Metabolic Dysfunction-associated Fatty Liver Disease Research Articles

Novel therapeutic opportunities of kisspeptin

Diseases associated with disorders of sexual development, the reproductive system, delayed of puberty onset are of high relevance. This negatively affect the health of young people, the demographic indicators, fertility and require a search for therapy. This review presents current data on the role of the kisspeptin ligand-receptor system KISS/KISS1R, the discovery of which was of revolutionary significance for deciphering the genesis of neuroendocrine regulation of the reproductive system.A review and analysis of clinical and experimental research from recent decades, aimed at studying kisspeptin and its agonists as a potential therapeutic approach. Data are presented on the positive effect of kisspeptin on the pulse secretion of GnRH and gonadotropins, which can be used in the treatment of hypogonadotropic hypogonadism, ovulation disorders and other diseases of the reproductive system. Outside the human hypothalamus, kisspeptin and its receptor are expressed in the brain in key limbic and paralimbic regions, and in peripheral tissues. We summarise data on the pharmacological use of kisspeptin in reproductive disorders and fertility treatment, as well as its putative utility in hypoactive sexual desire disorder, osteoporosis and non-alcoholic fatty liver disease, now known as metabolic dysfunction-associated fatty liver disease.

2024 Guidelines of the Taiwan Society of Cardiology on the Primary Prevention of Atherosclerotic Cardiovascular Disease --- Part I.

Atherosclerotic cardiovascular disease (ASCVD) is one of the leading causes of death worldwide and in Taiwan. It is highly prevalent and has a tremendous impact on global health. Therefore, the Taiwan Society of Cardiology developed these best-evidence preventive guidelines for decision-making in clinical practice involving aspects of primordial prevention including national policies, promotion of health education, primary prevention of clinical risk factors, and management and control of clinical risk factors. These guidelines cover the full spectrum of ASCVD, including chronic coronary syndrome, acute coronary syndrome, cerebrovascular disease, peripheral artery disease, and aortic aneurysm. In order to enhance medical education and health promotion not only for physicians but also for the general public, we propose a slogan (2H2L) for the primary prevention of ASCVD on the basis of the essential role of healthy dietary pattern and lifestyles: "Healthy Diet and Healthy Lifestyles to Help Your Life and Save Your Lives". We also propose an acronym of the modifiable risk factors/enhancers and relevant strategies to facilitate memory: " ABC2D2EFG-I'M2 ACE": Adiposity, Blood pressure, Cholesterol and Cigarette smoking, Diabetes mellitus and Dietary pattern, Exercise, Frailty, Gout/hyperuricemia, Inflammation/infection, Metabolic syndrome and Metabolic dysfunction-associated fatty liver disease, Atmosphere (environment), Chronic kidney disease, and Easy life (sleep well and no stress). Some imaging studies can be risk enhancers. Some risk factors/clinical conditions are deemed to be preventable, and healthy dietary pattern, physical activity, and body weight control remain the cornerstone of the preventive strategy.

Anti-inflammatory diet reduces risk of metabolic dysfunction-associated fatty liver disease among US adults: a nationwide survey

Background While dietary intervention was an important public health strategy for the prevention and intervention of metabolic dysfunction-associated fatty liver disease (MAFLD), the effect of diet-induced inflammation on MAFLD has not been studied in detail. Therefore, we aimed to analyze the relationship between dietary inflammatory index (DII) and MAFLD. Methods This study included data from the National Health and Nutrition Examination Survey 2017–2018. MAFLD was diagnosed based on the presence of hepatic steatosis, as determined by transient elastography, along with evidence of either overweight/obesity, type 2 diabetes mellitus, or metabolic dysfunction. DII was calculated using 27 dietary components collected through 24-hour dietary recall questionnaire. Weighted logistic regression was used to analyze the relationship between DII and MAFLD and its main components in three different models. Subgroup analyses were performed by age, sex, and alcohol use. Results A total of 1991 participants were included, and the MAFLD group had higher DII scores. After adjusting for age, sex, race, physical activity, smoking status, and alcohol use, the highest quartile of DII was associated with increased risk of MAFLD (OR:2.90, 95% CIs: 1.46, 5.75). Overweight/obesity, central obesity, low high density lipoprotein cholesterol (HDL-C) and high C-reactive protein (CRP) also shared the same characteristics in the main components of MAFLD. Results were consistent across subgroups (age, sex, and alcohol use). Conclusions A higher DII diet was positively associated with the risk of MAFLD in American adults, particularly as related to overweight/obesity, central obesity, high CRP level, and low HDL-C level.

