Liver Metabolic Disorders Research Articles

Lactobacillus fermentum KP101 fermentation broth improves high-fat diet-induced hyperlipidemia in mice by modulation of liver lipid metabolism and intestinal flora dysbiosis

Abstract Non-alcoholic fatty liver disease (NAFLD) is a primary chronic liver ailment around the world, posing a significant threat to human health. Probiotics, living microorganisms that enhance intestinal flora equilibrium and mitigate blood lipid levels. This study aimed to identify probiotics with excellent antioxidant capacity from naturally fermented foods, and investigate their potential mechanisms in relieving high-fat diet (HFD)-induced liver injury and modulating intestinal flora balance. These findings fundamentally benefit the advancement of functional probiotic foods. Lactobacillus fermentum KP101, isolated from kimchi, was evaluated for its antioxidant activity. Assessment of HFD-induced liver injury was based on the biochemical markers, protein expression levels, and liver histopathology. L. fermentum KP101 remarkably reduced mice serum and liver levels of TC, TG, LDL, ALT, and AST. L. fermentum KP101 intervention effectively modulated HFD-induced dyslipidemia and activated the AMPK signalling pathway to alleviate liver injury. Specifically, the protein expression levels of SREBP-1 and p-ACC presented an obvious reduction, while the expression of p-AMPK and PPARα was notably increased following L. fermentum KP101 treatment. Moreover, L. fermentum KP101 effectively mitigated intestinal flora dysbiosis in HFD-fed mice. In summary, L. fermentum KP101 demonstrated efficacy in improving hyperlipidemia and liver metabolic disorders in mice with HFD-induced conditions.

Microenvironment-induced programmable nanotherapeutics restore mitochondrial dysfunction for the amelioration of non-alcoholic fatty liver disease.

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

Gut Commensal Barnesiella Intestinihominis Ameliorates Hyperglycemia and Liver Metabolic Disorders.

Recent studies have highlighted the role of the gut microbiota in type 2 diabetes (T2D). Improving gut microbiota dysbiosis can be a potential strategy for the prevention and management of T2D. Here, this work finds that the abundance of Barnesiella intestinihominis is significantly decreased in the fecal of T2D patients from 2-independent centers. Oral treatment of live B. intestinihominis (LBI) considerably ameliorates hyperglycemia and liver metabolic disorders in HFD/STZ-induced T2D models and db/db mice. LBI-derived acetate has similar protective effects against T2D. Mechanistically, acetate enhances fibroblast growth factor 21 (FGF21) through inhibition of histone deacetylase 9 (HDAC9) to increase H3K27 acetylation at the FGF21 promoter. The screening puerarin from Gegen Qinlian decoction in a gut microbiota-dependent manner improved hyperglycemia and liver metabolic disorders by promoting the growth of B. intestinihominis. This study suggests that gut commensal B. intestinihominis and puerarin, respectively have the potential as a probiotic and prebiotic in the treatment of T2D.

Biological and clinical role of TREM2 in liver diseases.

Liver diseases constitute a major health burden worldwide, accounting for more than 4% of all disease-related mortalities. While the incidence of viral hepatitis is expected to decrease, metabolic liver disorders are increasingly diagnosed. Liver pathology is diverse, with functional and molecular alterations in both parenchymal and mesenchymal cells, including immune cells. Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane receptor of the immunoglobulin superfamily and mainly expressed on myeloid cells. Several studies have demonstrated that TREM2 plays a critical role in tissue physiology and various pathological conditions. TREM2 is recognized as being associated with the development of liver diseases by regulating tissue homeostasis and the immune microenvironment. The biological and clinical impact of TREM2 is complex, given its diverse context-dependent functions. This review aims to summarize recent progress in understanding the association between TREM2 and different liver disorders and shed light on the clinical significance of targeting TREM2.

Ameliorative effects of Bacillus subtilis C10 on alcoholic liver injury in mice.

