Metabolic and alcohol-related liver disease (MetALD) is a newly defined category within the spectrum of steatotic liver diseases, designed to capture the interplay between metabolic dysfunction and alcohol consumption more effectively. Bioactive compounds, celebrated for their potent antioxidant, anti-inflammatory, and hepatoprotective properties, have emerged as promising therapeutic agents for the management of MetALD. This review comprehensively examines the underlying mechanisms by which these compounds exert their effects, including the modulation of oxidative stress pathways, the enhancement of lipid metabolism, and the promotion of liver regeneration. Specific bioactive constituents, such as polyphenols, flavonoids, and omega-3 fatty acids, have demonstrated potential in ameliorating hepatic steatosis and fibrosis associated with MetALD. Incorporating these natural compounds into treatment regimens presents a novel strategy for managing MetALD, with significant implications for both lifestyle modifications and pharmacological interventions. Future research should prioritize clinical trials, improvements in bioavailability, and investigations into the synergistic effects of multi-compound formulations to establish effective and sustainable treatment strategies for MetALD.

The antioxidant 6PPD and its oxidized product 6PPD-Quinone (6PPDQ) have attracted considerable attention due to their various acute toxicities to aquatic organisms. However, the chronic toxicity of two compounds in aquatic animals is still unknown. Here, adult zebrafish were exposed to 6PPD and 6PPDQ at environmentally relevant concentrations (20 μg/L) for 28 days, and histological analysis showed that 6PPD caused more severe hepatic vacuolization than 6PPDQ. Meanwhile, 6PPD induced more serious lipid accumulation and a higher increase in triglyceride and total cholesterol levels than 6PPDQ, suggesting higher hepatotoxicity of 6PPD. Furthermore, transcriptomic analysis revealed that both compounds disturbed glucolipid metabolism to different degrees by altering the expression of different peroxisome proliferator-activated receptors (PPARs), in which 6PPD inhibited gene expressions in glucolipid metabolism possibly by PPARα, PPARβ and RXR, while 6PPDQ disrupted the expressions of partial genes in similar pathways probably via PPARγ. Additionally, 6PPD but not 6PPDQ increased Fe2+ content, decreased the protein levels of ferroportin 1, ferritin and glutathione peroxidase 4, accompanied with the increase of malondialdehyde level and the decrease of glutathione content, suggesting ferroptotic response by 6PPD. Overall, our data deepened the understanding of 6PPD- and 6PPDQ-induced hepatotoxicity association with glucolipid metabolism disorders and ferroptotic responses.

N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine-quinone (6PPD-Q) as a major metabolite of tire wear chemical 6PPD has been demonstrated to be an emerging burden of exposure in human populations, via contamination from drinking water, air particulate matter and food sources. Whilst increasing attention has been moved toward its adverse effect, the potential hepatotoxicity of 6PPD-Q in mammals at realistic dose remains unknown. Here, the toxic effects of 6PPD-Q at environmentally relevant dose on the liver of adult mice and its underlying mechanism were investigated through an integrative approach combining transcriptomic and lipidomic analyses. We found that 6PPD-Q exposure induced excessive lipid deposition following three weeks of exposure, ultimately contributing to the pathogenesis of fatty liver disease. Mechanistically, 6PPD-Q exposure caused a remarkable increase in the contents of fatty acids within the hepatic tissue of mice by enhancing their biosynthesis, thereby facilitating lipid deposition. In summary, this study provides a new understanding on the endocrine disrupting effects of 6PPD-Q on hepatic lipid metabolism and how it may contribute to elevated risk of fatty liver disease. Our findings call for a potential public health attention on the risk assessment of 6PPD-Q, particularly towards the risk of chronic metabolic diseases.

Obesity and type 2 diabetes mellitus (T2DM) are metabolic diseases at epidemic proportions. The economic burden for these diseases is at an all-time high, and as such, there is an urgent need for advancements in identifying targets for treating these complex disorders. The extracellular matrix (ECM), comprising collagen, fibronectin, laminin, elastin, and proteoglycan, surrounds skeletal muscles and plays a critical role in maintaining tissue homeostasis by providing structural support and facilitating cell-to-cell communication. Disruption of the ECM signaling results in changes to its micro/macroenvironment, thereby modifying tissue homeostasis. Skeletal muscle ECM remodeling has been shown to be associated with insulin resistance, an underlying feature of obesity and T2DM. This narrative review explores the critical components of skeletal muscle ECM and its accumulation and remodeling in metabolic diseases. In addition, we discuss potential treatments to mitigate the effects of ECM remodeling in skeletal muscle. We conclude that targeting ECM remodeling in skeletal muscle represents a promising yet underexplored therapeutic avenue in the management of metabolic disorders.

Liver steatosis (LS) is a condition that is characterised by hepatic fat accumulation unrelated to significant alcohol consumption. This study explored the serum proteomic profile associated with LS in people living with HIV (PLWH).

The study cohort comprised 266 PLWH, 21.1% and 78.9% of whom had LS and no LS, respectively. Serum samples were analysed using liquid chromatography coupled with mass spectrometry (LC-MS).

Among the 220 proteins detected, afamin (AFM) and apolipoprotein F (APOF) were identified as proteins associated with LS. Differential expression of AFM and APOF was observed in under- and normoweight patients, emphasising their potential as biomarkers in patients without overweight or obesity.

These findings suggest that the identified proteins could serve as promising biomarkers of LS in PLWH, paving the way for further investigations into the roles of these proteins in LS development in this unique population.

