Metabolic Dysfunction-associated Fatty Liver Disease Research Articles

Global prevalence of MAFLD-related hepatocellular carcinoma: A systematic review and meta-analysis.

The global proportion of hepatocellular carcinoma (HCC) attributable to metabolic dysfunction-associated fatty liver disease (MAFLD) is unclear. The MAFLD diagnostic criteria allows objective diagnosis in the presence of steatosis plus defined markers of metabolic dysfunction, irrespective of concurrent liver disease. We aimed to determine the total global prevalence of MAFLD in HCC cohorts (total-MAFLD), including the proportion with MAFLD as their sole liver disease (single-MAFLD), and the proportion of those with concurrent liver disease where MAFLD was a contributary factor (mixed-MAFLD). This systematic review and meta-analysis included studies systematically ascertaining MAFLD in HCC cohorts, defined using international expert panel criteria including ethnicity specific BMI cut-offs. A comparison of clinical and tumour characteristics was performed between single-MAFLD, mixed-MAFLD and non-MAFLD HCC. 22 studies (56,565 individuals with HCC) were included. Total and single-MAFLD HCC prevalence was 48.7% (95% CI; 34.5% - 63.0%) and 12.4% (95% CI; 8.3% - 17.3%), respectively. In HCC due to chronic hepatitis B, C and alcohol-related liver disease, mixed-MAFLD prevalence was 40.0% (95% CI; 30.2% - 50.3%), 54.1% (95% CI; 40.4% - 67.6%) and 64.3% (95% CI; 52.7% - 75.0%), respectively. Mixed-MAFLD HCC had significantly higher likelihood of cirrhosis and lower likelihood of metastatic spread compared to single-MAFLD HCC, and a higher platelet count and lower likelihood of macrovascular invasion compared to non-MAFLD HCC. MAFLD is common as a sole aetiology, but more so and as a co-factor in mixed-aetiology HCC, supporting the use of a positive diagnostic criteria.

Gastroenterology/Hepatology: What You May Have Missed in 2023.

This article summarizes clinically important gastroenterology developments from 2023 for internal medicine specialists. In colorectal cancer screening, a new RNA fecal screening test is on the horizon, as well as a new analysis on the benefits of using artificial intelligence in screening colonoscopy to detect more polyps. There is new evidence for management of gastrointestinal bleeding, a new drug for treatment of recurrent small-intestinal angiodysplasia, and a new endoscopic treatment method in patients with gastrointestinal tumor bleeding. The authors feature a randomized trial about amitriptyline as treatment for patients with irritable bowel syndrome by primary care providers and bring you news about new biologic agents for inflammatory bowel disease and eosinophilic esophagitis. Finally, they review 2 important articles on new terminology and management of metabolic dysfunction-associated fatty liver disease.

Impact of the diagnosis of metabolic dysfunction-associated fatty liver disease and non-alcoholic fatty liver disease in patients undergoing liver transplantation for hepatocellular carcinoma

PurposeWhether the diagnosis of non-alcoholic fatty liver disease or metabolic dysfunction-associated fatty disease has a different impact on liver transplant recipients with hepatocellular carcinoma is not yet clear.MethodsData from a two-center retrospective cohort study were collected to compare and investigate the differences between non-alcoholic fatty liver disease and metabolic dysfunction-associated fatty liver disease in clinicopathologic parameters and prognosis among liver transplant recipients with hepatocellular carcinoma.ResultsA total of 268 liver transplant recipients with hepatocellular carcinoma were included. The prevalence among pre- and post-transplant metabolic dysfunction-associated fatty liver disease was 10.82% and 30.22%, while for non-alcoholic fatty liver disease, it was 7.09% and 26.87%, respectively. The clinicopathological parameters were similar between the two pre-transplant groups. In contrast, the post-transplant group with metabolic dysfunction-associated fatty liver disease exhibited a higher prevalence of diabetes mellitus and a greater body mass index. However, the other parameters were similar between the two post-transplant groups (p > 0.05). Factors such as the largest tumor size > 4 cm, microvascular invasion, lack of tumor capsule, post-transplant metabolic dysfunction-associated fatty liver disease, and decreased post-transplant lymphocyte percentage were related to an increased risk of recurrence.ConclusionIn patients undergone liver transplantation for hepatocellular carcinoma, the diagnosis of metabolic dysfunction-associated fatty disease is more strongly associated with metabolic abnormalities than the diagnosis of non-alcoholic fatty liver disease and is an independent predictor of hepatocellular carcinoma recurrence.

