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BACKGROUND & AIMS: Metabolic syndrome (MS) is a growing epidemic and a risk factor for the development of hepatocellular carcinoma (HCC). This study investigated the long-term outcomes of liver resection (LR) for HCC in patients with MS. Rates, timing, patterns, and treatment of recurrences were investigated, and cancer-specific survivals were assessed. METHODS: Between 2001 and 2021, data from 24 clinical centers were collected. Overall survival (OS), recurrence-free survival (RFS), and cancer-specific survival were analyzed as well as recurrence patterns and treatment. The analysis was conducted using a competing-risk framework. The trajectory of the risk of recurrence over time was applied to a competing risk analysis. For post-recurrence survival, death resulting from tumor progression was the primary endpoint, whereas deaths with recurrence relating to other causes were considered as competing events. RESULTS: In total, 813 patients were included in the study. Median OS was 81.4 months (range 28.1-157.0 months), and recurrence occurred in 48.3% of patients, with a median RFS of 39.8 months (range 15.7-174.7 months). Cause-specific hazard of recurrence showed a first peak 6 months (0.027), and a second peak 24 months (0.021) after surgery. The later the recurrence, the higher the chance of receiving curative intent approaches (p = 0.001). Size >5 cm, multiple tumors, microvascular invasion, and cirrhosis were independent predictors of recurrence showing a cause-specific hazard over time. RFS was associated with death for recurrence (hazard ratio: 0.985, 95% CI: 0.977-0.995; p = 0.002). CONCLUSIONS: Patients with MS undergoing LR for HCC have good long-term survival. Recurrence occurs in 48% of patients with a double-peak incidence and time-specific hazards depending on tumor-related factors and underlying disease. The timing of recurrence significantly impacts survival. Surveillance after resection should be adjusted over time depending on risk factors. IMPACT AND IMPLICATIONS: Metabolic syndrome (MS) is a growing epidemic and a significant risk factor for the development of hepatocellular carcinoma (HCC). The present study demonstrated that patients who undergo surgical resection for HCC on MS have a good long-term survival and that recurrence occurs in almost half of the cases with a double peak incidence and time-specific hazards depending on tumor-related factors and underlying liver disease. Also, the timing of recurrence significantly impacts survival. Clinicians should therefore adjust follow-up after surgery accordingly, considering timing of recurrence and specific risk factors. Also, the results of the present study might help design future trials on the use of adjuvant therapy following resection.

Purpose: To characterize T1 relaxation times of the pancreas, liver, and spleen in children with and without abdominal pathology. Methods: This retrospective study included pediatric patients (< 18-years-old). T1 mapping was performed with a Modified Look-Locker Inversion Recovery sequence. Patients were grouped based on review of imaging reports and electronic medical records. The Kruskal–Wallis test with Dunn's multiple comparison was used to compare groups. Results: 220 participants were included (mean age: 11.4 ± 4.2 years (1.5 T); 10.9 ± 4.5 years (3 T)). Pancreas T1 (msec) was significantly different between subgroups at 1.5 T (p < 0.0001). Significant pairwise differences included: normal (median: 583; IQR: 561–654) vs. acute pancreatitis (731; 632–945; p = 0.0024), normal vs. chronic pancreatitis (700; 643–863; p = 0.0013), and normal vs. acute + chronic pancreatitis (1020; 897–1099; p < 0.0001). Pancreas T1 was also significantly different between subgroups at 3 T (p < 0.0001). Significant pairwise differences included: normal (779; 753–851) vs. acute pancreatitis (1087; 910–1259; p = 0.0012), and normal vs. acute + chronic pancreatitis (1226; 1025–1367; p < 0.0001). Liver T1 was significantly different between subgroups only at 3 T (p = 0.0011) with pairwise differences between normal (818, 788–819) vs. steatotic (959; 848–997; p = 0.0017) and normal vs. other liver disease (882; 831–904; p = 0.0455). Liver T1 was weakly correlated with liver fat fraction at 1.5 T (r = 0.39; 0.24–0.52; p < 0.0001) and moderately correlated at 3 T (r = 0.64; 0.49–0.76; p < 0.0001). There were no significant differences in splenic T1 relaxation times between subgroups. Conclusion: Pancreas T1 relaxation times are higher at 1.5 T and 3 T in children with pancreatitis and liver T1 relaxation times are higher in children with steatotic and non-steatotic chronic liver disease at 3 T. [ABSTRACT FROM AUTHOR]

Purpose: This study investigated the prevalence of non-alcoholic fatty pancreatic disease (NAFPD) in patients with obstructive sleep apnoea (OSA) and analysed the correlation between them. Materials and methods: Patients who underwent polysomnography and modified abdominal ultrasound examinations were continuously enrolled and divided into OSA and control groups. The OSA group was further divided into NAFPD and non-NAFPD groups. Differences in various indicators were compared. Binary logistic regression analyses were conducted to identify factors influencing NAFPD. Results: A total of 210 participants were included in the study, including 178 in the OSA group and 32 in the control group. The prevalence of NAFPD, weight, body mass index (BMI), and other indicators were significantly higher in the OSA group than that in the control group (p < 0.05). The above indices, prevalence of hypertension and metabolic associated steatotic liver disease (MASLD), and severity of sleep apnoea were higher in the NAFPD group than that in the non-NAFPD group (p < 0.05). Binary logistic regression analysis showed a 4.4% increased risk of NAFPD for each unit increase in apnea-hypopnea index (AHI) after adjusting for BMI and hypertension. Conclusion: The prevalence of NAFPD was higher in the OSA group than that in the control group, and chronic intermittent hypoxia was strongly associated with pancreatic fat infiltration; AHI, BMI, and hypertension were independent risk factors for NAFPD. The NAFPD group had a higher prevalence of obesity and some other diseases. STATEMENT OF SIGNIFICANCE: This study confirms that the modified ultrasound evaluation method can serve as an effective tool for screening pancreatic fat infiltration in OSA patients, aiding in the early identification of the risk of ectopic lipid deposition and metabolic excess. [ABSTRACT FROM AUTHOR]