Bacillus subtilis has been reported to maintain the homeostasis of intestinal flora. In this study, a mouse model of alcoholic liver injury (ALI) was constructed to study the ameliorative effect of B. subtilis C10 on ALI and to further clarify its mechanism of action. Significant correlations between intestinal flora and biochemical indicators of ALI were found by statistical correlation analysis. Supplementation with B. subtilis C10 modulated the equilibrium of gut flora by reducing the population of detrimental bacteria while enhancing the numbers of beneficial microorganisms, which resulted in an improvement in lipid metabolism and oxidative stress in the liver. The results of RT-qPCR showed that B. subtilis C10 intervention regulated the main regulatory factors of liver lipid metabolism (PPAR-α, SREBP-1c) and interfered with Nrf-2/Ho-1 signal pathway, which in turn ameliorated alcohol-induced lipid metabolism disorder and liver peroxidation stress. In addition, liver metabonomic analysis showed that B. subtilis C10 intervention reduced the production of harmful metabolites and increased beneficial metabolites in the liver, thereby reversing the metabolic disturbances caused by excessive alcohol consumption. KEGG analysis showed that B. subtilis C10 intervention modulated liver metabolic disorders and accelerated lipid metabolism by regulating glutathione metabolic pathway, purine metabolic pathway, pantothenic acid and CoA biosynthesis pathway, ABC transporter protein pathway, and HIF-1 signaling pathway. Taken together, these findings suggest that B. subtilis C10 ameliorates ALI by modifying the structure of intestinal flora and liver metabolic pathways to attenuate alcohol-exposure-induced liver oxidative damage and lipid metabolism abnormalities. PRACTICAL APPLICATION: Bacillus subtilis C10 is an effective probiotic intervention that significantly ameliorated alcoholic liver injury in mice through the gut-liver axis. B. subtilis C10 can be used as a dietary probiotic to develop functional foods with beneficial effects for the population of excessive alcohol consumption.

Hepatitis B small surface protein hijacking Bip is initial and essential to promote lipid synthesis

To date, the molecular pathogenic mechanisms between HBsAg and liver metabolic disorders have not been fully understood. To explore the overall effects of HBsAg on liver tissues from HBV transgenic mice, proteome, interactome, and signal pathway analysis were employed to uncover the underlying mechanisms. Bioinformatics analysis of 191 differentially expressed proteins suggested that HBV upregulated the expression of multiple enzymes involved in lipid synthesis, and small HBs (SHBs) caused lipid accumulation in cells. Further studies showed that SHBs bound to binding immunoglobulin protein (Bip), which normally functions in cell homeostasis against the unfolded protein response (UPR) signaling via occupying inositol-requiring enzyme 1 (IRE1). Hijacking Bip by SHBs alleviated the inhibition of post-endoplasmic reticulum (ER) signaling and sequential activation of the IRE1 downstream transcription factors involved in lipid synthesis, such as spliced X-box binding protein 1 (sXBP1) and sterol regulatory element-binding protein 1 (SREBP1), leading to lipid metabolism disorder. The restoration of Bip can alleviate ER stress, and block the sequential post-ER signaling caused by SHBs. This study revealed a new pathway through which SHBs promote lipid disorder, and suggests that Bip may serve as a novel target for intervention in HBV related liver diseases. SignificanceIn this study, we found a new pathway promoting the lipid disorder by SHBs through quantitative proteomics studies, and Bip may serve as a novel target for intervention in HBV related liver diseases. These findings highlight a novel role of SHBs in regulating cell lipid metabolism and provide an insight into the relationship between HBV infection and liver fatty disorders, which may serve as a potential therapeutic target for intervention of HBV related liver diseases.

Daphnetin ameliorates hepatic steatosis by suppressing peroxisome proliferator-activated receptor gamma (PPARG) in ob/ob mice

Non-alcoholic fatty liver disease (NAFLD) is the predominant metabolic liver disorder and currently lacks effective and safe pharmaceutical interventions. Daphnetin (DA), a natural coumarin derivative with anti-inflammatory and antioxidant activities, is a promising agent for NAFLD treatment. In this study, we evaluated the effects and mechanisms of DA on hepatic lipid metabolism in ob/ob mice. Our results showed that DA effectively ameliorates glucose metabolism and hepatic lipid accumulation in ob/ob mice. Metabolomics and RNA sequencing (RNA-seq), combined with GEO data analysis, suggest that DA primarily modulates the peroxisome proliferator-activated receptor gamma (PPARG) pathway, as validated in vivo in ob/ob mice. Mechanistically, DA selectively targets PPARG in hepatic cells by inhibiting PPARG promoter activity and downregulating its expression, resulting in decreased transcription of downstream lipid metabolism-related genes, including fatty acid binding protein 4 (Fabp4), cluster of differentiation 36 (Cd36), and fatty acid synthase (Fasn). This effect was abolished in PPARG-deficient HepG2 cells subjected to palmitic acid (PA) insult. Our findings provide evidence that DA acts as a selective suppressor of hepatic PPARG, suggesting an attractive strategy by targeting PPARG for the prevention of hepatic steatosis.