MAFLD as part of systemic metabolic dysregulation.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide. In recent years, a new terminology and definition of metabolic dysfunction-associated fatty liver disease (MAFLD) has been proposed. Compared to the NAFLD definition, MAFLD better emphasizes the pathogenic role of metabolic dysfunction in the development and progression of this highly prevalent condition. Metabolic disorders, including overweight/obesity, type 2 diabetes mellitus (T2DM), atherogenic dyslipidemia and hypertension, are often associated with systemic organ dysfunctions, thereby suggesting that multiple organ damage can occur in MAFLD. Substantial epidemiological evidence indicates that MAFLD is not only associated with an increased risk of liver-related complications, but also increases the risk of developing several extra-hepatic diseases, including new-onset T2DM, adverse cardiovascular and renal outcomes, and some common endocrine diseases. We have summarized the current literature on the adverse effect of MAFLD on the development of multiple extrahepatic (cardiometabolic and endocrine) complications and examined the role of different metabolic pathways and organ systems in the progression of MAFLD, thus providing new insights into the role of MAFLD as a multisystem metabolic disorder. Our narrative review aimed to provide insights into potential mechanisms underlying the known associations between MAFLD and extrahepatic diseases, as part of MAFLD as a multisystem disease, in order to help focus areas for future drug development targeting not only liver disease but also the risk of extrahepatic complications.

Differences in the prevalence of NAFLD, MAFLD, and MASLD according to changes in the nomenclature in a health check-up using MRI-derived proton density fat fraction.

International expert panels proposed new nomenclatures, metabolic dysfunction-associated fatty liver disease (MAFLD) in 2020 and metabolic dysfunction-associated steatotic liver disease (MASLD) in 2023, along with revised diagnostic criteria to replace non-alcoholic fatty liver disease (NAFLD). We aimed to investigate the differences in NAFLD, MAFLD, and MASLD prevalence with changing nomenclature in a health check-up using magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) to assess hepatic steatosis. We also examined the prevalence of the sub-classifications of steatotic liver disease (SLD) and the differences in characteristics among the sub-categories. We included 844 participants who underwent liver MRI-PDFF at our health check-up clinic between January 2020 and November 2022. Hepatic steatosis was defined as MRI-PDFF ≥ 5%. Participants were categorized according to NAFLD, MAFLD, MASLD, and sub-classifications of SLD. The prevalence rates of NAFLD, MAFLD, and MASLD were 25.9%, 29.5%, and 25.2%, respectively. 30.5% of the participants was categorized as SLD. The prevalence rates of the SLD sub-categories were 25.2% for MASLD, 3.7% for MASLD and alcohol-associated liver disease (MetALD), 0.1% for alcohol-associated liver disease, 1.3% for specific etiology SLD, and 0.1% for cryptogenic SLD. Compared with patients in the MASLD group, those in the MetALD group were younger, predominantly male, and exhibited higher levels of serum aspartate aminotransferase, gamma-glutamyl transpeptidase, and triglycerides. The prevalences of NAFLD and MASLD assessed using MRI-PDFF were similar, with MASLD accounting for 97.3% of the patients with NAFLD. The separate MetALD sub-category may have clinical characteristics that differ from those of MASLD.

Intestinal FGF15 regulates bile acid and cholesterol metabolism but not glucose and energy balance.