Objective: To assess the diagnostic performance of post-contrast CT for predicting moderate hepatic steatosis in an older adult cohort undergoing a uniform CT protocol, utilizing hepatic and splenic attenuation values. Materials and methods: A total of 1676 adults (mean age, 68.4 ± 10.2 years; 1045M/631F) underwent a CT urothelial protocol that included unenhanced, portal venous, and 10-min delayed phases through the liver and spleen. Automated hepatosplenic segmentation for attenuation values (in HU) was performed using a validated deep-learning tool. Unenhanced liver attenuation < 40.0 HU, corresponding to > 15% MRI-based proton density fat, served as the reference standard for moderate steatosis. Results: The prevalence of moderate or severe steatosis was 12.9% (216/1676). The diagnostic performance of portal venous liver HU in predicting moderate hepatic steatosis (AUROC = 0.943) was significantly better than the liver–spleen HU difference (AUROC = 0.814) (p < 0.001). Portal venous phase liver thresholds of 80 and 90 HU had a sensitivity/specificity for moderate steatosis of 85.6%/89.6%, and 94.9%/74.7%, respectively, whereas a liver–spleen difference of −40 HU and −10 HU had a sensitivity/specificity of 43.5%/90.0% and 92.1%/52.5%, respectively. Furthermore, livers with moderate–severe steatosis demonstrated significantly less post-contrast enhancement (mean, 35.7 HU vs 47.3 HU; p < 0.001). Conclusion: Moderate steatosis can be reliably diagnosed on standard portal venous phase CT using liver attenuation values alone. Consideration of splenic attenuation appears to add little value. Moderate steatosis not only has intrinsically lower pre-contrast liver attenuation values (< 40 HU), but also enhances less, typically resulting in post-contrast liver attenuation values of 80 HU or less. Clinical relevance statement: Moderate steatosis can be reliably diagnosed on post-contrast CT using liver attenuation values alone. Livers with at least moderate steatosis enhance less than those with mild or no steatosis, which combines with the lower intrinsic attenuation to improve detection. Key Points: The liver–spleen attenuation difference is frequently utilized in routine practice but appears to have performance limitations. The liver–spleen attenuation difference is less effective than liver attenuation for moderate steatosis. Moderate and severe steatosis can be identified on standard portal venous phase CT using liver attenuation alone. [ABSTRACT FROM AUTHOR]

Background and Aims: Recently, a new entity was introduced, MetALD, which includes patients with metabolic dysfunction‐associated steatotic liver disease (MASLD), who consume moderate amounts of alcohol. However, little is known regarding the metabolic and clinical characteristics of these patients. Methods: Data from the National Health and Nutrition Examination Surveys 2017–2020 was used. Participants without valid transient elastography (TE) measurements, incomplete alcohol consumption report, or with alternative etiologies of liver steatosis were excluded. Results: A total of 6901 patients were included in the study, of which 106 (1.5%) had MetALD. Overall, MetALD patients showed a metabolic profile that was more similar to patients with alcohol related liver disease (ALD) than MASLD. Specifically, while patients with MetALD showed values in‐between MASLD and ALD for body mass index (BMI), aspartate transaminase (AST), alanine transaminase (ALT), gamma glutamyltransferase (GGT) and haemoglobin A1c, they had similar high‐density lipoprotein cholesterol (HDL‐C), blood pressure, prevalence of diabetes and insulin resistance to ALD patients. Increasing alcohol consumption was associated with lower insulin resistance and A1c and higher triglycerides, HDL‐C and blood pressure. Moreover, while AST, ALT and GGT increased with alcohol consumption, this did not translate into worse hepatic steatosis or liver fibrosis by TE. Conclusions: MetALD patients share some characteristics with MASLD, but they resemble ALD patients more, especially after adjusting for BMI. Alcohol consumption produces a dissociation between insulin resistance and some cardiometabolic risk factors (blood pressure and HDL‐C), which may make the current classification of patients challenging. [ABSTRACT FROM AUTHOR]

The identification of biomarkers for the early diagnosis of nonalcoholic fatty liver disease (NAFLD) is urgently needed. Here, we aimed to identify NAFLD biomarkers in the early stages of steatosis (SS) and nonalcoholic steatohepatitis (NASH) based on differential gene expression from bioinformatics data. A meta-analysis was performed from transcriptomic databases retrieved from public repositories containing data from biopsies of patients at various stages of NAFLD development. The status of the selected molecules was validated in the serum of patients with NAFLD by ELISA. : We identified 121 differentially expressed genes (DEGs) associated with SS and 402 associated with NASH. Gene Ontology (GO) enrichment revealed that the altered genes were primarily associated with dysfunction of primary cellular processes, and pathway analyses were mainly related to cholesterol metabolism. We identified ACSS2, PCSK9, and CYP7A1 as candidate biomarkers for SS and ANGPTL3, CD36, CYP51A1, FASN, FAS, FDFT1, and LSS as candidate biomarkers for NASH. By experimental validation of bioinformatics data from patients with NAFLD, we identified promising biomarkers for detecting SS and NASH that might be useful for screening and diagnosing early NAFLD stages in humans. [ABSTRACT FROM AUTHOR]