From NAFLD to MAFLD and MASLD: a tale of alcohol, stigma and metabolic dysfunction

Liver steatosis is a frequent finding in clinical practice and it is estimated to affect 30% of the general adult population worldwide. It became one of the leading causes of end-stage liver disease and hepatocellular carcinoma. From its first description, a diagnosis of nonalcoholic fatty liver disease (NAFLD) required the exclusion of excessive alcohol consumption and concomitant chronic liver diseases of different origins, making it a diagnosis of exclusion. In recent years, the need to stress the strict association between liver steatosis and metabolic dysfunction (i.e., insulin resistance, overweight/obesity, type 2 diabetes, and metabolic syndrome), as well as the desire to define a condition in a positive rather than negative way, led to new definitions and new diagnostic criteria. Metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed by Eslam et al. in 2020. More recently, a Delphi consensus endorsed by several international hepatologic societies proposed a new terminology [metabolic dysfunction-associated steatotic liver disease (MASLD)] and a new set of diagnostic criteria. The MAFLD and MASLD definitions have a good degree of concordance. They mainly differ in the number of metabolic derangements needed to define “metabolic dysfunction” in normal-weight individuals and in alcohol consumption. Indeed, while MAFLD does not exclude patients with significant alcohol consumption, the recent Delphi consensus included the metabolic dysfunction and alcohol-related liver disease (MetALD) disease entity, a condition in which steatosis, metabolic dysfunction, and moderate alcohol intake coexist. In the present narrative review, we underline the strengths and possible limitations of each definition and summarize available evidence from epidemiologic studies evaluating the clinical usefulness of each set of diagnostic criteria.

Clinical features and mortality outcomes of patients with MASLD only compared to those with MAFLD and MASLD.

The applicability of the proposed metabolic dysfunction-associated steatotic liver disease (MASLD) definition has not been validated. We aimed to characterize the profiles and long-term survival of people meeting the criteria for MASLD, but not that of metabolic dysfunction-associated fatty liver disease (MAFLD), i.e. MASLD only. Using data from the Third National Health and Nutrition Examination Survey (NHANES III) 1988-1994, 7791 adult participants were included and categorized into four distinct groups: no SLD, non-MAFLD MASLD, MASLD-MAFLD, and cryptogenic SLD (steatosis without metabolic dysfunction). Participants in the MASLD-only group were younger and had better metabolic profiles and fibrosis degree compared to those with MASLD-MAFLD and those with no SLD. Their profiles were comparable to those with cryptogenic SLD. Similarly, the MASLD-only group tend to have lower cumulative incidence of all-cause and cardiovascular mortality. Clustering analysis showed that MASLD only clusters differently from individuals with MASLD-MAFLD. MASLD only is a distinct clinical group with substantial heterogeneity compared to those captured using the MAFLD criteria.

A functional genomic framework to elucidate novel causal metabolic dysfunction-associated fatty liver disease genes.

Metabolic dysfunction-associated fatty liver disease (MASLD) is the most prevalent chronic liver pathology in western countries, with serious public health consequences. Efforts to identify causal genes for MASLD have been hampered by the relative paucity of human data from gold-standard magnetic resonance quantification of hepatic fat. To overcome insufficient sample size, genome-wide association studies using MASLD surrogate phenotypes have been used, but only a small number of loci have been identified to date. In this study, we combined GWAS of MASLD composite surrogate phenotypes with genetic colocalization studies followed by functional in vitro screens to identify bona fide causal genes for MASLD. We used the UK Biobank to explore the associations of our novel MASLD score, and genetic colocalization to prioritize putative causal genes for in vitro validation. We created a functional genomic framework to study MASLD genes in vitro using CRISPRi. Our data identify VKORC1, TNKS, LYPLAL1 and GPAM as regulators of lipid accumulation in hepatocytes and suggest the involvement of VKORC1 in the lipid storage related to the development of MASLD. Complementary genetic and genomic approaches are useful for the identification of MASLD genes. Our data supports VKORC1 as a bona fide MASLD gene. We have established a functional genomic framework to study at scale putative novel MASLD genes from human genetic association studies.