Fibroblast growth factor 15/19 (FGF15/19, mouse/human ortholog) is expressed in the ileal enterocytes of the small intestine and released postprandially in response to bile acid absorption. Previous reports of FGF15-/- mice have limited our understanding of gut-specific FGF15's role in metabolism. Therefore, we studied the role of endogenous gut-derived FGF15 in bile acid, cholesterol, glucose, and energy balance. We found that circulating levels of FGF19 were reduced in individuals with obesity and comorbidities, such as type 2 diabetes and metabolic dysfunction-associated fatty liver disease. Gene expression analysis of ileal FGF15-positive cells revealed differential expression during the obesogenic state. We fed standard chow or a high-fat metabolic dysfunction-associated steatohepatitis-inducing diet to control and intestine-derived FGF15-knockout (FGF15INT-KO) mice. Control and FGF15INT-KO mice gained similar body weight and adiposity and did not show genotype-specific differences in glucose, mixed meal, pyruvate, and glycerol tolerance. FGF15INT-KO mice had increased systemic bile acid levels but decreased cholesterol levels, pointing to a primary role for gut-derived FGF15 in regulating bile acid and cholesterol metabolism when exposed to obesogenic diet. These studies show that intestinal FGF15 plays a specific role in bile acid and cholesterol metabolism regulation but is not essential for energy and glucose balance.

The role of vascular adhesion protein-1 in diabetes and diabetic complications.

Vascular adhesion protein-1 (VAP-1) plays a dual role with its adhesive and enzymatic properties, facilitating leukocyte migration to sites of inflammation and catalyzing the breakdown of primary amines into harmful by-products, which are linked to diabetic complications. Present in various tissues, VAP-1 also circulates in a soluble form in the bloodstream. Diabetes is associated with several complications such as cardiovascular disease, retinopathy, nephropathy, and neuropathy, significantly contributing to disability and mortality. These complications arise from hyperglycemia-induced oxidative stress, inflammation, and the formation of advanced glycation end-products (AGEs). Earlier research, including our own from the 1990s and early 2000s, has underscored the critical role of VAP-1 in these pathological processes, prompting extensive investigation into its contribution to diabetic complications. In this review, we examine the involvement of VAP-1 in diabetes and its complications, alongside its link to other conditions related to diabetes, such as cancer and metabolic dysfunction-associated fatty liver disease. We also explore the utility of soluble VAP-1 as a biomarker for diabetes, its complications, and other related conditions. Since the inhibition of VAP-1 to treat diabetic complications is a novel and promising treatment option, further studies are needed to translate the beneficial effect of VAP-1 inhibitors observed in animal studies to clinical trials recruiting human subjects. Besides, future studies should focus on using serum sVAP-1 levels for risk assessment in diabetic patients, identifying those who need intensive glycemic control, and determining the patient population that would benefit most from VAP-1 inhibitor therapies.

Food Insecurity, Low Household Income, and Low Education Level Increase the Risk of Having Metabolic Dysfunction-Associated Fatty Liver Disease Among Adolescents in the United States.

In the United States, 10.2% households (HH) report child food insecurity. We assessed associations between metabolic dysfunction-associated fatty liver disease (MASLD) and food insecurity among the adolescents in the United States. This cross-sectional study was performed using data from the National Health and Nutrition Examination Survey 2017-2018. Food insecurity was assessed by the US Department of Agriculture Child Food Security Survey Module. MASLD was defined by transient elastography. Among 771 adolescents (aged 12-18 years) (mean age 14.7 years; 52.5% male; 50.9% White, 12.7% Black, 24.4% Hispanic, and 12.1% other), 9.8% reported food insecurity; MASLD prevalence of 10.12% (95% confidence interval [CI] 7.13%-13.20%) affecting 4.27 million adolescents; and nonalcoholic fatty liver disease prevalence of 10.77% (95% CI 7.76-13.78) affecting 4.52 million adolescents. There was near-perfect concordance between MASLD and nonalcoholic fatty liver disease (Cohen's κ coefficient of 0.971, 95% CI 0.946-0.996). The prevalence of MASLD was greater among food-insecure adolescents vs food-secure ones (17.4% vs 9.4%) and adolescents living with a low HH income vs those with a higher HH income (15.0% vs 7.2%) and living with a head of HH with a lower education level vs one with a higher education level (18.0% vs 8.2%) ( P < 0.05). The fully adjusted model showed that compared with adolescents living in a higher HH income, food-insecure adolescents living in low income HH had a 3-fold greater risk (odds ratio [OR] 3.25, 1.31-8.08) of having MASLD, while food-secure adolescents living in low-income HH had no increased risk (OR 1.58, 0.85-2.93, P = 0.139). The fully adjusted odds of having MASLD was elevated by +163% with the presence of HTN (OR 2.63, 1.02-6.78), +241% with being Hispanic (OR 3.41, 1.36-8.56), and +138% with being male (OR 2.38, 1.20-4.75). In addition, a 1-unit increase in BMI was associated with 25% increase in the odds of having MASLD (OR 1.25, 1.17-1.33) among US adolescents. Food insecurity is associated with MASLD among US low-income adolescents especially Hispanic male individuals with obesity and hypertension. Policies addressing inequities are needed.