Background Objectives Animals Methods Results Conclusions and Clinical Importance Enteral nutrition (EN) is essential for management of hepatic lipidosis (HL) in cats.To determine if time to start of EN and other clinicopathologic variables are associated with outcome in cats with HL.Forty‐eight cats with HL.Retrospective study. Information retrieved from medical records and client communications included clinicopathologic findings, time to start of EN, initial % of resting energy requirements provided, type of feeding tube, duration of hospitalization, and 3‐month survival. Variables were compared between surviving and nonsurviving cats and between cats fed ≤12 hours and >12 hours after hospital admission. Multivariable statistical testing was performed to further investigate variables of interest.Seventeen of 25 (68%) cats fed ≤12 hours and 13 of 23 (57%) of cats fed >12 hours after hospital admission survived (P = .55). Only increasing age (odds ratio [OR], 1.313; 95% confidence interval [CI], 1.032‐1.671; P = .03) and the presence of ascites (OR, 6.415; 95% CI, 1.354‐30.395; P = .02) were associated with death in multivariable analysis. Hospitalization duration (median, interquartile range [IQR]) was shorter in cats fed >12 hours (2.8 days; IQR, 2.1‐3.8 days) as compared with cats fed ≤12 hours (4.8 days; IQR, 3.6‐6.2 days) after hospital admission (P < .001).An initial stabilization period before EN introduction does not decrease survival or increase duration of hospitalization in cats with HL. [ABSTRACT FROM AUTHOR]

Simple Summary: Diet is a fundamental determinant of health and longevity. This relationship is complex. Historically, among the most investigated variables have been quality and quantity of food. However, over the past 2 decades increasing attention has been devoted to dietary rhythms, including time of food consumption during the day and length of fasting intervals. In this respect, contrasting evidence has recently emerged in the literature regarding the effect of adequate intervals of fasting on the evolution of diet-related chronic liver diseases, including hepatocellular carcinoma. In this review, we briefly refer to this evidence and propose a hypothesis that may help reconcile apparently conflicting observations. Dietary rhythms have emerged as a relevant variable in the equation relating nutrition and health. Both experimental and epidemiological studies point to potential beneficial effects of adequate fasting intervals between meals on the evolution of chronic diseases associated with aging. Metabolic dysfunction-associated steatotic liver disease (MASLD) is eminently related to diet and unsurprisingly, diet-based approaches are a mainstay in countering its long-term clinical evolution, including the emergence of hepatocellular carcinoma (HCC). We briefly discuss current evidence linking fasting intervals, MASLD, and HCC and propose a working hypothesis to reconcile some of the apparently conflicting results. This hypothesis relates the beneficial effects of time-restricted eating schedules to the quantity and quality of food, and it is easily amenable to testing. [ABSTRACT FROM AUTHOR]

Introduction: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease in the world, and it is characterized by an excessive hepatic fat accumulation in more than 5% of hepatocytes documented by histology in the absence of alcohol consumption. It is a multifactorial pathology, where genetic component plays a fundamental role: the loss-offunction polymorphisms of genes coding for glutathione S-transferases would predispose to the pathology onset, also in the absence of other risk factors. The aim of the study was to evaluate the relation between the "NULL" GST-T1 and GST-M1 polymorphisms and the onset of NAFLD. Methods: A group of 117 "apparently healthy" Caucasian volunteers, selected from a larger population through the analysis of previously administered short questionnaires, underwent both magnetic resonance imaging-proton density fat fraction (MRI-PDFF) and buccal swabs: the aim was to identify the possible presence of hepatic steatosis and of the aforementioned "NULL" polymorphisms of interest. Results: A statistically significant association between the GST-T1 and GST-M1 "NULL" genotypes and the probability of developing NAFLD has been identified. In particular, the GST-T1 "NULL" genotype has been associated with a greater probability of developing steatosis in early age, while the GST-M1 "NULL" genotype seems to increase the risk of developing a higher grade of steatosis. No statistically significant correlations between the "NULL" genotype and sex have been detected. Discussion: Among the numerous risk factors capable of predisposing to NAFLD onset and progression, the genetic factors seem to play an important role. In particular, GST-T1 and GST-M1 "NULL" polymorphisms would appear to acquire even greater importance, as their loss of function results in an increase of oxidative stress. At high concentrations, ROS can determine oxidative modifications of cellular macromolecules, such as lipids, determining their accumulation into hepatocytes. The study also highlighted the importance of MRI-PDFF for hepatic steatosis diagnosis: this method allows the acquisition of data comparable to those of conventional biopsy; however, it permits the entire liver parenchyma to be visualized. Conclusion: A statistically significant correlation between the presence of GSTT1 and GST-M1 "NULL" genotypes and the presence of hepatic steatosis has been found. [ABSTRACT FROM AUTHOR]

Manganese is an important cofactor for numerous biological processes, including defense against reactive oxygen species. A common genetic variant in the manganese transporter SLC39A8 (p.Ala391Thr) has been associated with lower blood levels of manganese and with increases in markers of liver cell damage. Whether the variant confers an increased risk of liver disease is unclear. We tested the association of this variant with biochemical, imaging, and clinical hepatic traits and outcomes in large general population cohorts totaling up to one million individuals, including 991 cases with hepatocellular carcinoma (HCC) and 7191 cases with cirrhosis. We found that the Thr-allele of p.Ala391Thr was associated with slightly higher plasma alanine transaminase and aspartate transaminase, markedly higher corrected T1 on hepatic magnetic resonance imaging, a presumed marker of liver inflammation, and with lower hepatic computed tomography attenuation. However, the variant was not associated with hepatic fat content or with the risk of HCC or cirrhosis. In conclusion, SLC39A8 p.Ala391Thr is associated with biochemical and imaging markers of hepatic inflammation, but the variant does not confer a higher risk of chronic liver disease. We hypothesize that the associations with hepatic imaging traits are due to lower hepatic manganese levels in carriers of the variant. Antioxid. Redox Signal. 41, 591–596. [ABSTRACT FROM AUTHOR]