Reduced insulin clearance in paediatric metabolic (dysfunction)-associated fatty liver disease and its dual role in beta-cell offload and diabetes risk.

Diminished hepatic insulin clearance (HIC) is observed in obese adults and is presumed to be mediated by fatty liver. However, few reports have examined HIC in Chinese children with metabolic (dysfunction)-associated fatty liver disease (MAFLD). This study aimed to investigate the correlation between HIC, insulin sensitivity and β-cell function in obese Chinese children with MAFLD. In total, 204 obese children (74 MAFLD) aged 4-17 years were enrolled into this study. HIC, insulin sensitivity and β-cell function were calculated using the oral glucose tolerance test (1.75 g/kg body weight). Correlation analyses between the HIC and clinical variables were performed using Pearson's product-moment correlation coefficients. HIC and glucose homeostasis were assessed in a high-fat diet mouse model, and liver samples were collected for molecular analysis. Obese children with MAFLD exhibited significantly lower HIC (AUCC-peptide/insulin ratio, p = 0.0019), higher insulin resistance (homeostatic model assessment of insulin resistance, p = 0.002), and increased compensatory β-cell function (homeostatic model assessment-β, p = 0.046) than obese children without liver involvement. Notably, HIC was negatively correlated with insulin sensitivity (r = -0.5035, p < 0.0001) and β-cell function (r = -0.4576, p < 0.0001). However, pancreatic β-cell dysfunction (p = 0.046) was accompanied by future reduced HIC (p = 0.034) in children with MAFLD in prediabetes. In a high-fat diet mouse model, MAFLD mice showed a 50% reduction in insulin-degrading enzyme expression, consistent with the observed decrease in HIC. A lower HIC may offload pancreatic β-cells at an early stage. However, obese children with MAFLD are at risk of developing diabetes, and preventive efforts should be prioritized.

Additive effect of metabolic dysfunction-associated fatty liver disease on left ventricular function and global strain in type 2 diabetes mellitus patients: a 3.0 T cardiac magnetic resonance feature tracking study

BackgroundType 2 diabetes mellitus (T2DM) and metabolic-associated fatty liver disease (MAFLD) are both metabolic disorders that negatively impact the cardiovascular system. This study comprehensively analyzed the additive effect of MAFLD on left ventricular function and global strain in T2DM patients by cardiac magnetic resonance (CMR).MethodsData of 261 T2DM patients, including 109 with and 152 without MAFLD, as well as 73 matched normal controls from our medical center between June 2015 and March 2022 were retrospectively analyzed. CMR-derived parameters, including LV function and global strain parameters, were compared among different groups. Univariate and multivariate linear regression analyses were conducted to investigate the impact of various factors on LV function and global strain.ResultsOur investigation revealed a progressive deterioration in LV functional parameters across three groups: control subjects, T2DM patients without MAFLD, and T2DM patients with MAFLD. Statistically significant increases in left ventricular end-diastolic volume index (LVEDVI), left ventricular end-systolic volume index (LVESVI), left ventricular mass index (LVMI) were observed, along with decreases in left ventricular ejection fraction (LVEF) and left ventricular global function index (LVGFI). Among these three groups, significant reductions were also noted in the absolute values of LV global radial, circumferential, and longitudinal peak strains (GRPS, GCPS, and GLPS), as well as in peak systolic (PSSR) and peak diastolic strain rates (PDSR). MAFLD was identified as an independent predictor of LVEF, LVMI, LVGFI, GRPS, GCPS, and GLPS in multivariate linear analysis. Besides, the incidence of late gadolinium enhancement was higher in MAFLD patients than in non-MAFLD patients (50/109 [45.9%] vs. 42/152 [27.6%], p = 0.003). Furthermore, escalating MAFLD severity was associated with a numerical deterioration in both LV function parameters and global strain values.ConclusionsThis study thoroughly compared CMR parameters in T2DM patients with and without MAFLD, uncovering MAFLD’s adverse impact on LV function and deformation in T2DM patients. These findings highlight the critical need for early detection and comprehensive management of cardiac function in T2DM patients with MAFLD.