Inflammatory liver diseases and susceptibility to sepsis.

Patients with inflammatory liver diseases, particularly alcohol-associated liver disease and metabolic dysfunction-associated fatty liver disease (MAFLD), have higher incidence of infections and mortality rate due to sepsis. The current focus in the development of drugs for MAFLD is the resolution of non-alcoholic steatohepatitis and prevention of progression to cirrhosis. In patients with cirrhosis or alcoholic hepatitis, sepsis is a major cause of death. As the metabolic center and a key immune tissue, liver is the guardian, modifier, and target of sepsis. Septic patients with liver dysfunction have the highest mortality rate compared with other organ dysfunctions. In addition to maintaining metabolic homeostasis, the liver produces and secretes hepatokines and acute phase proteins (APPs) essential in tissue protection, immunomodulation, and coagulation. Inflammatory liver diseases cause profound metabolic disorder and impairment of energy metabolism, liver regeneration, and production/secretion of APPs and hepatokines. Herein, the author reviews the roles of (1) disorders in the metabolism of glucose, fatty acids, ketone bodies, and amino acids as well as the clearance of ammonia and lactate in the pathogenesis of inflammatory liver diseases and sepsis; (2) cytokines/chemokines in inflammatory liver diseases and sepsis; (3) APPs and hepatokines in the protection against tissue injury and infections; and (4) major nuclear receptors/signaling pathways underlying the metabolic disorders and tissue injuries as well as the major drug targets for inflammatory liver diseases and sepsis. Approaches that focus on the liver dysfunction and regeneration will not only treat inflammatory liver diseases but also prevent the development of severe infections and sepsis.

Inhibition of MERTK reduces organ fibrosis in mouse models of fibrotic disease.

Transforming growth factor-β (TGFβ) drives fibrosis and disease progression in a number of chronic disorders, but targeting this ubiquitously expressed cytokine may not yield a viable and safe antifibrotic therapy. Here, we sought to identify alternative ways to inhibit TGFβ signaling using human hepatic stellate cells and macrophages from humans and mice in vitro, as well as mouse models of liver, kidney, and lung fibrosis. We identified Mer tyrosine kinase (MERTK) as a TGFβ-inducible effector of fibrosis that was up-regulated during fibrosis in multiple organs in three mouse models. We confirmed these findings in liver biopsy samples from patients with metabolic dysfunction-associated fatty liver disease (MAFLD). MERTK also induced TGFβ expression and drove TGFβ signaling resulting in a positive feedback loop that promoted fibrosis in cultured cells. MERTK regulated both canonical and noncanonical TGFβ signaling in both mouse and human cells in vitro. MERTK increased transcription of genes regulating fibrosis by modulating chromatin accessibility and RNA polymerase II activity. In each of the three mouse models, disrupting the fibrosis-promoting signaling loop by reducing MERTK expression reduced organ fibrosis. Pharmacological inhibition of MERTK reduced fibrosis in these mouse models either when initiated immediately after injury or when initiated after fibrosis was established. Together, these data suggest that MERTK plays a role in modulating organ fibrosis and may be a potential target for treating fibrotic diseases.

