence of each health state. Results: There were 6358 patients in the cohort. The annual average liver-specific cost per patient was $7.02 for F0/F1, $35.30 for F2, $60.46 for F3, and $72.55 for F4. The projected Canada-wide liver-specific cost was $85.5 million in 2020 and was expected to increase by $51 million by 2050. The average annual total health-care cost per patient was $397.90 for F0/F1, $781.53 for F2, $2881.84 for F3, and $1598.82 for F4. Thus, the projected Canada-wide total health-care cost was $3.76 billion in 2020 and was expected to increase by almost $2 billion by 2050. Conclusion: These estimates underscore the need for a MASLD framework that focuses on both prevention and innovative care models to change the predicted trajectory of health-care costs.

Associations of Cannabis Use, Metabolic Dysfunction-Associated Steatotic Liver Disease, and Liver Fibrosis in U.S. Adults.

Introduction: Following the introduction of metabolic dysfunction-associated steatotic liver disease (MASLD) as a replacement term for nonalcoholic fatty liver disease, the relationship between MASLD and cannabis use has yet to be established. With the global rise in cannabis consumption, understanding its impact on MASLD is critical for clinical guidance. Our study investigated the association between cannabis use, MASLD, and clinically significant fibrosis (CSF) among U.S. adults. Methods: Data were collected from the National Health and Nutrition Examination Survey for the period 2017 to 2018 to conduct a cross-sectional analysis. The diagnosis of hepatic steatosis and CSF was based on median values of the controlled attenuation parameter and liver stiffness measurement, with thresholds of 285 dB/m and 8.6 kPa, respectively. Information on cannabis use was obtained through self-report questionnaires. Multinomial logistic regression models and subgroup analyses were used to investigate the association between cannabis use and MASLD with CSF. Results: Our study assessed data from 2,756 U.S. adults (51.1% female; 32.2% white; mean age 39.41 ± 11.83 years), who had complete information on liver stiffness measurements through transient elastography alongside reported cannabis use. Results indicated that cannabis use overall was not associated with liver stiffness in patients with MASLD. However, among females, cannabis use was associated with MASLD accompanied by CSF, with an adjusted odds ratio (OR) of 0.47 (95% confidence interval [CI]: 0.24-0.91). Heavy cannabis use (9 to 30 times per month) was associated with MASLD accompanied by CSF among female participants, with an adjusted OR of 0.12 (95% CI: 0.02-0.88). Conclusion: In our study, cannabis use did not show a significant association with liver stiffness in patients diagnosed with MASLD. However, heavy cannabis consumption in women was associated with MASLD accompanied by CSF. These findings suggest that the effects of cannabis on liver health may differ based on gender and frequency of cannabis use, emphasizing the need for further research in this area.

Circular RNA RRM2 alleviates metabolic dysfunction-associated steatotic liver disease by targeting miR-142-5p to increase NRG1 expression.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver condition worldwide, demanding further investigation into its pathogenesis. Circular RNAs (circRNAs) are emerging as pivotal regulators in MASLD processes, yet their pathological implications in MASLD remain poorly understood. This study focused on elucidating the role of circular RNA ribonucleotide reductase subunit M2 (circRRM2) in MASLD progression. In this study, we used both in vitro and in vivo MASLD models using long-chain-free fatty acid (FFA)-treated hepatocytes and high-fat diet (HFD)-induced MASLD in mice, respectively. We determined the expression patterns of circRRM2, microRNA-142-5p (miR-142-5p), and neuregulin 1 (NRG1) in livers of MASLD-afflicted mice and MASLD hepatocytes by RT-qPCR. Dual-luciferase reporter assays verified the binding relationships among circRRM2, miR-142-5p, and NRG1. We conducted further analyses of their roles in MASLD hepatocytes and modulated circRRM2, miR-142-5p, and NRG1 expression in vitro by transfection. Our findings were validated in vivo. The results demonstrated reduced levels of circRRM2 and NRG1, along with elevated miR-142-5p expression in MASLD livers and hepatocytes. Overexpression of circRRM2 downregulated lipogenesis-related genes and decreased triglycerides accumulation in livers of MASLD mice. MiR-142-5p, which interacts with circRRM2, effectively counteracted the effects of circRRM2 in MASLD hepatocytes. Furthermore, NRG1 was identified as a miR-142-5p target, and its overexpression mitigated the regulatory impact of miR-142-5p on MASLD hepatocytes. In conclusion, circRRM2, via its role as a miR-142-5p sponge, upregulating NRG1, possibly influenced triglycerides accumulation in both in vitro and in vivo MASLD models.NEW & NOTEWORTHY CircRRM2 expression was downregulated in free fatty acid (FFA)-challenged hepatocytes and high-fat diet (HFD) fed mice. Overexpressed circular RNA ribonucleotide reductase subunit M2 (circRRM2) attenuated metabolic dysfunction-associated steatotic liver disease (MASLD) development by suppressing FFA-induced triglycerides accumulation. CircRRM2 targeted microRNA-142-5p (miR-142-5p), which served as an upstream inhibitor of neuregulin 1 (NRG1) and collaboratively regulated MASLD progression.

The role of dietary modification in the prevention and management of metabolic dysfunction-associated fatty liver disease: An international multidisciplinary expert consensus.

Metabolic dysfunction-associated fatty liver disease (MAFLD) or metabolic dysfunction-associated steatotic liver disease (MASLD), has become the leading cause of chronic liver disease worldwide. Optimal dietary intervention strategies for MAFLD are not standardized. This study aimed to achieve consensus on prevention of MAFLD through dietary modification. A multidisciplinary panel of 55 international experts, including specialists in hepatology, gastroenterology, dietetics, endocrinology and other medical specialties from six continents collaborated in a Delphi-based consensus development process. The consensus statements covered aspects ranging from epidemiology to mechanisms, management, and dietary recommendations for MAFLD. The recommended dietary strategies emphasize adherence to a balanced diet with controlled energy intake and personalized nutritional interventions, such as calorie restriction, high-protein, or low-carbohydrate diets. Specific dietary advice encouraged increasing the consumption of whole grains, plant-based proteins, fish, seafood, low-fat or fat-free dairy products, liquid plant oils, and deeply colored fruits and vegetables. Concurrently, it advised reducing the intake of red and processed meats, saturated and trans fats, ultra-processed foods, added sugars, and alcohol. Additionally, maintaining the Mediterranean or DASH diet, minimizing sedentary behavior, and engaging in regular physical activity are recommended. These consensus statements lay the foundation for customized dietary guidelines and proposing avenues for further research on nutrition and MAFLD.