Inter-visit and inter-reader reproducibility of multi-parametric diffusion-weighted MR imaging in longitudinally imaged patients with metabolic dysfunction-associated fatty liver disease and healthy volunteers.

BackgroundDespite the widespread use of diffusion-weighted imaging (DWI) in metabolic dysfunction-associated fatty liver disease (MAFLD), MRI acquisition and quantification techniques vary in the literature suggesting the need for established and reproducible protocols. The goal of this study was to assess inter-visit and inter-reader reproducibility of DWI- and IVIM-derived parameters in patients with MAFLD and healthy volunteers using extensive sampling of the “fast” compartment, non-rigid registration, and exclusion voxels with poor fit quality. MethodsFrom June 2019 to April 2023, 31 subjects (20 patients with biopsy-proven MAFLD and 11 healthy volunteers) were included in this IRB-approved study. Subjects underwent MRI examinations twice within 40 days. 3.0 T DWI was acquired using a respiratory-triggered spin-echo diffusion-weighted echo-planar imaging sequence (b-values of 0, 10, 20, 30, 40, 50, 100, 200, 400, 800 s/mm2). DWI series were co-registered prior to voxel-wise non-linear regression of the IVIM model and voxels with poor fit quality were excluded (normalized root mean squared error ≥ 0.05). IVIM parameters (perfusion fraction, f; diffusion coefficient, D; and pseudo-diffusion coefficient, D*), and apparent diffusion coefficients (ADC) were computed from manual segmentation of the right liver lobe performed by two analysts on two MRI examinations. ResultsAll results are reported for f, D, D*, and ADC respectively. For inter-reader agreement on the first visit, ICC were of 0.985, 0.994, 0.986, and 0.993 respectively. For intra-reader agreement of analyst 1 assessed on both imaging examinations, ICC between visits were of 0.805, 0.759, 0.511, and 0.850 respectively. For inter-reader agreement on the first visit, mean bias and 95 % limits of agreement were (0.00 ± 0.03), (−0.01 ± 0.03) × 10−3 mm2/s, (0.70 ± 10.40) × 10−3 mm2/s, and (−0.02 ± 0.04) × 10−3 mm2/s respectively. For intra-reader agreement of analyst 1, mean bias and 95 % limits of agreement were (0.01 ± 0.09) × 10−3 mm2/s, (−0.01 ± 0.21) × 10−3 mm2/s, (−13.37 ± 56.19) × 10−3 mm2/s, and (−0.01 ± 0.16) × 10−3 mm2/s respectively. Except for parameter D* that was associated with between-subjects parameter variability (P = 0.009), there was no significant variability between subjects, examinations, or readers. ConclusionWith our approach, IVIM parameters f, D, D*, and ADC provided excellent inter-reader agreement and good to very good inter-visit or intra-reader agreement, thus showing the reproducibility of IVIM-DWI of the liver in MAFLD patients and volunteers.

Changes in the epidemiological trends of primary liver cancer in the Asia–Pacific region

Primary liver cancer is the third leading cause of cancer-related mortality. The increasing prevalence of metabolic syndrome and alcohol consumption, along with the existing burden of viral hepatitis, could significantly heighten the impact of primary liver cancer. However, the specific effects of these factors in the Asia–Pacific region, which comprises more than half of the global population, remain largely unexplored. This study aims to analyze the epidemiology of primary liver cancer in the Asia–Pacific region. We evaluated regional and national data from the Global Burden of Disease study spanning 2010 to 2019 to assess the age-standardized incidence, mortality, and disability-adjusted life years associated with primary liver cancer in the Asia–Pacific region. During the study period, there were an estimated 364,700 new cases of primary liver cancer and 324,100 deaths, accounting for 68 and 67% of the global totals, respectively. Upward trends were observed in the age-standardized incidence rates of primary liver cancer due to metabolic dysfunction-associated fatty liver disease (MASLD) and alcohol-associated liver disease (ALD) in the Asia–Pacific region, as well as an increase in primary liver cancer from Hepatitis B virus infection in the Western Pacific region. Notably, approximately 17% of new cases occurred in individuals aged 15–49 years. Despite an overall decline in the burden of primary liver cancer in the Asia–Pacific region over the past decade, increases in incidence were noted for several etiologies, including MASLD and ALD. However, viral hepatitis remains the leading cause, responsible for over 60% of the total burden. These findings underscore the urgent need for comprehensive strategies to address the rising burden of primary liver cancer in the Asia–Pacific region.