Obesity is a major global health problem associated with numerous metabolic dysfunctions, an increased risk of developing Metabolic Associated Steatotic Liver Disease (MASLD) and osteoarthritis. Recently, we demonstrated that in Diet-induced-Obesity (DIO) mouse model, preventive furan fatty acids (FuFA-F2) supplementation, a natural compounds found in many foods, reduced the onset of metabolic disorders and increased muscle mass. Here, we aimed to determine whether a short FuFA-F2 supplementation is capable of providing beneficial health effects in obese mice, notably by reversing metabolic disorders and limiting cartilage degradation. 6-month-old obese C57Bl/6 J mice were fed for four additional weeks on a high-fat and high-sucrose (HFHS) diet, supplemented or not with FuFA-F2 (40 mg/day/kg of body weight). Liver triglyceride content and histologic analysis revealed that 4 weeks of FuFA-F2 supplementation fully reversed hepatic steatosis in obese mice. Liver RNA-sequencing analysis highlighted that FuFA-F2 partly reversed the gene expression signature induced by the HFHS diet and favorably changed the expression of many genes known to be involved in the development of hepatic steatosis such as Pcsk9, Stard4, Insig1 and Sulf2. We also found that FuFA-F2 supplementation increased skeletal muscle mass and protected against cartilage degradation and synovitis induced by obesity. Our findings demonstrated that FuFA-F2 supplementation for 4 weeks in obese mice was enough to reverse the development of MASLD, promote an increase in skeletal muscle mass and protect against cartilage degradation induced by the HFHS diet. This study highlights that nutritional supplementation with FuFA-F2 could be an effective approach to treat obesity-related disorders.

Mendelian randomization has become a popular tool to assess causal relationships using existing observational data. While randomized controlled trials are considered the gold standard for establishing causality between exposures and outcomes, it is not always feasible to conduct a trial. Mendelian randomization is a causal inference method that uses observational data to infer causal relationships by using genetic variation as a surrogate for the exposure of interest. Publications using the approach have increased dramatically in recent years, including in the field of hepatology. In this concise review, we describe the concepts, assumptions, and interpretation of Mendelian randomization as related to studies in hepatology. We focus on the strengths and weaknesses of the approach for a non-statistical audience, using an illustrative example to assess the causal relationship between body mass index and NAFLD.

Famoxadone (FAM) is a widely used chiral fungicide that may contribute to metabolic dysfunction-associated fatty liver disease (MAFLD). However, the enantioselective toxicity and mechanism of action of famoxadone enantiomers remain unclear. The enantioselective bioaccumulation of famoxadone in mice was investigated, and the hepatotoxicity of famoxadone enantiomers, specifically in relation to MAFLD, was evaluated by a 12 week oral exposure to Rac-FAM, R-FAM, and S-FAM. R-FAM showed higher bioaccumulation than S-FAM, in which the concentrations of R-FAM were 3.52 and 242.69 times that of S-FAM in the liver at the no observed effect level (NOEL) and 1/10 NOEL, respectively. R-FAM was found to cause an increase in liver coefficients, a decrease in the AST/ALT ratio, enhanced expression of inflammation-related genes, and lipid droplet accumulation in the liver. In contrast, mice treated with S-FAM exhibited no significant changes in the quality of these indicators. These results suggest that R-famoxadone is more likely to be the dominant enantiomer affecting the liver. Furthermore, the important functional genes involved in glucose and lipid metabolism were detected. It was found that R-FAM significantly disrupted key lipid metabolic pathways in the liver, including glucose metabolism, fatty acid synthesis, triglyceride synthesis, and fatty acid β-oxidation. Additionally, R-FAM induced more severe disruptions in liver glucose and lipid metabolism compared to S-FAM. These research findings provide insights into the enantioselective toxicity of famoxadone enantiomers in terms of their role in promoting MAFLD development, contributing to the safe utilization of the chiral pesticide famoxadone.

Metabolic syndrome (MetS) is a disease with complex and diverse etiologies. Extrinsic factors such as diet and lifestyle can induce dysbiosis of gut microbes, compromising intestinal barrier integrity and leading to inflammation and insulin resistance, thereby advancing MetS. Probiotic interventions have shown potential in ameliorating gut microbiota dysbiosis and regulating host metabolism by assimilating lipids, metabolizing carbohydrates, and producing short-chain fatty acids (SCFA), indole compounds, secondary bile acids, conjugated linoleic acid (CLA), and other active ingredients. An increasing number of new strains are being isolated and validated for their effective roles intervening on MetS in animal and population studies. This review aims to provide updated insights into the pathogenic mechanisms of MetS, highlight the newly identified probiotic strains that have demonstrated improvements in MetS, and elucidate their mechanisms of action, with the aim of offering contemporary perspectives for the future use of probiotics in mitigating MetS.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become a prevalent liver condition in children and teenagers with obesity. Unfortunately, there is no standardized treatment.

To examine the connection between apolipoprotein B (apoB), apolipoprotein A1 (apoA1), and the apoB/apoA1 ratio with the occurrence of MASLD in this population.

A retrospective study was made on children and adolescents with obesity in a children's hospital between the period 2020 and 2022. Anthropometric data, ultrasound results, and blood biochemistry were analysed to assess the connection between apoB, apoA1, and the presence of MASLD.

Of the 916 participants included, 313 were diagnosed with MASLD. The level of serum apoB reflected a substantial dose-response correlation with the odds of having MASLD. When apoB levels exceeded the 50th percentile, the risk increased significantly, and at the 95th percentile, the odds were 4.83 times higher than at the 50th percentile (95% CI: 2.02-11.56). The ratio of apoB/apoA1 at the 95th percentile was connected to a 2.41-fold higher prevalence compared to the 50th percentile (95% CI: 1.33-4.37). No significant correlation was found between the levels of apoA1 and MASLD prevalence.

Elevated levels of apoB and the apoB/apoA1 ratio have been strongly connected to increased MASLD prevalence in children and adolescents with obesity; hence, signifying their potential usefulness as biomarkers for early detection and intervention.