Ultrasonic evaluation MAFLD in screening severety matabolic disorders

Metabolic dysfunction associated fatty liver disease (MAFLD) is a new proposed term for non-alcoholic fatty liver disease (NAFLD). a liver steatosis associated with Type 2 diabetes mellitus or increased physical weight/thickness, or with two or more metabolic disorders. This indicates metabolic abnormalities that result in fat accumulation in hepatocytes without the presence of alcoholic liver disease or other causes that would lead to hepatocyte abnormalities. Our goal was determine the correlation between certain stages of fatty liver disease determined by ultrasonography with increased body weight/obesity, diabetes mellitus and other metabolic disorders and with the values of biochemical parameters of liver enzymes. A prospective study was conducted at the public health institution Zivinice Health Center from August 2022 until January 2024 on a random sample of 101 patients. Observing the entire examined group, a difference in the gender distribution of hepatic steatosis is noticed, and graphically it is shown that men have hepatic steatosis more often than women. In fatty liver disease (MAFLD), stage G2 was most prevalent in 32% of patients. Ultrasonography, along with clinical and biochemical indicators, should be an integral part of screening and monitoring of metabolic disorders as it is a non-invasive and easily accessible imaging method and allows timely therapeutic action and prevention of hepatic and extrahepatic complications.

The Many Faces of Metabolic Dysfunction-Associated Fatty Liver Disease Treatment: From the Mediterranean Diet to Fecal Microbiota Transplantation

The gastrointestinal tract is inhabited by the gut microbiota. The main phyla are Firmicutes and Bacteroidetes. In non-alcoholic fatty liver disease, now renamed metabolic dysfunction-associated fatty liver disease (MAFLD), an alteration in Firmicutes and Bacteroidetes abundance promotes its pathogenesis and evolution into non-alcoholic steatohepatitis, liver cirrhosis, and hepatocellular carcinoma. For this reason, early treatment is necessary to counteract its progression. The aim of the present narrative review is to evaluate the different therapeutic approaches to MAFLD. The most important treatment for MAFLD is lifestyle changes. In this regard, the Mediterranean diet could be considered the gold standard in the prevention and treatment of MAFLD. In contrast, a Western diet should be discouraged. Probiotics and fecal microbiota transplantation seem to be valid, safe, and effective alternatives for MAFLD treatment. However, more studies with a longer follow-up and with a larger cohort of patients are needed to underline the more effective approaches to contrasting MAFLD.

Association between dietary carbohydrate to fiber ratio and metabolic dysfunction associated fatty liver disease in adults: evidence from the NHANES 2017–2020

This study aimed to explore the association of carbohydrate to fiber ratio (CFR) with metabolic dysfunction-associated fatty liver disease (MAFLD) in adults. In this study, data from the 2 cycles (2017–2018 and 2019–2020) of the NHANES were used. Univariate and multivariate weighted logistic regression analyses were applied to evaluate the association between CFR and MAFLD. Odds ratios (ORs) and 95% confidence levels (CIs) were estimated. Subgroup analysis was further performed in terms of gender, age and comorbidity (diabetes, hypertension). A total of 3180 individuals were included, with 1408 (44.28%) in the non-MAFLD group and 1772 (55.72%) in the MAFLD group. After adjusting different variables, a dietary fiber intake of 11.15–18.40 g was associated with significantly lower odds of MAFLD compared with a fiber intake < 11.15 g (OR = 0.71, 95% CI 0.54–0.93). In contrast to a dietary CFR < 12.58, a CFR > 19.91 was associated with significantly higher odds of MAFLD (OR = 1.57, 95% CI 1.09–2.27). Compared with females with a dietary CFR < 12.58, those with a CFR > 19.91 had significantly increased odds of MAFLD (OR = 1.87, 95% CI 1.29–2.73). Among individuals aged < 65 years, a dietary CFR > 19.91 was associated with higher odds of MAFLD than a dietary CFR < 12.58 (OR = 1.52, 95% CI 1.02–2.25). For participants without diabetes (OR = 1.79, 95% CI 1.26–2.54) or hypertension (OR = 1.93, 95% CI 1.02–3.65), a dietary CFR > 19.91 was associated with elevated odds of MAFLD than a CFR < 12.58. In summary, a higher CFR was associated with significantly greater odds of MAFLD, indicating the negative association between carbohydrate quality and MAFLD. The research would be conducive to metabolic dysfunction-associated fatty liver disease treatment.

Update in lean metabolic dysfunction-associated steatotic liver disease.