Retrospective Longitudinal Observational Study on the Long-Term Effects of Sodium-Glucose Cotransporter-2 Inhibitors on the Development of Metabolic Dysfunction-Associated Steatotic Liver Disease in Type 2 Diabetic Japanese Patients.

Background/Objectives: The health burden of metabolic dysfunction-associated fatty liver disease (MASLD) has been increasing lately. Cardiovascular disease (CVD) is the main cause of death in MASLD patients; therefore, the treatments for MASLD should improve both CV risk factors such as obesity, diabetes, and dyslipidemia, in addition to an improvement in liver function. The evidence on the long-term effects of sodium-glucose cotransporter 2 inhibitors (SGLT2is) on the progression of MASLD in Asian populations is very limited. Methods: The retrospective longitudinal study was performed by using the medical records at our institute. We picked up patients with type 2 diabetes who had taken SGLT2is for at least 3 years or longer between 1 April 2014 and 31 March 2018. We collected the data on metabolic parameters, including laboratory data and anthropometric parameters, and compared the data before and after the initiation of SGLT2is treatment. Results: During the observation period, 324 patients had taken SGLT2is for 3 years. Three-year SGLT2is treatment significantly reduced body weight, hemoglobin A1c, low-density lipoprotein cholesterol, triglyceride, and non-high-density lipoprotein cholesterol (non-HDL-C). Such favorable changes in serum lipids were remarkable in patients with statins. Furthermore, this treatment significantly improved liver function and the markers for hepatic steatosis and hepatic fibrosis. Conclusions: Considering that the development of CVD determines the prognosis of MASLD patients, long-term SGLT2is treatment may be an ideal therapy for MASLD patients.

Genotype-First Approach Identifies an Association between rs28374544/FOG2S657G and Liver Disease through Alterations in mTORC1 Signaling.

Metabolic dysfunction-associated Fatty Liver Disease (MAFLD) has emerged as one of the leading cardiometabolic diseases. Friend of GATA2 (FOG2) is a transcriptional co-regulator that has been shown to regulate hepatic lipid metabolism and accumulation. Using meta-analysis from several different biobank datasets, we identified a coding variant of FOG2 (rs28374544, A1969G, S657G) predominantly found in individuals of African ancestry (minor allele frequency~20%), which is associated with liver failure/cirrhosis phenotype and liver injury. To gain insight into potential pathways associated with this variant, we interrogated a previously published genomics dataset of 38 human induced pluripotent stem cell (iPSCs) lines differentiated into hepatocytes (iHeps). Using Differential Gene Expression Analysis and Gene Set Enrichment Analysis, we identified the mTORC1 pathway as differentially regulated between iHeps from individuals with and without the variant. Transient lipid-based transfections were performed on the human hepatoma cell line (Huh7) using wild-type FOG2 and FOG2S657G and demonstrated that FOG2S657G increased mTORC1 signaling, de novo lipogenesis, and cellular triglyceride synthesis and mass. In addition, we observed a significant downregulation of oxidative phosphorylation in FOG2S657G cells in fatty acid-loaded cells but not untreated cells, suggesting that FOG2S657G may also reduce fatty acid to promote lipid accumulation. Taken together, our multi-pronged approach suggests a model whereby the FOG2S657G may promote MAFLD through mTORC1 activation, increased de novo lipogenesis, and lipid accumulation. Our results provide insights into the molecular mechanisms by which FOG2S657G may affect the complex molecular landscape underlying MAFLD.