Nonalcoholic fatty liver disease (NAFLD) is a common liver condition resulting from metabolic syndrome characterized by fat accumulation in the liver. It is often associated with obesity and diabetes, contributing to hepatic steatosis in liver cells. The prevalence of NAFLD is increasing globally, with 32% of the adult population affected. Genetic modifiers, such as single nucleotide polymorphisms, can increase susceptibility to the disease. Gene expression analysis and genetic variation can help identify disease-causing pathways and reveal biomarkers involved in NAFLD. This study employed integrative bioinformatics analysis, including bulk RNA-seq and single-cell RNA-seq, to explore differentially expressed genes and their genetic variants in NAFLD vs. control and NAFLD vs. cirrhosis, highlighting genes influencing NAFLD progression. Moreover, this study identified AKR1D1, LIPC, UGT2B17, DGAT2, and SERPINE1 implicated in metabolic, immune, and lipid functions while being overexpressed in both hepatocyte cells among obese patients identified and validated through Liver Cell Atlas, highlighting their pivotal role in the pathogenesis of the disease in obese patients through perturbed hepatocytes. Furthermore, novel pathogenic variants of AKR1D1, LIPC, and SERPINE1, associated with congenital bile acid synthesis defects, abnormal circulating lipid concentrations, and plasminogen activator inhibitor type 1 deficiency conditions, were identified. Conclusively, this integrative multiomics study highlights the novel pathogenic variants of AKR1D1, LIPC, and SERPINE1 in metabolic, immune, and lipid pathways that are highly expressed among hepatocytes in obese patients while possibly carrying pathogenic mutations that may be associated with NAFLD, emphasizing their potential as novel targets for therapeutic strategies and biomarker development in early diagnosis and treatment before the onset of cirrhosis or hepatocellular carcinoma.

Obesity in children is a global health crisis, with 46% of children in Puerto Rico classified as overweight or obese based on Body Mass Index. This condition is linked to serious comorbidities, including early-onset type 2 diabetes, hypertension, and Metabolic-Associated Fatty Liver Disease (MAFLD), the most common liver disease in U.S. children. This study examines the relationship between body weight, liver size, and texture in children from Puerto Rico.

A craniocaudal right liver lobe (RLL) measurement was performed using a panoramic ultrasound image. RLL length and liver texture were assessed based on fat infiltration. BMI was calculated to classify participants into healthy and unhealthy weight groups, and waist circumference (WC) was compared. Statistical analyses, including Shapiro-Wilk, Student's t-tests, ANOVA, and post hoc Tukey HSD, were conducted with significance at p ≤ 0.05.

Forty-three children aged 7-19 years were recruited. Significant differences were observed in liver size and texture between healthy and unhealthy weight groups: RLL length (p = 0.003), WC (p < 0.001), and BMI (p < 0.001). Obese children had significantly larger RLL and WC than healthy-weight group (p = 0.02; p < 0.001). More children in unhealthy weight group exhibited hepatomegaly (n = 12) and fat infiltration (n = 15).

The findings indicate that large liver and MAFLD are common among children with overweight and obesity, suggesting liver changes related to obesity begin early in life. Strategies to maintain a healthy weight in children are essential to reduce the risk of chronic diseases and potential disabilities in adulthood.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multifactorial disease characterized by hepatic steatosis. Mitochondrial dysfunction resulting in the incomplete digestion of surplus fat is one of the key factors that lead to hepatic steatosis but the reason for this remains unclear. We investigated the role of neurotensin (NTS), a gut hormone, in inducing maladaptive fat metabolism in steatotic liver. We identify CD36 and PGC1α, two critical drivers of MASLD, as direct NTS signaling targets in the liver. NTS upregulates CD36, a free fatty acid receptor, in hepatocytes and promotes long chain lipid uptake. Conversely, NTS inhibits PGC1α, which acts as a lipid sensor and translocates to the nucleus to activate lipid catabolism-related genes in an AMPK-dependent manner. Thus, a high fat diet decreases the fatty acid oxidation and oxidative phosphorylation capacity of the liver and hepatocytes from NTS or NTS receptor 1 (NTSR1) wild type mice; whereas NTS deficiency preserves the lipid metabolism capacity of the liver. NTS signaling is significantly upregulated in MASLD and in metabolic dysfunction-associated steatohepatitis (MASH) human liver samples when compared to normal livers, which correlates with the expression of CD36 and oxidative phosphorylation proteins. These findings provide critical mechanistic insights into the maladaptive fat metabolism noted with steatosis in mice and humans and suggest novel strategies for therapeutic intervention of MASLD, which affects nearly one-quarter of the global population.

Obesity has been linked to an elevated susceptibility to development of erectile dysfunction, yet the interplay between sex hormone levels, sexual function, and obesity remains unclear. This study aimed to investigate sexual dysfunction among male patients with obesity and to emphasize the importance of recognizing the problem and pursuing solutions.

A total of 60 patients were included in the study (30 patients from the obesity center and 30 patients without obesity as the control group). Assessment of androgen hormone deficiency and erectile dysfunction was conducted through the implementation of AMS and IIEF-5 tests. The questionnaire includes aspects of medical history, demographic features, and lifestyle factors. Comprehensive measurements included BMI, WC, BP, lipid panel, total/free testosterone, sex-hormone-binding-globulin (SHBG), dehydroepiandrosterone-sulfate (DHEAS), fasting blood glucose (FBG), fasting insulin, and HbA1C levels. Results were evaluated using SPSS.

The AMS score in the obesity group was significantly lower compared to the group without obesity. The IIEF-5 score did not exhibit a statistically significant difference between the groups. Testosterone, free testosterone, SHBG, and HDL values were lower in the obesity group compared to the group without obesity.

Although conducted in a small sample, our findings strongly indicate a positive correlation between obesity and the risk of moderate to severe ED. Most of the time, this condition goes unarticulated, thereby adversely affecting the quality of life for individuals with obesity. Clinicians should pay more attention to patients experiencing sexual dysfunction, especially those with obesity.