A new nomenclature consensus has emerged for liver diseases that were previously known as non-alcoholic fatty liver disease (NAFLD) and metabolic dysfunction-associated fatty liver disease (MAFLD). They are now defined as metabolic dysfunction-associated steatotic liver disease (MASLD), which includes cardiometabolic criteria in adults. This condition, extensively studied in obese or overweight patients, constitutes around 30% of the population, with a steady increase worldwide. Lean patients account for approximately 10%-15% of the MASLD population. However, the pathogenesis is complex and is not well understood. To systematically review the literature on the diagnosis, pathogenesis, characteristics, and prognosis in lean MASLD patients and provide an interpretation of these new criteria. We conducted a comprehensive database search on PubMed and Google Scholar between January 2012 and September 2023, specifically focusing on lean NAFLD, MAFLD, or MASLD patients. We include original articles with patients aged 18 years or older, with a lean body mass index categorized according to the World Health Organization criteria, using a cutoff of 25 kg/m2 for the general population and 23 kg/m2 for the Asian population. We include 85 studies in our analysis. Our findings revealed that, for lean NAFLD patients, the prevalence rate varied widely, ranging from 3.8% to 34.1%. The precise pathogenesis mechanism remained elusive, with associations found in genetic variants, epigenetic modifications, and adaptative metabolic response. Common risk factors included metabolic syndrome, hypertension, and type 2 diabetes mellitus, but their prevalence varied based on the comparison group involving lean patients. Regarding non-invasive tools, Fibrosis-4 index outperformed the NAFLD fibrosis score in lean patients. Lifestyle modifications aided in reducing hepatic steatosis and improving cardiometabolic profiles, with some medications showing efficacy to a lesser extent. However, lean NAFLD patients exhibited a worse prognosis compared to the obese or overweight counterpart. MASLD is a complex disease comprising epigenetic, genetic, and metabolic factors in its pathogenesis. Results vary across populations, gender, and age. Limited data exists on clinical practice guidelines for lean patients. Future studies employing this new nomenclature can contribute to standardizing and generalizing results among lean patients with steatotic liver disease.

The Reduced Gut Lachnospira Species Is Linked to Liver Enzyme Elevation and Insulin Resistance in Pediatric Fatty Liver Disease.

The objective of this study was to investigate gut dysbiosis and its metabolic and inflammatory implications in pediatric metabolic dysfunction-associated fatty liver disease (MAFLD). This study included 105 children and utilized anthropometric measurements, blood tests, the Ultrasound Fatty Liver Index, and fecal DNA sequencing to assess the relationship between gut microbiota and pediatric MAFLD. Notable decreases in Lachnospira spp., Faecalibacterium spp., Oscillospira spp., and Akkermansia spp. were found in the MAFLD group. Lachnospira spp. was particularly reduced in children with MAFLD and hepatitis compared to controls. Both MAFLD groups showed a reduction in flavone and flavonol biosynthesis sequences. Lachnospira spp. correlated positively with flavone and flavonol biosynthesis and negatively with insulin levels and insulin resistance. Body weight, body mass index (BMI), and total cholesterol levels were inversely correlated with flavone and flavonol biosynthesis. Reduced Lachnospira spp. in children with MAFLD may exacerbate insulin resistance and inflammation through reduced flavone and flavonol biosynthesis, offering potential therapeutic targets.

Abstract 2169: Dietary inflammatory potential and mortality among patients with MAFLD