Amelioration of metabolic and behavioral defects through base editing in the PahR408W phenylketonuria mouse model

Phenylketonuria (PKU) is a liver metabolic disorders mainly caused by a deficiency of the hepatic phenylalanine hydroxylase (PAH) enzyme activity, often leading to severe brain function impairment in patients if untreated or if treatment is delayed. In this study, we utilized dual-AAV8 vectors to deliver a near PAM-less adenine base editor variant, known as ABE8e-SpRY, to treat the PahR408W PKU mouse model carrying a frequent R408W mutation in the Pah gene. Our findings revealed that a single intravenous injection in adult mice and a single intraperitoneal injection in neonatal mice resulted in 19.1% to 34.6% A-to-G editing efficiency at the pathogenic mutation site with minimal bystander edits. Furthermore, the dual-AAV8 treated mice exhibited reduced blood Phe levels to below the therapeutic threshold of 360 μmol L-1 and restored weight and fur color to normal levels. Importantly, the brain function of the mice was restored after the treatment, particularly when administered during the neonatal stage, as levels of monoamine neurotransmitters and metabolites in the brain returned to normal and near-normal levels. Our study demonstrated that ABE8e-SpRY-based base editing could effectively correct the point mutation in the PahR408W PKU mouse model, indicating potential clinical applications for PKU and other genetic diseases.

Schisandrin A alleviates non-alcoholic fatty liver disease by improving liver metabolic disorders and suppressing the GSK3β signaling pathway

Non-alcoholic fatty liver disease (NAFLD) is a clinical pathological syndrome characterized by excessive fat deposition in liver cells, posing a new challenge in the field of contemporary medicine. Schisandrin A (SchA) is a lignan derived from the fruit of Schisandra chinensis, a functional food and also a traditional herbal medicine known for its hepatic protective effects. The study aims to identify potential target and regulation mechanism of SchA on NAFLD treatment. Metabolomics analysis revealed that SchA improved the abnormal metabolic profile of the liver in NAFLD mice. In addition to ameliorating lipid metabolism, SchA showed potential in elevating the levels of amino acids such as L-tryptophan, beta-alanine, L-aspartic acid, and L-tyrosine, which were deficient in NAFLD mouse livers, as well as restored the metabolism of abnormal vitamins like vitamin B6. Network pharmacology research and molecular docking suggested that GSK3β was a direct target of SchA, which was experimentally validated as well. These findings highlight the potential value of the active component SchA from Schisandra chinensis in the prevention and treatment of NAFLD.

Comparative analysis of high-fat diets: Effects of mutton, beef, and vegetable fats on body weight, biochemical profiles, and liver histology in mice

BackgroundHigh-fat diets are associated with metabolic syndrome, cardiovascular diseases, and liver disorders. Beef and mutton, both widely consumed meats, are significant sources of animal fat, while soybean oil, a commonly used cooking oil, is a prominent source of plant-derived fat. This study aimed to compare the effects of regular consumption of beef fat, mutton fat, and soybean oil in mice to assess potential health risks. MethodsSixty Swiss albino male mice were divided into four groups: a control group (Group A) fed a standard mice pellet, and three treatment groups (Groups B, C, D) receiving 10 % dietary fat from mutton, beef, and soybean oil, respectively. Parameters such as body weight, caloric intake, serum markers, and liver histopathology were studied. ResultsConsumption of mutton fat, beef fat, or soybean oil supplemented diet in groups B, C, and D led to higher caloric intake and body weight compared to control group A, which received a standard diet. These diets also caused elevated serum glucose, impaired glucose tolerance, and increased triglycerides, cholesterol, LDL-C, and reduced HDL-C. Elevated AST and ALT levels in the high-fat diet groups, indicated liver damage and fat accumulation. Histological analysis confirmed steatosis, hepatocyte ballooning, and inflammation in all three high-fat diet groups, while the control group had normal liver histology. ConclusionHigh-fat diets, whether plant- or animal-based, led to weight gain in mice and resulted, poor glucose tolerance, dyslipidemia, liver damage and steatohepatitis. Further research is needed to explore the mechanisms behind these effects and improve understanding and management of high-fat diet consequences.

Immune remodulation in pediatric inherited metabolic liver diseases.