Far-infrared radiation alleviates steatohepatitis and fibrosis in metabolic dysfunction-associated fatty liver disease

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a disease that causes an abnormal accumulation of fat in the liver, triggering inflammation and fibrosis, the mechanism of which is not fully understood and for which there is a lack of specific drug therapy. Far-infrared radiation (FIR) has demonstrated evident therapeutic efficacy across various diseases, and novel nanomaterial graphene patches can emit it through electric heating. This study aimed to investigate the potential protective effects of FIR against MAFLD. Mice were fed with a MCD diet to mimic MAFLD progression, and histopathology analysis, biochemical analysis, RT-qPCR, and Western blotting analysis were performed to assess the effect of FIR on MAFLD in vivo. The effect of FIR treatment on MAFLD in vitro was investigated by biochemical analysis and gene expression profiling of hepatocytes. Mice subjected to the MCD diet and treated with FIR exhibited reduced hepatic lipid deposition, inflammation, fibrosis and liver damage. The therapeutic effect exerted by FIR in mice may be caused by the enhancement of AMPK phosphorylation and inhibition of the TGFβ1-SMAD2/3 pathway. Besides, FIR intervention alleviated MAFLD in hepatocytes in vitro and the results were verified by gene expression profiling. Our results revealed a promising potential of FIR as a novel therapeutic approach for MAFLD.

Metabolic Profiles of the Gut Microbiota in Patients with Different Stages of Metabolism Dysfunction-Associated Fatty Liver Disease

Aim: to study the metabolic activity of the intestinal microbiota depending on the stage of metabolic dysfunction-associated fatty liver disease (MAFLD). Materials and methods. The study included 85 patients with MAFLD (27 patients with steatosis without steatohepatitis and fibrosis, 42 patients with steatohepatitis, 16 patients with cirrhosis as an outcome of MAFLD, Child — Pugh class A–B) and 20 healthy people who formed the control group. The level and spectrum of short-chain fatty acids (SCFA) were determined by gas-liquid chromatography. Results. It was found that patients with MAFLD at the stage of steatosis and cirrhosis of the liver have unidirectional changes in the metabolic activity of the intestinal microbiota. We established a decrease in the absolute concentrations of SCFA — their total content, the level of acetate, propionate, butyrate, a decrease in the level of isoacids. The SCFA profiles showed an increase in the proportion of acetate and a decrease in propionate and butyrate. Moreover, changes in the named parameters of SCFAs are aggravated with progression to liver cirrhosis. At the stage of steatohepatitis, we identified two subgroups of patients with different levels of metabolic activity of the microbiota. Patients whose microbiota metabolism for SCFA production was high had correspondingly elevated SCFA levels. And, on the contrary, patients in whom the metabolic activity of the microbiota was reduced were characterized by a steady decrease in SCFAs and disease progression to liver cirrhosis. In the study, we showed an inverse correlation between the calculated prognostic indices of NFS and FIB-4, elastography values with the total level of SCFA, the level of acetate, propionate, butyrate. Thus, a decrease in the content of SCFA for patients with MAFLD can be considered as a prognostic marker of an unfavorable course of liver disease.

Metabolic dysfunction-associated fatty liver disease and osteoporosis: the mechanisms and roles of adiposity.

Nonalcoholic fatty liver disease (NAFLD) has recently been renamed metabolic dysfunction-associated fatty liver disease (MAFLD) by international consensus. Both MAFLD and osteoporosis are highly prevalent metabolic diseases. Recent evidence indicates that NAFLD increases the risk of low bone mineral density and osteoporosis, likely mediated by obesity. NAFLD has a close association with obesity and other metabolic disorders. Although obesity was previously thought to protect against bone loss, it now heightens osteoporotic fracture risk. This overview summarizes current clinical correlations between obesity, NAFLD, and osteoporosis, with a focus on recent insights into potential mechanisms interconnecting these three conditions. This study reviewed the scientific literature on the relationship between obesity, nonalcoholic fatty liver disease, and osteoporosis as well as the scientific literature that reveals the underlying pathophysiologic mechanisms between the three. Emerging evidence suggests obesity plays a key role in mediating the relationship between NAFLD and osteoporosis. Accumulating laboratory evidence supports plausible pathophysiological links between obesity, NAFLD, and osteoporosis, including inflammatory pathways, insulin resistance, gut microbiota dysbiosis, bone marrow adiposity, and alterations in insulin-like growth factor-1 signaling. Adiposity has important associations with NAFLD and osteoporosis, the underlying pathophysiologic mechanisms between the three may provide new therapeutic targets for this complex patient population.