Numerous studies highlight the potential of natural antioxidants, such as those found in foods and plants, to prevent or treat nonalcoholic fatty liver disease (NAFLD). Inflammation is a key factor in the progression from high‐fat diet‐induced NAFLD to nonalcoholic steatohepatitis (NASH). Injured liver cells and immune cells release inflammatory cytokines, activating hepatic stellate cells. These cells acquire a profibrogenic phenotype, leading to extracellular matrix accumulation and fibrosis. Persistent fibrosis can progress to cirrhosis. Fatty infiltration, oxidative stress, and inflammation exacerbate fatty liver diseases. Thus, many plant‐derived antioxidants, like silymarin, silibinin, curcumin, resveratrol, berberine, and quercetin, have been extensively studied in experimental models and clinical patients with NAFLD. Experimentally, these compounds have shown beneficial effects in reducing lipid accumulation, oxidative stress, and inflammatory markers by modulating the ERK, NF‐κB, AMPKα, and PPARγ pathways. They also help decrease metabolic endotoxemia, intestinal permeability, and gut inflammation. Clinically, silymarin and silibinin have been found to reduce transaminase levels, while resveratrol and curcumin help alleviate inflammation in NAFLD patients. However, these phytocompounds exhibit poor water solubility, leading to low oral bioavailability and hindering their biological efficacy. Additionally, inconclusive clinical results highlight the need for further trials with larger populations, longer durations, and standardized protocols. Significance Statement: This review explores hepatoprotective phytochemicals for nonalcoholic fatty liver disease at the molecular level. Existing literature supports that silymarin, silibinin, resveratrol, curcumin, and berberine exhibit antioxidant and anti‐inflammatory properties by inhibiting inflammatory pathways, while also mitigating metabolic endotoxemia, intestinal permeability, and gut inflammation. However, their poor solubility and limited oral bioavailability in clinical settings reduce their potential benefits for patients with nonalcoholic fatty liver disease. [ABSTRACT FROM AUTHOR]

Objectives Severe macrovesicular steatosis in donor livers is associated with primary graft dysfunction. The Banff Working Group on Liver Allograft Pathology has proposed recommendations for steatosis assessment of donor liver biopsy specimens with a consensus for defining "large droplet fat" (LDF) and a 3-step algorithmic approach. Methods We retrieved slides and initial pathology reports from potential liver donor biopsy specimens from 2010 to 2021. Following the Banff approach, we reevaluated LDF steatosis and employed a computer-assisted manual quantification protocol and artificial intelligence (AI) model for analysis. Results In a total of 113 slides from 88 donors, no to mild (<33%) macrovesicular steatosis was reported in 88.5% (100/113) of slides; 8.8% (10/113) was reported as at least moderate steatosis (≥33%) initially. Subsequent pathology evaluation, following the Banff recommendation, revealed that all slides had LDF below 33%, a finding confirmed through computer-assisted manual quantification and an AI model. Correlation coefficients between pathologist and computer-assisted manual quantification, between computer-assisted manual quantification and the AI model, and between the AI model and pathologist were 0.94, 0.88, and 0.81, respectively (P <.0001 for all). Conclusions The 3-step approach proposed by the Banff Working Group on Liver Allograft Pathology may be followed when evaluating steatosis in donor livers. The AI model can provide a rapid and objective assessment of liver steatosis. [ABSTRACT FROM AUTHOR]

The introduction of the term "Metabolic Steatotic Liver Disease" (MASLD) underscores the critical role of metabolic dysfunction in the development and progression of chronic liver disease and emphasizes the need for strategies that address both liver disease and its metabolic comorbidities. In recent years, a liver-focused perspective has revealed that altered endocrine function of the fatty liver is a key contributor to the metabolic dysregulation observed in MASLD. Due to its secretory capacity, the liver's increased production of proteins known as "hepatokines" has been linked to the development of insulin resistance, explaining why MASLD often precedes dysfunction in other organs and ultimately contributes to systemic metabolic disease. Among these hepatokines, fibroblast growth factor 21 (FGF21) and fetuin-A play central roles in regulating the metabolic abnormalities associated with MASLD, explaining why their dysregulated secretion in response to metabolic stress has been implicated in the metabolic abnormalities of MASLD. This review postulates why their modulation by GLP1-Ras may mediate the beneficial metabolic effects of these drugs, which have increased attention to their emerging role as pharmacotherapy for MASLD. By discussing the crosstalk between GLP1-Ras-FGF21-fetuin-A, this review hypothesizes that the possible modulation of fetuin-A by the novel GLP1-FGF21 dual agonist pharmacotherapy may contribute to the management of metabolic and liver diseases. Although research is needed to go into the details of this crosstalk, this topic may help researchers explore the mechanisms by which this type of pharmacotherapy may manage the metabolic dysfunction of MASLD. [ABSTRACT FROM AUTHOR]