Inherited metabolic liver diseases arise from genetic mutations that lead to disruptions in liver metabolic pathways and are predominantly observed in pediatric populations. The spectrum of genetic metabolic liver disorders is diverse, encompassing a range of conditions associated with aberrations in iron, copper, carbohydrate, lipid, protein, and amino acid metabolism. Historically, research in the domain of genetic metabolic liver diseases has predominantly concentrated on hepatic parenchymal cell alterations. Nevertheless, emerging studies suggest that inherited metabolic liver diseases exert significant influences on the immune microenvironment, both within the liver and systemically. This review endeavors to encapsulate the immunological features of genetic metabolic liver diseases, aiming to expand the horizons of researchers in this discipline, and to elucidate the underlying pathophysiological mechanisms pertinent to hereditary metabolic liver diseases and to propose innovative therapeutic approaches.

Biomarkers for Health Functional Foods in Metabolic Dysfunction-Associated Steatotic Liver Disorder (MASLD) Prevention: An Integrative Analysis of Network Pharmacology, Gut Microbiota, and Multi-Omics.

Metabolic dysfunction-associated steatotic liver disorder (MASLD) is increasingly prevalent globally, highlighting the need for preventive strategies and early interventions. This comprehensive review explores the potential of health functional foods (HFFs) to maintain healthy liver function and prevent MASLD through an integrative analysis of network pharmacology, gut microbiota, and multi-omics approaches. We first examined the biomarkers associated with MASLD, emphasizing the complex interplay of genetic, environmental, and lifestyle factors. We then applied network pharmacology to identify food components with potential beneficial effects on liver health and metabolic function, elucidating their action mechanisms. This review identifies and evaluates strategies for halting or reversing the development of steatotic liver disease in the early stages, as well as biomarkers that can evaluate the success or failure of such strategies. The crucial role of the gut microbiota and its metabolites for MASLD prevention and metabolic homeostasis is discussed. We also cover state-of-the-art omics approaches, including transcriptomics, metabolomics, and integrated multi-omics analyses, in research on preventing MASLD. These advanced technologies provide deeper insights into physiological mechanisms and potential biomarkers for HFF development. The review concludes by proposing an integrated approach for developing HFFs targeting MASLD prevention, considering the Korean regulatory framework. We outline future research directions that bridge the gap between basic science and practical applications in health functional food development. This narrative review provides a foundation for researchers and food industry professionals interested in developing HFFs to support liver health. Emphasis is placed on maintaining metabolic balance and focusing on prevention and early-stage intervention strategies.

Proteomic analysis of toxic effects of short-term cadmium exposure on goat livers.

Food safety is closely related to environmental pollution. It is worth noting that the long-term accumulation of Cd, a toxic heavy metal, in animals may pose a threat to human health through food chain. Previous studies have found that Cd exposure may cause liver metabolic disorders of black goats, but the mechanism of its impact on liver proteome of goats has not been widely studied. Therefore, in this study, ten male goats (Nubian black goat × native black goat) were exposed to Cd via drinking water containing CdCl2 (20mg Cd·kg-1·BW) for 30days (five male goats per group). Blood physiology and liver antioxidant indices in black goats were determined and differentially expressed proteins (DEPs) in the livers of Cd-exposed goats were profiled by using TMT-labelled proteomics. It was found that plasma Hb and RBC levels as well as PCV values were decreased, liver SOD, GSH-Px, T-AOC and CAT levels were decreased, and MDA level was increased in Cd-treated goats, and 630 DEPs (up 326, down 304) in the livers of Cd-treated goats. Proteomics analysis revealed that Cd exposure affected glutathione metabolism and drug metabolism-cytochrome P450. We identified GP×2, GSTM3, and TBXAS1 as potential protein markers of early Cd toxicity in goats. This study provided theoretical basis for early diagnosis of Cd poisoning in goats.

Portable Sensing Probe for Real-Time Quantification of Ammonia in Blood Samples.