Integrative clinical and preclinical studies identify FerroTerminator1 as a potent therapeutic drug for MASH

The complex etiological factors associated with metabolic dysfunction-associated fatty liver disease (MAFLD), including perturbed iron homeostasis, and the unclear nature by which they contribute to disease progression have resulted in a limited number of effective therapeutic interventions. Here, we report that patients with metabolic dysfunction-associated steatohepatitis (MASH), a pathological subtype of MAFLD, exhibit excess hepatic iron and that it has a strong positive correlation with disease progression. FerroTerminator1 (FOT1) effectively reverses liver injury across multiple MASH models without notable toxic side effects compared with clinically approved iron chelators. Mechanistically, our multi-omics analyses reveal that FOT1 concurrently inhibits hepatic iron accumulation and c-Myc-Acsl4-triggered ferroptosis in various MASH models. Furthermore, MAFLD cohort studies suggest that serum ferritin levels might serve as a predictive biomarker for FOT1-based therapy in MASH. These findings provide compelling evidence to support FOT1 as a promising novel therapeutic option for all stages of MAFLD and for future clinical trials.

Acute-on-chronic liver failure in metabolic dysfunction-associated fatty liver disease patients: a disease multiplier.

Acute-on-chronic liver failure (ACLF) is a syndrome of liver failure due to an acute hepatic insult leading to liver failure with or without extra-hepatic organ failure in a patient of chronic liver disease (CLD) with or without cirrhosis presenting for the first time. The definition is still with controversy; hence, homogeneity and clarity of the case is an unmet need. There is a paradigm shift noted as far as the etiology of CLD is concerned with rise in metabolic dysfunction-associated fatty liver disease (MAFLD) and ethanol as the dominant cause even in developing countries. MAFLD is the change in nomenclature from NAFLD to justify the metabolic derangement in these group of patients. The shift from an exclusion-based criteria to one that has evolved to a diagnosis that requires positive criteria has profound significance. Clearly there is a difference in terms of its prevalence, disease progression, and liver-related events, as well as management of metabolic risk factors and MAFLD itself which requires further understanding. In tandem with the global rise in MAFLD, the incidence of MAFLD-ACLF is increasing. Excessive alcohol consumption causes metabolic and toxic injury to the liver resulting in nearly similar pathway of fatty liver, hepatitis, and cirrhosis. The interaction of MAFLD as an additional underlying chronic liver injury in ACLF patients is complex due to the presence of metabolic risk factors that are unique to MAFLD. There is lack of clarity on how MAFLD affects the clinical course of ACLF due to scarcity of this specific data. This narrative review aims to understand the unique effects, consequences, and management of MAFLD as the chronic liver injury component in ACLF.

Abstract Tu042: Fatty Acid Dysregulation Drives Cardio-Hepatic Crosstalk in Heart Failure with Preserved Ejection Fraction (HFpEF)

Introduction: Heart failure with preserved ejection fraction (HFpEF) is a heterogenous clinical syndrome that accounts for nearly half of all heart failure cases world-wide. The pathophysiological mechanisms underlying HFpEF include a variety of extracardiac abnormalities such as metabolic derangements, arterial hypertension, and microvascular endothelial dysfunction, that all drive left ventricular remodeling and dysfunction. The phenotypic diversity presented in HFpEF involves functional and structural changes in several organs including the liver. As a highly vascularized organ, the liver is highly sensitive to any hemodynamic changes in the heart and clinical studies have established the presence of liver injury in HFpEF patients. However, there is limited evidence of this relationship in preclinical mouse models, thereby hindering the exploration of the pathological mechanisms linking the two organs. Cardio-hepatic interactions are poorly understood yet play a critical role in the pathophysiology of HFpEF where aberrant metabolic signaling pathways such as insulin resistance, inflammation and oxidative stress significantly contribute to disease progression and further perpetuate a vicious cycle of cardio-hepatic deterioration. Hypothesis: With limited preclinical data in the field, we sought to elucidate the potential pathophysiological mechanisms driving cardio-hepatic crosstalk in HFpEF. Methods: We used a two-hit preclinical mouse model that recapitulates cardiometabolic HFpEF to characterize the coexistence of cardiac and hepatic dysfunction in HFpEF. Male mice were kept on the HFpEF model for 15 weeks and subjected to echocardiography, glucose tolerance tests, histopathology, and multi-omics analyses. Results: We report that markers of HFpEF severity such as diastolic dysfunction and left ventricular hypertrophy, significantly correlated with hepatic injury and dysfunction that exacerbated metabolic dysfunction-associated fatty liver disease (MAFLD) progression. Impaired energy substrate utilization due to fatty acid dysregulation was a major mechanism underlying cardio-hepatic crosstalk in HFpEF. Conclusion: Our findings highlight fatty acid metabolism as a potential target to mitigate inter-organ dysfunction in HFpEF, representing a promising opportunity to create new treatment paradigms and drive positive outcomes in HFpEF.