Simple Summary: Pathological hyperlipidemia is a significant emerging condition in dogs, associated with liver diseases such as hepatic lipidosis or steatosis. Ultrasound attenuation imaging (ATI) is used in humans to quantitatively evaluate liver parenchyma. The aim of this prospective study was to verify the applicability of ATI on hyperlipidemic dogs. Fifty-three dogs underwent clinical examination, blood tests, abdominal ultrasound and ATI between January 2021 and December 2022, divided into two groups: a total of 21 healthy dogs (A) and 32 hyperlipidemic dogs (B). The dogs of Group B were divided into mild hyperlipidemic (B1; n = 15) and moderate/severe hyperlipidemic (B2; n = 17). Based on the qualitative B-mode evaluation, the grade of severity of hepatic steatosis was classified into four degrees, from normal to severe, with 2, 16, 14 and 2 dogs, respectively. The mean AC value was significantly higher in Group B (0.95 ± 0.23 dB/cm/MHz) compared to Group A (0.81 ± 0.10 dB/cm/MHz). No statistically significant differences in AC values were found between Group B1 and Group B2. In conclusion, ATI could be a useful diagnostic tool in patients suspected of hepatic steatosis. (1) Background: Ultrasound attenuation imaging (ATI) is an innovative technique that allows for the evaluation of the degree of lipid infiltration of the liver parenchyma in a simple and non-invasive way. The objective of this study was to verify the applicability of the ATI method in the evaluation of hyperlipidemia. (2) Methods: This study included 53 dogs between January 2021 and December 2022, of which 21 were healthy (A) and 32 had hyperlipidemia (B). The dogs of Group B were divided into mild hyperlipidemic (B1; n = 15) and moderate/severe hyperlipidemic (B2; n = 17). Each dog underwent biochemical examination, B-mode ultrasound and ATI investigation at the liver level via a right intercostal approach. (3) Results: The mean AC value was significantly higher in Group B (0.95 ± 0.23 dB/cm/MHz) compared to Group A (0.81 ± 0.10 dB/cm/MHz). No statistically significant differences were highlighted regarding the ATI values between the subjects with mild and moderate/severe hyperlipidemia. (4) Conclusion: ATI could be a promising method for the non-invasive evaluation of hepatic steatosis in veterinary medicine. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated fatty liver disease (MAFLD) and viral hepatitis due to chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection are common liver diseases worldwide. Excessive alcohol consumption and alcoholic liver disease (ALD) are also emerging health problems. Therefore, in clinical practice, we may encounter subjects with dual etiology of liver diseases such as coexisting MAFLD/HBV, MAFLD/HCV, and MAFLD/ALD. In this review, we summarize the epidemiology, clinical features, and mutual interactions of MAFLD with coexisting HBV, HCV, or ALD. The impact of MAFLD on the progression of liver diseases and treatment outcomes in patients with chronic viral hepatitis and the clinical questions to be addressed regarding dual MAFLD and ALD are also discussed. [ABSTRACT FROM AUTHOR]

In the past thirty years, childhood obesity rates have risen significantly worldwide, affecting over 340 million children in affluent nations. This surge is intricately tied to metabolic disorders, notably insulin resistance, type 2 diabetes mellitus (T2DM), and the continually evolving spectrum of metabolic-associated (dysfunction) steatotic liver disease (MASLD). This review underscores the alarming escalation of childhood obesity and delves comprehensively into the evolving and dynamic changes of nomenclature surrounding diverse conditions of hepatic steatosis, from the initial recognition of non-alcoholic fatty liver disease (NAFLD) to the progressive evolution into MASLD. Moreover, it emphasizes the crucial role of pediatric endocrinologists in thoroughly and accurately investigating MASLD onset in children with T2DM, where each condition influences and exacerbates the progression of the other. This review critically highlights the inadequacies of current screening strategies and diagnosis, stressing the need for a paradigm shift. A proposed solution involves the integration of hepatic magnetic resonance imaging assessment into the diagnostic arsenal for children showing insufficient glycemic control and weight loss post-T2DM diagnosis, thereby complementing conventional liver enzyme testing. This holistic approach aims to significantly enhance diagnostic precision, fostering improved outcomes in this vulnerable high-risk pediatric population. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty acid disease (NAFLD) is caused by a build-up of fat in the liver, inducing local inflammation and fibrosis. We evaluated the effects of probiotic lactic acid-generating bacteria (LAB) derived from a traditional fermented beverage in a mouse model of NAFLD. The LAB isolated from this traditional Korean beverage were screened using the human hepatic cell line HepG2, and Lactocaseibacillus paracasei HY7207 (HY7207), which was the most effective inhibitor of fat accumulation, was selected for further study. HY7207 showed stable productivity in industrial-scale culture. Whole-genome sequencing of HY7207 revealed that the genome was 2.88 Mbp long, with 46.43% GC contents and 2778 predicted protein-coding DNA sequences (CDSs). HY7207 reduced the expression of lipogenesis and hepatic apoptosis-related genes in HepG2 cells treated with palmitic acid. Furthermore, the administration of 109 CFU/kg/day of HY7207 for 8 weeks to mice fed an NAFLD-inducing diet improved their physiologic and serum biochemical parameters and ameliorated their hepatic steatosis. In addition, HY7207 reduced the hepatic expression of genes important for lipogenesis (Srebp1c, Fasn, C/ebpa, Pparg, and Acaca), inflammation (Tnf, Il1b, and Ccl2), and fibrosis (Col1a1, Tgfb1, and Timp1). Finally, HY7207 affected the expression of the apoptosis-related genes Bax (encoding Bcl2 associated X, an apoptosis regulator) and Bcl2 (encoding B-cell lymphoma protein 2) in the liver. These data suggest that HY7207 consumption ameliorates NAFLD in mice through effects on liver steatosis, inflammation, fibrosis, and hepatic apoptosis. Thus, L. paracasei HY7207 may be suitable for use as a functional food supplement for patients with NAFLD. [ABSTRACT FROM AUTHOR]

Chalcones constitute an important group of natural compounds abundant in fruits and comestible plants. They are a subject of increasing interest because of their biological activities, including anti-diabetic and anti-obesity effects. The simple chalcone structural scaffold can be modified at multiple sites with different chemical moieties. Here, we generated an artificial chalcone, i.e., 3,5-dimethyl-2,4,6-trimethoxychalcone (TriMetChalc), derived from 2′,4′-Dihydroxy-6′-methoxy-3′,5′-dimethylchalcone (DMC). DMC is a major compound of Cleistocalyx operculatus, a plant widely used in Asia for its anti-hyperglycemic activity. Using ob/ob mice as an obesity model, we report that, after 3 weeks of per os administration, TriMetChalc modified food intake through the specific activation of brain structures dedicated to the regulation of energy balance. TriMetChalc also decreased weight gain, glucose intolerance, and hepatic steatosis. Moreover, through extensive liver lipidomic analysis, we identified TriMetChalc-induced modifications that could contribute to improving the liver status of the animals. Hence, TriMetChalc is a chalcone derivative capable of reducing food intake and the addition of glucose intolerance and hepatic steatosis in a mouse model of obesity. In light of these results, we believe that TriMetChalc action deserves to be more deeply evaluated over longer treatment periods and/or in combination with other chalcones with protective effects on the liver. [ABSTRACT FROM AUTHOR]