The detection of ammonia levels in blood is critical for diagnosing and monitoring various medical conditions, including liver dysfunction and metabolic disorders. However, traditional diagnostic methods are slow and cumbersome, often involving multiple contact-based steps such as ammonia separation in alkali conditions followed by distillation or microdiffusion, leading to delays in diagnosis and treatment. Herein, we developed a colorimetric assay capable of rapid detection of ammonia in whole blood or plasma samples, utilizing 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO)-oxidized cellulose nanocrystals (TCNC) coupled with gold nanoparticles (AuNPs). The basis of our assay relies on either (i) the interaction between the carboxylate group (-COO) of TEMPO and ammonium ions or (ii) the manipulation of AuNPs surface plasmon resonance (SPR) through the formation of Au(NH3)43+, which displaces a redox mediator, resazurin, resulting in observable multicolor displays at various concentrations of ammonia. The colorimetric assay exhibits a wide linear detection range for dissolved NH4+ (0.1-37 μM) with a low limit of detection (LOD) of 0.1 μM. Additionally, it effectively measures NH3(g) concentrations in the range of 0.5-144 μM. The fabricated electrochemical nose (E-nose) device demonstrates excellent analytical performance for plasma ammonia sensing (0.05-256 μM). Experimental results demonstrate a linear detection range suitable for clinical applications, with excellent correlation to standard laboratory methods, offering a practical solution for point-of-care (PoC) testing. We anticipate that this approach can be applied broadly to improve patient monitoring and treatment by providing immediate and accurate ammonia measurements in a clinical setting.

Unexpected role of blood platelets in early liver metabolic disorders

Unexpected role of blood platelets in early liver metabolic disorders

Correlation of Liver Enzymes and Serum Ferritin in Patients With β-Thalassaemia Major

Background: β-Thalassemia major is a hereditary hematological disorder that necessitates regular blood transfusions, leading to iron overload and subsequent liver injury. Elevated serum liver enzymes and ferritin are commonly used to monitor liver function in these patients; however, their reliability in predicting true hepatic dysfunction remains unclear. Objective: To determine the sensitivity, specificity, and diagnostic accuracy of serum liver enzymes and ferritin in predicting liver dysfunction, with hypoalbuminemia as the gold standard, in pediatric patients with β-thalassemia major. Methods: This cross-sectional validation study was conducted at the Department of Paediatrics, Combined Military Hospital, Rawalpindi, from July 2022 to February 2024. A total of 75 pediatric patients with β-thalassemia major were included using consecutive non-probability sampling. Patients with concurrent liver diseases, metabolic disorders, or conditions that could alter liver enzyme levels were excluded. Blood samples were collected to measure serum Alanine Transaminase (ALT), Aspartate Transaminase (AST), γ-Glutamyltransferase (γ-GT), ferritin, and albumin levels. Hypoalbuminemia was defined as a serum albumin level <3.5 g/L. The diagnostic accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of ALT, AST, γ-GT, and ferritin in predicting hypoalbuminemia were calculated using 2×2 contingency tables. Data were analyzed using SPSS version 25. Results: Among the 75 patients, 18 (24.0%) exhibited hypoalbuminemia. The sensitivity, specificity, and diagnostic accuracy of ALT in detecting hypoalbuminemia were 83.33%, 31.58%, and 44.00%, respectively. For AST, these values were 50.00%, 29.82%, and 34.67%, respectively. γ-GT showed a sensitivity of 83.33%, specificity of 14.04%, and diagnostic accuracy of 30.67%. Ferritin had a sensitivity of 83.33%, specificity of 19.30%, and diagnostic accuracy of 34.67%. None of the markers showed satisfactory predictive value for hypoalbuminemia. There was a partial correlation between hyperferritinemia and elevated liver enzymes, with γ-GT showing the highest sensitivity (91.80%) and diagnostic accuracy (82.67%). Conclusion: Serum liver enzymes and ferritin are not reliable markers for predicting liver dysfunction as indicated by hypoalbuminemia in pediatric patients with β-thalassemia major. These findings suggest that additional clinical assessments and more specific biomarkers are necessary for accurate evaluation of liver health in this population.

Gene editing in liver diseases.

The deliberate and precise modification of the host genome using engineered nucleases represents a groundbreaking advancement in modern medicine. Several clinical trials employing these approaches to address metabolic liver disorders have been initiated, with recent remarkable outcomes observed in patients with transthyretin amyloidosis, highlighting the potential of these therapies. Recent technological improvements, particularly CRISPR Cas9-based technology, have revolutionized gene editing, enabling in vivo modification of the cellular genome for therapeutic purposes. These modifications include gene supplementation, correction, or silencing, offering a wide range of therapeutic possibilities. Moving forward, we anticipate witnessing the unfolding therapeutic potential of these strategies in the coming years. The aim of our review is to summarize preclinical data on gene editing in animal models of inherited liver diseases and the clinical data obtained thus far, emphasizing both therapeutic efficacy and potential limitations of these medical interventions.