Effect of Immunosuppressive Regimens on Metabolic Dysfunction-associated Fatty Liver Disease Following Liver Transplantation

BackgroundMetabolic dysfunction-associated fatty liver disease has been linked to negative outcomes in patients with end stage liver disease following liver transplantation. However, the influence of immunosuppressive regimens on it has not been explored. MethodsA retrospective analysis was conducted using the preoperative and postoperative data from patients with end-stage liver disease. The study compared three different groups: tacrolimus-based group, sirolimus-based group, and combined tacrolimus and sirolimus-based regimens. Binary logistic regression analysis was employed to identify risk factors for metabolic dysfunction-associated fatty liver disease. ResultsA total of 171 patients participated in the study, consisting of 127 males and 44 females, with a mean age of 49.6 years. The prevalence of post-transplant metabolic dysfunction-associated fatty liver disease was 29.23%. Among the three groups, there were 111 liver transplant recipients in the tacrolimus-based group, 28 in the sirolimus-based group, and 32 in the combination group. A statistically significant difference was observed in the incidence of metabolic dysfunction-associated fatty liver disease (P < 0.05), whereas the other preoperative and postoperative parameters showed no significant differences. Multivariate analysis revealed that a low-calorie diet (95% confidence intervals: 0.15∼0.90, P = 0.021) and a combination of tacrolimus and sirolimus-based immunosuppressive regimen (95% confidence intervals: 1.01∼2.77, P = 0.046) were associated with lower risk of post-transplant metabolic dysfunction-associated fatty liver disease. ConclusionsOur study indicates that implementing a low-calorie diet and utilizing a combination of tacrolimus and sirolimus-based immunosuppressive regimen can effectively lower the risk of post-transplant metabolic dysfunction-associated fatty liver disease following liver transplantation.

Integrating Multi-Omics with environmental data for precision health: A novel analytic framework and case study on prenatal mercury induced childhood fatty liver disease

BackgroundPrecision Health aims to revolutionize disease prevention by leveraging information across multiple omic datasets (multi-omics). However, existing methods generally do not consider personalized environmental risk factors (e.g., environmental pollutants). ObjectiveTo develop and apply a precision health framework which combines multiomic integration (including early, intermediate, and late integration, representing sequential stages at which omics layers are combined for modeling) with mediation approaches (including high-dimensional mediation to identify biomarkers, mediation with latent factors to identify pathways, and integrated/quasi-mediation to identify high-risk subpopulations) to identify novel biomarkers of prenatal mercury induced metabolic dysfunction-associated fatty liver disease (MAFLD), elucidate molecular pathways linking prenatal mercury with MAFLD in children, and identify high-risk children based on integrated exposure and multiomics data. MethodsThis prospective cohort study used data from 420 mother–child pairs from the Human Early Life Exposome (HELIX) project. Mercury concentrations were determined in maternal or cord blood from pregnancy. Cytokeratin 18 (CK-18; a MAFLD biomarker) and five omics layers (DNA Methylation, gene transcription, microRNA, proteins, and metabolites) were measured in blood in childhood (age 6–10 years). ResultsEach standard deviation increase in prenatal mercury was associated with a 0.11 [95% confidence interval: 0.02–0.21] standard deviation increase in CK-18. High dimensional mediation analysis identified 10 biomarkers linking prenatal mercury and CK-18, including six CpG sites and four transcripts. Mediation with latent factors identified molecular pathways linking mercury and MAFLD, including altered cytokine signaling and hepatic stellate cell activation. Integrated/quasi-mediation identified high risk subgroups of children based on unique combinations of exposure levels, omics profiles (driven by epigenetic markers), and MAFLD. ConclusionsPrenatal mercury exposure is associated with elevated liver enzymes in childhood, likely through alterations in DNA methylation and gene expression. Our analytic framework can be applied across many different fields and serve as a resource to help guide future precision health investigations.