Background: Metabolic effects of oleoylethanolamide-based dietary supplement (OEA-DS) were studied in a model of dietary-induced obesity in mice. Obesity was induced by a 2-month high-fat, high-cholesterol diet, resulting in significant morphological changes in liver tissues and elevated cholesterol levels in the animals' blood serum. Elevated levels of proinflammatory cytokines, oxidative stress, and hepatocyte apoptosis were also observed in the liver tissue. The aim of this study was to examine the mechanisms through which an OEA-based dietary supplement (OEA-DS) exerts a comprehensive influence on multiple aspects of the pathogenesis of MASLD, thereby demonstrating a robust hepatoprotective effect. Methods: mice were fed a high-fat, high-cholesterol diet with or without OEA-DS supplementation. Liver tissues and blood serum were analyzed for cholesterol levels, inflammatory markers (CD68, Iba-1, CD163, IL-1β, IL-6, TNFα), apoptotic markers (Bad, Bax, Bcl-2), nuclear receptors (PPAR-α, PPAR-γ, AdipoR1), and enzymes involved in lipolysis (Acox1, Cpt1a) and cholesterol metabolism (Ldlr, Furin, Pcsk9). Immunohistochemistry, Western blotting, and RT-PCR were used to assess protein expression and gene transcription. Results: administration of OEA-DS normalized cholesterol levels, decreased expression of inflammatory markers (CD68 and Iba-1), pro-apoptotic markers (Bad, Bax) and levels of pro-inflammatory cytokines (IL-1β, IL-6, TNFα). In parallel, the expression of nuclear receptors PPAR-α and PPAR-γ, adiponectin receptor 1 (AdipoR1), and anti-inflammatory (CD163) and anti-apoptotic (Bcl-2) markers have risen. OEA-DS administration induced the expression of liver lipolysis enzymes (Acox1, Cpt1a) and cholesterol metabolism factors (Ldlr, Furin), while simultaneously reducing the transcription of the proatherogenic factor Pcsk9. Conclusions: The results of this study suggest a complex action of OEA-DS in obesity-associated liver damage, which includes reduction of systemic inflammation.

Actin dynamics, mediated by various actin-binding proteins, plays an important role in adipocyte differentiation. We investigated the role of coactosin-like F-actin binding protein (Cotl1) in adipocyte differentiation in vitro and in vivo. Cotl1 expression level was increased during adipocyte differentiation in mouse 3T3-L1 cells and primary cultured adipose-derived stem cells (ADSCs) and during weight gain in adipose tissues. However, Cotl1 deficient in 3T3-L1 and ADSCs inhibited adipocyte differentiation, and Cotl1-/- mice displayed resistance to high-fat diet (HFD)-induced weight gain, hepatic steatosis and adipocyte enlargement compared to HFD-fed wild type (WT) mice. Ingenuity Pathway Analysis of RNA-sequencing in adipose tissues of HFD-WT and HFD-Cotl1-/- mice predicted complicated relationships between Cotl1, differentiation of adipocytes, obesity and organization of actin cytoskeleton. Particularly, peroxisome proliferator-activated receptor gamma (Pparg) emerged as a central player, with Cotl1 influencing Pparg expression, consequently regulating adipocyte differentiation. These findings suggest Cotl1 as a pivotal regulator of terminal adipocyte differentiation by modulating adipogenic genes.

To describe clinical characteristics, disease burden, and treatment patterns among people with obesity disease (PwOD) in Japan, using data from the Adelphi Real World Obesity Disease Specific Programme™ (DSP).

Secondary data from the Japanese DSP cohort (July to December 2022) were analyzed. PwOD had a BMI ≥25 kg/m2 and ≥1 obesity-related complications (ORCs). Outcomes were summarized for all PwOD or stratified by obesity class (BMI ≥25-<35 or ≥35 kg/m2 [high-degree obesity disease]) and use of anti-obesity medications (AOMs).

The study included 442 PwOD (mean age: 52.8 years; 54.8% males; BMI ≥25-<35 kg/m2: 64.5%; BMI ≥35 kg/m2: 35.5%; AOM users: n = 228; non-AOM users: n = 214). High-degree obesity disease was associated with worsened SF-36v2 scores (Physical Component Summary, Physical Functioning, Bodily Pain, and General Health), greater activity impairment, and reduced work productivity. Common weight management approaches were diet (79.9%) and exercise (51.1%). Common prescription AOMs included traditional herbal medicine (67.5%) and mazindol (21.1%). People with high-degree obesity disease (BMI ≥35 vs. ≥25-<35 kg/m2) used more prescription AOMs (57.3 vs. 48.4%), behavioral therapy (9.6 vs. 1.8%), and weight loss surgery (2.6 vs. 0.4%). The difference in weight reduction between AOM and non-AOM users was modest.

People with high-degree obesity disease experienced greater disease burden. Diet and exercise are common for weight management, while behavioral therapy is less frequently implemented. These findings highlight the challenges and unmet medical needs in treating obesity in Japan and could inform better treatment strategies in Japan and globally among the Asian population.

Obesity, characterized by the excessive accumulation of white adipose tissue, is a significant global health burden and a major risk factor for a range of diseases, including malignancies and metabolic disorders. Individuals with high visceral fat content are particularly susceptible to severe complications such as type 2 diabetes, cardiovascular diseases, and liver disorders. However, the pathogenesis of obesity-related metabolic diseases extends beyond simple adiposity. Chronic obesity triggers a prolonged inflammatory response, which leads to tissue fibrosis and sustained organ damage, contributing to multi-organ dysfunction. This review explores the autoimmune mechanisms and inflammatory pathways underlying obesity-induced type 2 diabetes, atherosclerosis, and non-alcoholic fatty liver disease, with an emphasis on their interrelated pathophysiology and the potential for therapeutic interventions.

Systemic metabolism ensures energy homeostasis through inter-organ crosstalk regulating thermogenic adipose tissue. Unlike the well-described inductive role of the sympathetic system, the inhibitory signal ensuring energy preservation remains poorly understood. Here, we show that, via the mechanosensor Piezo2, sensory neurons regulate morphological and physiological properties of brown and beige fat and prevent systemic hypermetabolism. Targeting runt-related transcription factor 3 (Runx3)/parvalbumin (PV) sensory neurons in independent genetic mouse models resulted in a systemic metabolic phenotype characterized by reduced body fat and increased insulin sensitivity and glucose tolerance. Deletion of Piezo2 in PV sensory neurons reproduced the phenotype, protected against high-fat-diet-induced obesity, and caused adipose tissue browning and beiging, likely driven by elevated norepinephrine levels. Finding that brown and beige fat are innervated by Runx3/PV sensory neurons expressing Piezo2 suggests a model in which mechanical signals, sensed by Piezo2 in sensory neurons, protect energy storage and prevent a systemic hypermetabolic phenotype.

To demonstrate the feasibility of hepatic 3D MR elastography (MRE) at 0.55 T in healthy volunteers using Hadamard encoding and to study the effects of concomitant fields in the domain of MRE in general.