Background: Consumption of flavonoid-rich orange juice has been shown to reduce adiposity and liver steatosis in murine models of diet-induced obesity. However, little is known about the effects of whole orange intake, independent of body weight changes, on liver function and steatosis in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD). The goal is to understand the direct impact of orange consumption on metabolic health. Methods: Sixty-two men and women aged 30–65 with MASLD (Controlled Attenuation Parameter, (CAP) > 275 dB/m) were randomly assigned to consume either 400 g of whole oranges or non-citrus fruits daily for 4 weeks. Baseline evaluations included medical assessments, blood tests, and body composition. Liver health was assessed using transient elastography (FibroScan®) for steatosis and fibrosis, conducted by blinded personnel. This clinical trial was registered at ClinicalTrials.gov (NCT05558592). Results: After 4 weeks of orange supplementation, liver steatosis decreased in the treatment group, with 70.9% showing steatosis compared to 100% in controls (p < 0.004), indicating a 30% reduction in liver disease prevalence. There were no significant changes in fibrosis or plasma liver enzymes, though plasma gamma glutaril transferase (GGT) levels decreased significantly. Body weight, waist circumference, body composition, lipid profile, fasting glucose, insulin, and C-reactive protein levels remained unchanged. Dietary analysis revealed no change in caloric intake, but vitamins C, A, thiamine, and riboflavin increased in the orange group. Conclusions: Our findings suggest that phytochemical-rich foods, especially whole fruits like oranges, may enhance liver function as an adjunct treatment for MASLD. The notable reduction in liver steatosis prevalence occurred independently of body weight changes. Further studies are needed to investigate the long-term effects of orange supplementation on steatosis and fibrosis progression and to identify the specific bioactive compounds and mechanisms involved. [ABSTRACT FROM AUTHOR]

Background: Edible plants have been linked to the mitigation of metabolic disturbances in liver and adipose tissue, including the decrease of lipogenesis and the enhancement of lipolysis and adipocyte browning. In this context, plant microRNAs could be key bioactive molecules underlying the cross-kingdom beneficial effects of plants. This study sought to explore the impact of plant-derived microRNAs on the modulation of adipocyte and hepatocyte genes involved in metabolism and thermogenesis. Methods: Plant miR6262 was selected as a candidate from miRBase for the predicted effect on the regulation of human metabolic genes. Functional validation was conducted after transfection with plant miRNA mimics in HepG2 hepatocytes exposed to free fatty acids to mimic liver steatosis and hMADs cells differentiated into brown-like adipocytes. Results: miR6262 decreases the expression of the predicted target RXRA in the fatty acids-treated hepatocytes and in brown-like adipocytes and affects the expression profile of critical genes involved in metabolism and thermogenesis, including PPARA, G6PC, SREBF1 (hepatocytes) and CIDEA, CPT1M and PLIN1 (adipocytes). Nevertheless, plant miR6262 mimic transfections did not decrease hepatocyte lipid accumulation or stimulate adipocyte browning. Conclusions: these findings suggest that plant miR6262 could have a cross-kingdom regulation relevance through the modulation of human genes involved in lipid and glucose metabolism and thermogenesis in adipocytes and hepatocytes. [ABSTRACT FROM AUTHOR]

Background: The association between nonalcoholic fatty liver disease (NAFLD) and atrial fibrillation (AF) has been inconsistent, and the impact of hepatic fibrosis on this relationship remains uncertain. We investigated the association between NAFLD and the risk of new-onset AF across different age groups. Methods: A total of 3,179,582 participants from the 2009 Korean National Health Screening Program were divided into five groups based on NAFLD status: no NAFLD (fatty liver index [FLI] < 30); grade 1 NAFLD without advanced fibrosis (FLI 30–59 & BARD < 2); grade 1 NAFLD with advanced fibrosis (FLI 30–59 & BARD ≥ 2); grade 2 NAFLD without advanced fibrosis (FLI ≥ 60 & BARD < 2); and grade 2 NAFLD with advanced fibrosis (FLI ≥ 60 & BARD ≥ 2). The primary outcome was incident AF. Results: During the median follow-up of 9.3 years, 62,542 patients were diagnosed with new-onset AF. In the age- and sex-adjusted model, the risk of new-onset AF increased across NAFLD grades and fibrosis categories: grade 1 NAFLD without advanced fibrosis (hazard ratio [HR] 1.120, 95% confidence interval [CI]: 1.081–1.161); grade 1 NAFLD with advanced fibrosis (HR 1.275, 95% CI 1.251–1.300); grade 2 NAFLD without advanced fibrosis (HR 1.305, 95% CI: 1.252–1.360); and grade 2 NAFLD with advanced fibrosis (HR 1.627, 95% CI: 1.586–1.670). In the multivariate model, the excess risk of AF in patients with NAFLD and advanced fibrosis remained significant, even in participants aged 20–39 years. Conclusion: Patients with NAFLD had a higher risk of new-onset AF, which increased progressively with NAFLD severity, particularly in those aged 20–29 years. [ABSTRACT FROM AUTHOR]