Abstract Background: Inflammation is important in metabolic dysfunction-associated fatty liver disease (MAFLD) development and progression. However, evidence regarding the influence of dietary inflammatory potential and mortality among people with MAFLD is rare. This study aimed to elucidate the association of the energy-density dietary inflammatory index (E-DII) with all-cause and cause-specific mortality among MAFLD patients. Methods: Data were obtained from the National Health and Nutrition Examination Survey (NHANES) (1988-1994, 1999-2010). MAFLD was defined as the evidence of hepatic steatosis with ≥1 of the following: type 2 diabetes (T2DM), overweight/obesity (OW, BMI ≥ 25 kg/m2), or lean metabolic dysregulation (MD). Dietary intake was assessed through 24-hour dietary recalls. E-DII scores and component intakes were divided into tertiles, with T1 as the reference. Through linkage to National Death Index by December 31, 2019, mortality from all cause, cardiovascular disease (CVD), and cancer were identified. Multivariable Cox proportional hazards regression model and restricted cubic splines (RCS) were used to analyze the association between dietary inflammatory potential and mortality among MAFLD and its subtypes patients. Results: A total of 6537 MAFLD patients were included in the present analysis. During the median follow-up of 16.8 years, 2281 total deaths (534 cancer-related, 750 CVD-related) were documented. Compared to high dietary inflammatory potential, low dietary inflammatory potential presented a inverse association with all-cause mortality risk in MAFLD patients (HR T2 vs. T1 = 0.83, 95% CI = 0.72-0.95, HR T3 vs. T1 = 0.88, 95% CI = 0.76-1.01, P trend = 0.092) and OW subtype patients (HR T2 vs. T1 = 0.77, 95% CI = 0.63-0.93, HR T3 vs. T1 = 0.76, 95% CI = 0.63-0.92, P trend = 0.009). No significant benefit was observed among T2DM and MD subtype patients. Further component analysis found that eicosapentaenoic acid (EPA) (HR = 0.74, 95% CI = 0.66-0.83), docosapentaenoic acid (DPA) (HR = 0.72, 95% CI = 0.65-0.80), docosahexaenoic acid (DHA) (HR = 0.85, 95% CI = 0.65-0.80), and linoleic acid (HR = 0.86, 95% CI = 0.79-0.94) were linked with reduced cancer mortality risk in MAFLD patients. Further RCS analyses found that the effect pattern of EPA, DPA, and DHA on both all-cause and cause-specific mortality was presented as “J shaped” (P non-linear &amp;lt; 0.05). Similar results were observed for all-cause and CVD mortality among both MAFLD and OW subtype patients. When excluding participants who died within five years, consistent results were presented. Conclusions: The findings of this study suggest that keep low-inflammatory dietary pattern, especially appropriate level of PUFAs component (EPA, DPA, and DHA) intake were associated with a lower risk of cancer mortality in MAFLD patients. These findings may inform future public health guidelines regarding specific dietary consumption, and liver-related health promotion. Citation Format: Zhangyan Lyu, Yacong Zhang, Wenxuan Li, Guoijn Si, Kexin Chen. Dietary inflammatory potential and mortality among patients with MAFLD [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2169.

Abstract 2637: Super-enhancer-related m6A modification promotes immune escape in hepatocellular carcinoma associated with metabolic dysfunction-associated fatty liver disease via CCL4 signaling pathway inhibition

Abstract The incidence and mortality rates of hepatocellular carcinoma caused by metabolic dysfunction-associated fatty liver disease (MAFLD) have been increasing in recent decades, emphasizing the urgent need for new therapeutic approaches. Emerging evidence suggests that approximately 80% of super-enhancer RNAs (seRNAs) undergo selective m6A modifications. seRNA and m6A modifications have been implicated in the progression of various cancers, making them potential targets for therapeutic intervention. Based on our previous research, we hypothesize that the lack of m6A modification on the super-enhancer of CCL4 may contribute to the reduced expression of the CCL4 gene in HCC.To validate our hypothesis, we employ nano-chromatin immunoprecipitation combined with high-throughput sequencing (nano-ChIP-seq), m6A-seq (m6A-seq), single-cell RNA sequencing (scRNA-seq) on multiple models including clinical samples, cell lines, and mouse models. Interestingly, we have made a significant discovery that overexpression of CCL4 in tumor cells enhances the infiltration of CD8+ T cells, which are crucial for anti-tumor immune responses. In contrast, normal tissue cells undergo m6A modification on the CCL4 seRNAs, while this modification is notably absent in cancerous tissue. Consequently, the reduced expression of CCL4 could impair the tumor-killing capabilities of CD8+ T cells and facilitate immune evasion by the tumor.Furthermore, our results shed light on the underlying molecular mechanisms involving super-enhancers and m6A modifications in the regulation of immune escape in MAFLD HCC. We identify the specific super-enhancer and downstream regulatory genes influenced by m6A modification in MAFLD-associated HCC, providing valuable insights and novel targets for the treatment of this condition. Citation Format: Liangliang Xu. Super-enhancer-related m6A modification promotes immune escape in hepatocellular carcinoma associated with metabolic dysfunction-associated fatty liver disease via CCL4 signaling pathway inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2637.