Concomitant field effects in MRE are assessed using a Taylor series expansion and an encoding scheme is proposed to study the corresponding effects on 3D MRE at 0.55 T in numerical simulations and in phantom experiments. In addition, five healthy volunteers were enrolled and scanned at 60 Hz mechanical excitation with a Hadamard-encoded 3D MRE sequence at 0.55 T and were also scanned with a reference 3D MRE sequence at 3 T for comparison. The retrieved biomechanical parameters were the magnitude of the complex shear modulus (|G*|), the shear wave speed (Cs), and the loss modulus (G″). Comparison of apparent SNR between 3 T and 0.55 T was performed.

Theoretical analysis, numerical simulations and phantom experiments demonstrated that the effects of concomitant fields in 3D MRE at 0.55 T are negligible. In the healthy volunteer experiments, the mean values of |G*|, Cs, and G″ in the liver were 2.1 ± 0.3 kPa, 1.5 ± 0.1 m/s, and 0.8 ± 0.1 kPa at 0.55 T, respectively, and 2.0 ± 0.2 kPa, 1.5 ± 0.1 m/s, and 0.9 ± 0.1 kPa at 3 T, respectively. Bland-Altman analysis demonstrated good agreement between the biomechanical parameters retrieved at 0.55 T and 3 T. A 2.1-fold relative apparent SNR decrease was observed in 3D MRE at 0.55 T in comparison with 3 T.

Hepatic 3D MRE is feasible at 0.55 T, showing promising initial results in healthy volunteers.

Nonalcoholic fatty liver disease (NAFLD), first named in 1980, is currently the most common chronic liver disease, imposing significant health, social, and economic burdens. However, it is defined as a diagnosis of exclusion, lacking a clear underlying cause in its diagnostic criteria. In 2020, metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed as a replacement for NAFLD, introducing additional criteria related to metabolic dysfunction. In 2023, metabolic dysfunction-associated steatotic liver disease (MASLD) was suggested to replace NAFLD, aiming to avoid the stigmatizing term "fatty" and incorporating cardiometabolic criteria for metabolic dysfunction. This divergence in nomenclature and diagnostic criteria between MAFLD and MASLD presents challenges to medical communication and progress. This review outlines the pros and cons of both terminologies, based on current research evidence, in the hope of fostering global consensus in the future.

Glutamine availability may be reduced in chronic diseases, such as type 2 diabetes mellitus (T2DM)-induced by obesity. Herein, the antioxidant, anti-inflammatory and lipid metabolism effects of chronic oral glutamine supplementation in its free and dipeptide form were assessed in ob/ob mice. Adult male C57BL/6J ob/ob mice were supplemented with L-alanyl-L-glutamine (DIP) or free L-glutamine (GLN) in the drinking water for 40 days, whilst C57BL/6J Wild-type lean (WT) and control ob/ob mice (CTRL) received fresh water only. Plasma and tissue (skeletal muscle and liver) glutamine levels, and insulin resistance parameters (e.g., GTT, ITT, insulin) were determined. Oxidative stress (e.g., GSH system, Nrf2 translocation), inflammatory (e.g., NFkB translocation, TNF-α gene expression) and lipid metabolism parameters (e.g., plasma and liver triglyceride levels, SRBP-1, FAS, ACC, and ChRBP gene expression) were also analyzed. CTRL ob/ob mice showed lower glutamine levels in plasma and tissue, as well as increased insulin resistance and fat in the liver. Conversely, chronic DIP supplementation restored glutamine levels in plasma and tissues, improved glucose homeostasis and reduced plasma and liver lipid levels. Also, Nrf2 restoration, reduced NFkB translocation, and lower TNF-α gene expression was observed in the DIP group. Interestingly, chronic free GLN only increased muscle glutamine stores but reduced overall insulin resistance, and attenuated plasma and liver lipid metabolic biomarkers. The results presented herein indicate that restoration of body glutamine levels reduces oxidative stress and inflammation in obese and T2DM ob/ob mice. This effect attenuated hepatic lipid metabolic changes observed in obesity.

The need for early non-invasive diagnostic tools for chronic liver fibrosis is growing, particularly in individuals with obesity, non-alcoholic fatty liver disease (NAFLD), and the metabolic syndrome (MetS) since prevalence of these conditions is increasing. This case-control study compared non-invasive liver fibrosis markers in obesity with NAFLD and MetS (NAFLD-MetS, n = 33), in obese (n = 28) and lean (n = 27) control groups. We used MRI (T1 relaxation times (T1) and liver stiffness), circulating biomarkers (CK18, PIIINP, and TIMP1), and algorithms (FIB-4 index, Forns score, FNI, and MACK3 score) to assess their potential in predicting liver fibrosis risk. We found that T1 (892 ± 81 ms vs. 818 ± 64 ms, p < 0.001), FNI (15 ± 12% vs. 9 ± 7%, p = 0.018), CK18 (166 ± 110 U/L vs. 113 ± 41 U/L, p = 0.019), and MACK3 (0.18 ± 0.15 vs. 0.05 ± 0.04, p < 0.001) were higher in the NAFLD-MetS group compared with the obese control group. Moreover, correlations were found between CK18 and FNI (r = 0.69, p < 0.001), CK18 and T1 (r = 0.41, p < 0.001), FNI and T1 (r = 0.33, p = 0.006), MACK3 and FNI (r = 0.79, p < 0.001), and MACK3 and T1 (r = 0.50, p < 0.001). We show that liver fibrosis markers are increased in obese individuals with NAFLD and MetS without clinical signs of liver fibrosis. More studies are needed to validate the use of these non-invasive biomarkers for early identification of liver fibrosis risk.

Nonalcoholic fatty liver disease (NAFLD) is a growing global health concern linked to obesity.

This study employed a Mendelian randomization approach to explore the causal influence of BMI on metabolic biomarkers and the subsequent risk of NAFLD. We analyzed data from multiple sources, including 249 metabolic traits, to establish direct and mediating relationships among BMI, metabolic factors, and NAFLD risk.