Background: The prevalence and incidence of Nonalcoholic fatty liver disease (NAFLD) are increasing worldwide, and NAFLD has emerged as a prominent global health concern. The link between serum alanine aminotransferase (ALT) to aspartate aminotransferase (AST) ratio and NAFLD remains unclear. This study investigated the association between the ALT/AST ratio and NAFLD prevalence, including liver steatosis and fibrosis levels in the population. Methods: We conducted a cross-sectional study using data from the National Health and Nutrition Examination Survey (NHANES) 2017–2018, including 4753 participants. Subgroup analyses, stratified by age, gender, and body mass index (BMI), were performed, along with adjusted multivariable logistic regression analyses to evaluate the relationship between ALT/AST levels and the likelihood of NAFLD, liver steatosis, and hepatic fibrosis stage. A generalized additive model examined the non-linear relationship between ALT/AST and the probability of developing NAFLD. Results: Among 4753 participants, 1508 (31.73%) were diagnosed with NAFLD. Significant positive correlations between ALT/AST and NAFLD risk were found across all models. In addition, the subgroup analysis by gender, age, and BMI suggested that ALT/AST showed a positive correlation with NAFLD. The ALT/AST ratio was positively correlated with the degree of liver steatosis and liver fibrosis. The correlation between ALT/AST and the incidence of NAFLD showed a non linear pattern. In women, the non-linear trend is particularly evident, showing an inverted U-shaped curve with an inflection point of 1.302. A receiver operating characteristic (ROC) analysis showed that the predictive value of ALT/AST for NAFLD was better than that of traditional liver enzyme parameters. Conclusion: A higher ALT/AST ratio was independently associated with a significantly higher risk of NAFLD and liver fibrosis within American cohorts. This link is robust among females, children, and adolescents. ALT/AST ratio can be used as a simple and effective noninvasive biomarker to identify individuals with high risk of NAFLD. [ABSTRACT FROM AUTHOR]

Background and objective: Metabolic associated fatty liver disease (MAFLD) is associated with abnormal lipid metabolism. Mitochondrial dysfunction is considered an important factor in the onset of MAFLD, whereas altered fatty acid composition has been linked to the severity of the disease. Tetradecylthioacetic acid (TTA), shown to induce mitochondrial proliferation and alter the fatty acid composition, was used to delay the accumulation of hepatic triacylglycerol. This study aimed to evaluate how impaired mitochondrial fatty acid beta-oxidation affects fatty acid composition by incorporating meldonium into a high-carbohydrate diet. Methods: C57BL/6 mice (n = 40) were fed high-carbohydrate diets supplemented with meldonium, TTA, or a combination of meldonium and TTA for 21 days. Lipid levels were determined in liver samples, and fatty acid composition was measured in both liver and plasma samples. Additionally, desaturase and elongase activities were estimated. The hepatic activities and gene expression levels of enzymes involved in fatty acid metabolism were measured in liver samples, whereas carnitines, their precursors, and acylcarnitines were measured in plasma samples. Results: The meldonium-induced depletion of L-carnitine and mitochondrial fatty acid oxidation was confirmed by reduced plasma levels of L-carnitine and acylcarnitines. Principal component analyses of the hepatic fatty acid composition revealed clustering dependent on meldonium and TTA. The meldonium-induced increase in hepatic triacylglycerol levels correlated negatively with estimated activities of elongases and was associated with higher estimated activities of delta-6 desaturase (D6D; C18:4n-3/C18:3n-3 and C18:3n-6/C18:2n-6), and increased circulating levels of C18:4n-3 and C18:3n-6 (gamma-linolenic acid). TTA mitigated meldonium-induced triacylglycerol levels by 80% and attenuated the estimated D6D activities, and elongation of n-6 polyunsaturated fatty acids (PUFAs). TTA also attenuated the meldonium-mediated reduction of C24:1n-9 (nervonic acid), possibly by stimulating Elovl5 and increased elongation of erucic acid (C22:1n-9) to nervonic acid. The hepatic levels of nervonic acid and the estimated activity of n-6 PUFA elongation correlated negatively with the hepatic triacylglycerol levels, while the estimated activities of D6D correlated positively. Conclusion: Circulating levels of gamma-linolenic acid, along with reduced estimated elongation of n-6 PUFAs and D6D desaturation activities, were associated with hepatic triacylglycerol levels.

Abstract Background The association between nonalcoholic fatty liver disease (NAFLD) and atrial fibrillation (AF) has been inconsistent, and the impact of hepatic fibrosis on this relationship remains uncertain. We investigated the association between NAFLD and the risk of new-onset AF across different age groups. Methods A total of 3,179,582 participants from the 2009 Korean National Health Screening Program were divided into five groups based on NAFLD status: no NAFLD (fatty liver index [FLI]

Aim: Tirzepatide, a dual agonist of glucagon‐like peptide receptor and glucose‐dependent insulinotropic polypeptide receptor, is expected to exhibit high clinical efficacy in obese type 2 diabetic patients. We evaluated the effects of tirzepatide on pancreatic β‐cells and the liver, an insulin‐target organ, in a mouse model of obese type 2 diabetes mellitus. Materials and Methods: Obese type 2 diabetic db/db mice (BKS.Cg−/+ Leprdb/+ Leprdb/Jcl*) were used in this study. Starting at 7 weeks of age, mice were treated with tirzepatide (30 nmol/kg, subcutaneous injection twice a week) or semaglutide (200 nmol/kg, subcutaneous injection twice a week). The control group received phosphate‐buffered saline (40–50 μL/subcutaneous injection twice a week). After 4 weeks of drug administration, pancreatic β‐cells and the liver were removed and examined. Results: Compared to the control group, blood glucose and body weight were significantly reduced in the group that received either tirzepatide or semaglutide (p < 0.001 and p < 0.05, respectively). Fasting insulin was significantly higher in the semaglutide and tirzepatide groups compared to the control group (p < 0.001). β‐Cell mass and quality of insulin granules in β‐cells similarly increased in the semaglutide and tirzepatide groups compared to the control group (p < 0.05 and p < 0.001, respectively). The fat staining area in the liver in oil red O staining and the liver–spleen ratio in computed tomography showed improvement only in the tirzepatide group (p < 0.001 and p < 0.005, respectively). Liver macrophage M1/M2 ratio similarly improved with semaglutide and tirzepatide (p < 0.05). Conclusion: Tirzepatide and semaglutide exhibited similar potent glucose‐lowering effects. At concentrations used in the present experiments, tirzepatide exhibited more beneficial effects on β‐cell‐related gene expression, insulin granule count and glucose‐stimulated insulin secretion compared to semaglutide. In addition, tirzepatide exhibited a stronger favourable effect on hepatic fat deposition and improved inflammation in the liver. This is the first report showing that tirzepatide, a novel diabetes drug, exhibits a superior effect on pancreatic β‐cells and the liver of obese type 2 diabetic mice. [ABSTRACT FROM AUTHOR]