Aberrant DNA methylation associated with the development of metabolic dysfunction-associated fatty liver disease

The literature review deals with DNA methylation, a key epigenetic mechanism that controls the activity of gene transcription, plays a decisive role in the formation of genomic imprinting, gene silencing, X-chromosome inactivation, RNA splicing, DNA repair, cell differentiation and cell reprogramming, and also determines the occurrence and development of liver steatotic lesions and metabolic disorders. Methylation of DNA cytosine dinucleotide (CpG) can be represented in two types: de novo CpG methylation, which is carried out by 5mC DNA writers — DNA-(cytosine-5)-methyltransferase (DNMT) 3a and 3b, and suppor­ting DNA methylation, which is performed by DNMT1 during DNA replication. It has been found that the maintenance DNA methylation allows the preservation of the methylation pattern characteristic of progenitor cells in the cells of the new generation, and the DNA methylation of the gene body is associated with its increased expression. Active demethylation of 5mC is carried out by TET dioxygenases, including three enzymatic representatives: TET1, TET2 and TET3. It has been demonstrated that aberrant methylation of DNA nucleotides is directly related to the activity of lipid synthesis, the degree of oxidative stress, the development of liver steatosis, low-grade inflammation, insulin resistance, and the progression of liver fibrosis. The authors presented in detail the functions and features of DNA methyltransferases, erasers, and readers of 5mC sites; possible violations of the balance of activity of writers and erasers of 5mC DNA; DNA methylation landscape and patterns; clinical significance of DNA methylation signatures in metabolic dysfunction-associated fatty liver disease. Global hypomethylation of genome, at least 55 genes, is observed in patients with metabolic dysfunction-associated fatty liver disease. The authors emphasize that the use of DNA methylation signatures is a promising direction for early diagnosis and prognosis of the course of metabolic dysfunction-associated fatty liver disease, while the study of molecular components of DNA methylation mechanisms involved in the regulation of gene expression, the dependence of their activity on exposure to the exposome will allow to persona­lize and improve recommendations for lifestyle and diet modification in patients with metabolic dysfunction-associated fatty liver disease.

Metabolic dysfunction associated fatty liver disease in healthy weight individuals

Metabolic dysfunction associated fatty liver disease (MAFLD) is an increasing public health problem, affecting one third of the global population. Contrary to conventional wisdom, MAFLD is not exclusive to obese or overweight individuals. Epidemiological studies have revealed a remarkable prevalence among healthy weight individuals, leading investigations into the genetic, lifestyle, and dietary factors that contribute to the development of MAFLD in this population. This shift in perspective requires reconsideration of preventive strategies, diagnostic criteria and therapeutic approaches tailored to address the unique characteristics of MAFLD healthy weight individuals. It also underscores the importance of widespread awareness and education, within the medical community and among the general population, to promote a more inclusive understanding of liver metabolic disorders. With this review, we aim to provide a comprehensive exploration of MAFLD in healthy weight individuals, encompassing epidemiological, pathophysiological, and clinical aspects.

Effects of Semaglutide on Muscle Structure and Function in the SLIM LIVER Study.

Semaglutide, a GLP-1 receptor agonist, is highly effective for decreasing weight. Concomitant loss of muscle mass often accompanies weight loss and may have consequences on muscle function. This is a secondary analysis from the SLIM LIVER (ACTG A5371) study, a single-arm study of semaglutide in people with HIV (PWH) with metabolic dysfunction-associated steatotic liver disorder (MASLD). Participants received subcutaneous semaglutide for 24 weeks (titrated to 1 mg/week by week 4). Psoas volume and fat fraction were assessed from liver magnetic resonance imaging and physical function by 10-time chair rise test and 4m gait speed. Mean change from baseline to week 24 was estimated with linear regression modeling. 51 PWH enrolled; muscle measures were available from 46 participants. The mean age was 50 (standard deviation [SD] 11) years and BMI 35.5 (5.6) kg/m2, 43% were women, 33% Black, and 39% Hispanic/Latino. Psoas muscle volume decreased by 9.3% (95% confidence interval [CI]: -13.4, -5.2; p<0.001) over 24 weeks but psoas muscle fat did not significantly change (-0.42%, CI: -1.00, 0.17; p=0.16). Chair rise and gait speed had non-significant improvements of 1.27 seconds (CI: -2.7, 0.10) and 0.05 m/sec (CI: -0.01, 0.10), respectively (both p>0.07). The prevalence of slow gait speed (< 1 m/sec) decreased from 63% to 46% (p=0.029). In PWH receiving low-dose semaglutide for MASLD, despite decreased psoas muscle volume, there was no significant change in physical function. This suggests that function was maintained despite significant loss of muscle concomitant with weight loss.