Our findings revealed a significant positive correlation between BMI and NAFLD across various datasets. We identified 176 metabolites associated with BMI, of which 106 were also linked to NAFLD. Importantly, 86 metabolites were found to mediate the relationship between BMI and NAFLD risk. Specifically, elevated levels of branched-chain amino acids, triglycerides, and certain cholesterol esters were notably associated with increased NAFLD risk, whereas changes in free cholesterol and phospholipid levels also played critical roles.

This study highlights the complex interactions between BMI, metabolic biomarkers, and NAFLD risk. By elucidating these relationships, we highlight potential targets for interventions aimed at reducing NAFLD incidence in populations with elevated BMI, ultimately contributing to improved metabolic health.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver disorder with limited treatment options. This review explores the role of post-translational modifications (PTMs) in MASLD pathogenesis, highlighting their potential as therapeutic targets. We discuss the impact of PTMs, including their phosphorylation, ubiquitylation, acetylation, and glycosylation, on key proteins involved in MASLD, drawing on studies that use both human subjects and animal models. These modifications influence various cellular processes, such as lipid metabolism, inflammation, and fibrosis, contributing to disease progression. Understanding the intricate PTM network in MASLD offers the potential for developing novel therapeutic strategies that target specific PTMs to modulate protein function and alleviate disease pathology. Further research is needed to fully elucidate the complexity of PTMs in MASLD and translate these findings into effective clinical applications.

Hepatic lipid metabolism dysfunction caused by cyanobacteria bloom-released microcystin-LR (MC-LR) contributes to the development of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH), thereby severely impacting the health and safety of animals and humans. In this study, the effects and mechanisms of different environmental concentrations of MC-LR (0, 0.1, 1, and 10 μg/L) on fatty liver metabolic disease in zebrafish were investigated using in vivo, in vitro, and in silico models. Exposure to 10 μg/L of MC-LR-induced NASH in zebrafish, characterized by hepatic steatosis, toxic saturated fatty acid (SFA) accumulation, and inflammation. Analyses of the liver transcriptome, molecular docking, molecular dynamics simulation, and in vitro experiments indicated that PPARα might be a key molecular target in MC-LR-induced steatosis and in toxic-SFA accumulation. The results obtained from molecular docking, molecular dynamics simulation, and NOD1-inhibitor experiments further revealed that MC-LR-derived SFAs, such as palmitic acid, could target the NOD1 protein to initiate hepatitis in zebrafish. The benchmark dose model identified palmitic acid as a sensitive indicator of MC-LR-induced NASH, and the point of departure value was estimated to be 1.634 μg/L. In conclusion, our findings offer new insights into the mechanism of MC-LR-induced NASH and aid in the prognosis and treatment of MC-LR-related liver metabolic diseases, as well as in assessing the health risks associated with cyanobacterial blooms.

Metabolic dysfunction associated fatty liver disease (MAFLD) is a chronic condition with hepatic fat accumulation. The intergenerational effect of obesity has predominantly focused on mothers, with limited studies on paternal obesity. Nutritional intervention with fish oil (FO) has beneficial effects in reducing markers of obesity. We hypothesized that supplementing obese fathers with FO before conception could enhance the metabolic health of their offspring liver. Male mice were assigned to low-fat (LF), high fat (HF), or HF supplemented with FO for 10 weeks. Subsequently, these males were mated with females on a chow diet. Offspring were sacrificed at 8 weeks, and liver tissues were analyzed for gene expression and histology. Offspring body weight was not significantly impacted by paternal diet. However, male offspring of HF fathers had higher levels of markers of inflammation and fatty acid synthesis compared to offspring of LF fed fathers. Paternal FO supplementation significantly reduced fatty acid synthesis and glucose metabolism, while increasing fatty acid oxidation in male offspring, with a less pronounced effect in female offspring. These findings suggest that FO supplementation in obese fathers prior to conception attenuates the development of MAFLD in male offspring. This data underscores the significance of paternal nutritional intervention in promoting offspring health.

Steatotic liver disease (SLD) is a potentially reversible condition but often goes unnoticed with the risk for end-stage liver disease.

To opportunistically estimate SLD on lung screening chest computed tomography (CT) and investigate its prognostic value in heavy smokers participating in the National Lung Screening Trial (NLST).

We used a deep learning model to segment the liver on non-contrast-enhanced chest CT scans of 19,774 NLST participants (age 61.4 ± 5.0 years; 41.2% female) at baseline and on the 1-year follow-up scan if no cancer was detected. SLD was defined as hepatic fat fraction (HFF) ≥5% derived from Hounsfield unit measures of the segmented liver. Participants with SLD were categorized as lean (body mass index [BMI] < 25 kg/m2) and overweight (BMI ≥ 25 kg/m2). The primary outcome was all-cause mortality. Cox proportional hazard regression assessed the association between (1) SLD and mortality at baseline and (2) the association between a change in HFF and mortality within 1 year.

There were 5.1% (1000/19,760) all-cause deaths over a median follow-up of 6 (range, 0.8-6) years. At baseline, SLD was associated with increased mortality in lean but not in overweight/obese participants as compared to participants without SLD (hazard ratio [HR] adjusted for risk factors: 1.93 [95% confidence interval 1.52-2.45]; p = 0.001). Individuals with an increase in HFF within 1 year had a significantly worse outcome than participants with stable HFF (HR adjusted for risk factors: 1.29 [1.01-1.65]; p = 0.04).

SLD is an independent predictor for long-term mortality in heavy smokers beyond known clinical risk factors.