Exploring the impacts of ketogenic diet on reversible hepatic steatosis: initial analysis in male mice.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common chronic liver disease. Ketogenic diet (KD), a diet with very low intake in carbohydrates, gained popularity as a weight-loss approach. However, in mice models, it has been reported that an excess exposition of dietary fat induces hepatic insulin resistance and steatosis. However, data published is inconsistent. Herein, we investigated in a mouse model, the metabolic effects of KD and its contribution to the pathogenesis of NALFD. Mice were exposed to KD or CHOW diet for 12 weeks while a third group was exposed to KD for also 12 weeks and then switched to CHOW diet for 4 weeks to determine if we can rescue the phenotype. We evaluated the effects of diet treatments on fat distribution, glucose, and insulin homeostasis as well as hepatic steatosis. Mice fed with KD developed glucose intolerance but not insulin resistance accompanied by an increase of inflammation. KD-fed mice showed an increase of fat accumulation in white adipose tissue and liver. This effect could be explained by an increase in fat uptake by the liver with no changes of catabolism leading to MAFLD. Interestingly, we were able to rescue the phenotype by switching KD-fed mice for 4 weeks on a CHOW diet. Our studies demonstrate that even if mice develop hepatic steatosis and glucose intolerance after 12 weeks of KD, they do not develop insulin resistance and more importantly, the phenotype can be reversed by switching the mice from a KD to a CHOW.

Breastfeeding and fatty liver - is there any association?

The campaign to promote the natural feeding of infants, at least for the first six months of life, conducted over recent years has deep justification from a medical point of view. Numerous gynecological and pediatric societies around the world recommend breastfeeding as the most appropriate way of feeding infants. It has been proven that the benefits of this type of nutrition go beyond nutritional aspects, proper growth and development. The list of long-term metabolic benefits, which include reducing the incidence of obesity, allergies, infections and diabetes, is constantly growing. It has been shown that the method of feeding infants using various mechanisms may influence the tendency of the liver to accumulate fatty compounds and develop fatty liver disease with its metabolic consequences leading to liver failure, cirrhosis and hepatocellular carcinoma. This is an important discovery due to the growing obesity epidemic in adults and children. Metabolic dysfunction - associated fatty liver disease (MAFLD) has become the most common cause of chronic liver disease, affecting 25% of the global population. The results of studies conducted in recent years have shown the protective effect of breastfeeding on the risk of developing MAFLD later in life in both children and breastfeeding women. New scientific reports provide the basis for qualifying breastfeeding as a modifiable risk factor for MAFLD.

Relevant Aspects of Combined Protocols for Prevention of N(M)AFLD and Other Non-Communicable Diseases.

Obesity is a global health issue characterized by the excessive fat accumulation, leading to an increased risk of chronic noncommunicable diseases (NCDs), including metabolic dysfunction-associated fatty liver disease (MAFLD), which can progress from simple steatosis to steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Currently, there are no approved pharmacological protocols for prevention/treatment of MAFLD, and due the complexity lying beneath these mechanisms, monotherapies are unlikely to be efficacious. This review article analyzes the possibility that NCDs can be prevented or attenuated by the combination of bioactive substances, as they could promote higher response rates, maximum reaction results, additive or synergistic effects due to compounds having similar or different mechanisms of action and/or refraining possible side effects, related to the use of lower doses and exposures times than monotherapies. Accordingly, prevention of mouse MAFLD is observed with the combination of the omega-3 docosahexaenoic acid with the antioxidant hydroxytyrosol, whereas attenuation of mild cognitive impairment is attained by folic acid plus cobalamin in elderly patients. The existence of several drawbacks underlying published monotherapies or combined trials, opens space for adequate and stricter experimental and clinical tryouts to achieve meaningful outcomes with human applicability.