Asiasarum root and rhizome (Asarum) is commonly used as a diaphoretic. Due to its warm and pungent characteristics in traditional Chinese and Korean medicine, it is considered as having the potential to prevent disease. The present study investigated the effects of Asarum extract on the symptoms of obesity in mice, and the regulation of energy metabolism in the liver and skeletal muscle tissues. In addition, to identify the potential molecular targets and signaling pathways involved in the mechanism of action of Asarum extract in obesity, network pharmacological and molecular docking analysis was performed. In vitro studies demonstrated that Asarum extract significantly increased the expression of regulators of energy metabolism [sirtuin 1 (SIRT1), peroxisome proliferator‑activated receptor γ coactivator 1‑α (PGC1α), nuclear respiratory factor 1, AMP‑activated protein kinase (AMPK) and glucose transporter type 4 (GLUT4)] and myogenic regulatory factors (MyoD, myogenin and myosin heavy chain) in C2C12 myotubes. Furthermore, the in vivo studies demonstrated that Asarum extract could reduce increases in body weight, and the levels of blood glucose, insulin, total cholesterol, triglycerides and low‑density lipoprotein cholesterol in the sera of obese mice. Asarum extract also improved pathological changes in the liver and pancreatic tissues of obese mice, and significantly increased the ratio of brown fat mass to body weight. In addition, Asarum extract reversed the expression of energy metabolism regulators and myogenic regulatory factors in the gastrocnemius tissues of obese mice. Asarum extract also activated the expression of SIRT1, PGC1α and AMPK in the liver tissues of obese mice. These findings indicated that Asarum extract may exert anti‑obesity effects, such as body weight loss, decreases in lipid metabolite levels, and inhibition of pancreatic and liver damage. Using network pharmacological analysis, the mechanisms underlying the effects of Asarum extract on the regulation of energy metabolism were explored, particularly in skeletal muscle and liver tissues.

Weight gain presents a substantial problem for people with psychotic disorders. Three quarters of individuals are overweight or obese and those starting antipsychotics experience rapid weight gain in the first 6-12months of treatment and this weight gain does not appear to plateau. The high prevalence of modifiable lifestyle risk factors and antipsychotic medication use all contribute to the increased risk of weight gain and cardiovascular disease. Sex may also play a role in the amount of weight gained. Crucially, a 5-10 % reduction in weight has a positive impact on cardiovascular disease risk factors. This study aimed to investigate clinically relevant weight loss (CRWL) and its associated factors, separately by sex. This naturalistic longitudinal study examined the weight of 372 men and women with psychotic disorders at baseline and follow-up on average 3.3 years later and compared those who had lost ≥7 % of their baseline weight with those who had not. Results showed 20.3 % of men and 19.9 % of women had CRWL and a different set of factors were observed to be associated with CRWL for each sex. For men, older age, higher baseline weight, and stopping use of antipsychotics compared to use of antipsychotics with a high-risk of weight gain were associated with an increased odds of CRWL. For women, only better quality of sleep was associated with an increased odds of CRWL. Greater understanding of the factors associated with weight loss in men and women with psychotic disorders may inform the development and implementation of targeted strategies.

The goal of this study was to determine the role of histone deacetylase 9 (HDAC9) in the development of diet-induced metabolic dysfunction-associated steatohepatitis (MASH) and white adipose tissue (WAT) dysfunctions.

We fed male and female mice with global Hdac9 knockout (KO) and their wild-type (WT) littermates an obesogenic high-fat/high-sucrose/high-cholesterol (35%/34%/2%, w/w) diet for 20 weeks.

Hdac9 deletion markedly inhibited body weight gain and liver steatosis with lower liver weight and triglyceride content than WT in male mice but not females. Consistently, hepatic expression of genes crucial for de novo lipogenesis was markedly suppressed only in male, but not female, Hdac9 KO mice. However, Hdac9 deletion had a minimal effect on hepatic inflammation and fibrosis. In WAT, Hdac9 KO showed less adipocyte hypertrophy, inflammation, and fibrosis in male mice compared with WT. In addition, indirect calorimetry demonstrated that male Hdac9 KO mice had significantly higher metabolic rates, respiratory exchange ratios, and energy expenditure without altering physical activities than WT, which was not observed in female mice.

Our findings indicate that global deletion of Hdac9 prevented the development of obesity, hepatic steatosis, and WAT inflammation and fibrosis in male mice with diet-induced obesity and MASH, suggesting that a sex-dependent role of HDAC9 may exist in the pathways mentioned above.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), represent a growing global health problem linked to obesity, insulin resistance, and dyslipidemia. MASLD often leads to fibrosis, cirrhosis, and hepatocellular carcinoma. Currently, therapeutic options are limited, emphasizing the need for novel, targeted pharmacological interventions. Resmetirom, a selective thyroid hormone receptor beta (THR-β) agonist, offers a promising approach by specifically enhancing hepatic metabolism while minimizing systemic effects. Clinical trials have demonstrated its capacity to reduce hepatic triglyceride accumulation and improve lipid profiles. Early- and advanced-phase studies, including the MAESTRO program, highlight significant reductions in hepatic fat content and favorable impacts on noninvasive biomarkers of fibrosis with minimal side effects. This review highlights evidence from pivotal studies, explores resmetirom's mechanism of action, and compares its efficacy and safety with other emerging therapeutic agents. While resmetirom marks a breakthrough in non-cirrhotic MASH management, further long-term studies are essential to fully evaluate its clinical benefits and potential regulatory approval for broader use in MASLD and MASH.

The carnitine palmitoyltransferases (CPTs) play a key role in controlling the oxidation of long-chain fatty acids and are potential therapeutic targets for diseases with a strong metabolic component, such as obesity, diabetes, and cancer. Four distinct proteins are CPT1A, CPT1B, CPT1C, and CPT2, differing in tissue expression and catalytic activity. CPT1s are finely regulated by malonyl-CoA, a metabolite whose intracellular levels reflect the cell's nutritional state. Although CPT1C does not exhibit significant catalytic activity, it is capable of modulating the functioning of other neuronal proteins. Structurally, all CPTs share a Y-shaped catalytic tunnel that allows the entry of 2 substrates and accommodation of the acyl group in a hydrophobic pocket. Several molecules targeting these enzymes have been described, some showing potential in normalizing blood glucose levels in diabetic patients, and others that, through a central mechanism, are anorexigenic and enhance energy expenditure. However, given the critical roles that CPTs play in certain tissues, such as the heart, liver, and brain, it is essential to fully understand the differences between the various isoforms. We analyze in detail the structure of these proteins, their cellular and physiological functions, and their potential as therapeutic targets in diseases such as obesity, diabetes, and cancer. We also describe drugs identified to date as having inhibitory or activating capabilities for these proteins. This knowledge will support the design of new drugs specific to each isoform, and the development of nanomedicines that can selectively target particular tissues or cells. SIGNIFICANCE STATEMENT: Carnitine palmitoyltransferase (CPT) proteins, as gatekeepers of fatty acid oxidation, have great potential as pharmacological targets to treat metabolic diseases like obesity, diabetes, and cancer. In recent years, significant progress has been made in understanding the 3-dimensional structure of CPTs and their pathophysiological functions. A deeper understanding of the differences between the various CPT family members will enable the design of selective drugs and therapeutic approaches with fewer side effects.

Background/Objectives: Obesity is associated with numerous metabolic complications including insulin resistance, dyslipidemia, and a reduced capacity for physical activity. Whole-body ablation of liver fatty acid-binding protein (LFABP) in mice was shown to alleviate several of these metabolic complications; high-fat (HF)-fed LFABP knockout (LFABP-/-) mice developed higher fat mass than their wild-type (WT) counterparts but displayed a metabolically healthy obese (MHO) phenotype with normoglycemia, normoinsulinemia, and reduced hepatic steatosis compared with WT. Since LFABP is expressed in both liver and intestine, in the present study, we generated LFABP conditional knockout (cKO) mice to determine the contributions of LFABP specifically within the liver or within the intestine, to the whole-body phenotype of the global knockout. Methods: Female liver-specific LFABP knockout (LFABPliv-/-), intestine-specific LFABP knockout (LFABPint-/-), and "floxed" LFABP (LFABPfl/fl) control mice were fed a 45% Kcal fat semipurified HF diet for 12 weeks. Results: While not as dramatic as found for whole-body LFABP-/- mice, both LFABPliv-/- and LFABPint-/- mice had significantly higher body weights and fat mass compared with LFABPfl/fl control mice. As with the global LFABP nulls, both LFABPliv-/- and LFABPint-/- mice remained normoglycemic and normoinsulinemic. Despite their greater fat mass, the LFABPliv-/- mice did not develop hepatic steatosis. Additionally, LFABPliv-/- and LFABPint-/- mice had higher endurance exercise capacity when compared with LFABPfl/fl control mice. Conclusions: The results suggest, therefore, that either liver-specific or intestine-specific ablation of LFABP in female mice is sufficient to induce, at least in part, the MHO phenotype observed following whole-body ablation of LFABP.

Fatty acid synthase (FAS) is predominantly expressed in the liver and adipose tissue. It plays vital roles in de novo synthesis of saturated fatty acids and regulates insulin sensitivity. We previously demonstrated that serum circulating FAS (cFAS) is a clinical biomarker for advanced atherosclerosis, and that it is conjugated to low-density lipoproteins (LDL). However, it remains unknown whether cFAS can directly impact atheroprogression. To investigate this, we evaluate whether cFAS impacts macrophage foam cell formation - an important cellular process leading to atheroprogression. Macrophages exposed to human serum containing high levels of cFAS show increased foam cell formation as compared to cells exposed to serum containing low levels of cFAS. This difference is not observed using serum containing either high or low LDL. Pharmacological inhibition of cFAS using Platensimycin (PTM) decreases foam cell formation in vitro. In Apoe-/- mice with normal FAS expression, administration of PTM over 16 weeks along with a high fat diet decreases cFAS activity and aortic atherosclerosis without affecting circulating total cholesterol. This effect is also observed in Apoe-/- mice with liver-specific knockout of hepatic Fasn. Reductions in aortic root plaque are associated with decreased macrophage infiltration. These findings demonstrate that cFAS plays an important role in arterial atheroprogression.

Post-Liver transplantation (LT) survival rates stagnate, with biliary complications (BC) as a major cause of death. We analyzed longitudinal data with a median 19-month follow-up. BC was diagnosed with ultrasounds and MRCP. Missing data was imputed using mean and median. Data preprocessing involved feature scaling and one-hot encoding. Survival analysis used filter (Cox-P, Cox-c) and embedded (RSF, LASSO) feature selection methods. Seven survival machine learning algorithms were used: LASSO, Ridge, RSF, E-NET, GBS, C-GBS, and FS-SVM. Model development employed 5-fold cross-validation, random oversampling, and hyperparameter tuning. Random oversampling addressed data imbalance. Optimal hyperparameters were determined based on average C-index. Features importance was assessed using standardized regression coefficients and permutation importance for top models. Stability was evaluated using 5-fold cross-validation standard deviation. Finally, 1799 observations with 40 outcome predictors were included. RSF with Ridge achieved the highest performance (C-index: 0.699) for BC prediction, while RSF with RSF had the highest performance (C-index: 0.784) for mortality prediction. Top BC predictors were LT graft types, IBD in recipients, recipient's BMI, recipient's history of PVT, and previous LT history. For mortality, they were post-transplant AST, creatinine, recipient's age, post-transplant ALT, and tacrolimus consumption. We identified BC and mortality risk factors, improving decision-making and outcomes.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and obesity increases risk of cardiovascular disease. This cohort study examines the prognostic value of MASLD, across body weight categories, in a secondary preventative acute myocardial infarction (AMI) cohort.

Patients with AMI were stratified into four phenotypes-obesity MASLD, non-obesity MASLD, obesity non-MASLD, non-obesity non-MASLD. The primary outcome was all-cause mortality. Cox regression analysis was performed to investigate determinants of long-term all-cause mortality.

Of 5702 patients, majority were in the non-obesity non-MASLD group (66.7%), followed by obesity MASLD (16.1%), non-obesity MASLD (11.2%) and non-obesity MASLD (6.0%). Across the four phenotypes, obesity MASLD had the highest cardiometabolic burden, followed by non-obesity MASLD. Non-obesity MASLD had the highest risk of heart failure (p = 0.034), cardiogenic shock (p < 0.001), and all-cause long-term mortality (p = 0.019). The non-obesity MASLD (HR 1.400, 95%CI 1.077-1.820, p = 0.012) and obesity MASLD phenotypes (HR 1.222, 95%CI 1.005-1.485, p = 0.044) were independently associated with long-term all-cause mortality.

Obesity and non-obesity MASLD phenotypes were predictors of all-cause mortality following AMI, with an even larger magnitude of mortality risk in the non-obesity MASLD group. The recognition of MASLD and its body weight phenotypes will be beneficial in the prognostication following AMI.