Background. Chronic liver disease is one of the most common diseases. In many countries, liver disease is among the top five causes of death. The liver is one of the main organs responsible for basic metabolic functions, protein and hormone synthesis, detoxification and waste elimination. In chronic liver disease, there is a continuous process of inflammation, destruction and regeneration, ultimately leading to severe dysfunction, causing the development of fibrosis and cirrhosis. The main task of the radiation diagnosis of chronic liver disease is the development and introduction into clinical practice of new noninvasive biomarkers for a comprehensive assessment of the structure of the liver parenchyma in order to choose further treatment tactics.Aim a comprehensive analysis of the modern possibilities of radiation imaging methods in the diagnosis of chronic liver disease.Materials and methods. The analysis of 107 modern publications of domestic and foreign literature devoted to the diagnosis of chronic liver disease of various etiologies was carried out.Conclusion. the review reflects the most common modern and promising methods of radiodiagnosis for chronic liver disease, which in most cases make it possible to avoid invasive interventions in the process of establishing a diagnosis and monitoring the response to treatment

Abstract Liver sinusoidal endothelial cells (LSECs) are highly specialized endothelial cells that represent the interface between blood cells on one side and hepatocytes on the other side. LSECs not only form a barrier within the hepatic sinus, but also play important physiological functions such as regulating hepatic vascular pressure, anti-inflammatory and anti-fibrotic. Pathologically, pathogenic factors can induce LSECs capillarization, that is, loss of fenestra and dysfunction, which are conducive to early steatosis, lay the foundation for the progression of metabolic dysfunction-associated fatty liver disease (MAFLD), and accelerate metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis. The unique localization, phenotype, and function of LSECs make them potential candidates for reducing liver injury, inflammation, and preventing or reversing fibrosis in the future.

Nonalcoholic steatohepatitis (NASH) is characterized by severe inflammation and fibrosis due to an excessive accumulation of triglycerides (TGs) in the liver with a dysregulated de novo lipogenesis (DNL) pathway. In this study, we aimed to evaluate the effectiveness of YC-1102, an extract obtained from the roots of Rosa multiflora, as a nutritional supplement in a diet-induced NASH mouse model. C57BL/6 wild-type mice were fed a fructose, palmitate, and cholesterol (FPC)-containing diet for 16 weeks to induce experimental NASH. A daily oral gavage of YC-1102 and obetichoic acid (OCA) was conducted for 9 weeks. After sacrifice, disease parameters related to hepatic lipids, inflammation, and fibrosis were evaluated. The treatment with YC-1102 significantly decreased the liver/body weight ratio, epididymal fat weight, and plasma ALT and AST levels, which are indicators of NASH injuries. YC-1102 attenuated hepatic lipid accumulation by inhibiting the transcription of DNL genes in the livers exhibiting NASH. Additionally, we found that YC-1102 blocked the development of hepatic inflammation and fibrosis by directly disturbing macrophage activation, resulting in an amelioration of hepatic fibrosis. Our findings suggest that YC-1102 could ameliorate NASH progression by inhibiting uncontrolled DNL and inflammation.

Abstract We aimed to implement four data partitioning strategies evaluated with four federated learning (FL) algorithms and investigate the impact of data distribution on FL model performance in detecting steatosis using B-mode US images. A private dataset (153 patients; 1530 images) and a public dataset (55 patient; 550 images) were included in this retrospective study. The datasets contained patients with metabolic dysfunction-associated fatty liver disease (MAFLD) with biopsy-proven steatosis grades and control individuals without steatosis. We employed four data partitioning strategies to simulate FL scenarios and we assessed four FL algorithms. We investigated the impact of class imbalance and the mismatch between the global and local data distributions on the learning outcome. Classification performance was assessed with area under the receiver operating characteristic curve (AUC) on a separate test set. AUCs were 0.93 (95% CI 0.92, 0.94) for source-based partitioning scenario with FedAvg, 0.90 (95% CI 0.89, 0.91) for a centralized model, and 0.83 (95% CI 0.81, 0.85) for a model trained in a single-center scenario. When data was perfectly balanced on the global level and each site had an identical data distribution, the model yielded an AUC of 0.90 (95% CI 0.88, 0.92). When each site contained data exclusively from one single class, irrespective of the global data distribution, the AUC fell in the range of 0.34–0.70. FL applied to B-mode US images provide performance comparable to a centralized model and higher than single-center scenario. Global data imbalance and local data heterogeneity influenced the learning outcome.

High-fat diets (HFDs) shape the gut microbiome and promote obesity, inflammation, and liver steatosis. Fish and soybean are part of a healthy diet; however, the impact of these fats, in the absence of sucrose, on gut microbial dysbiosis and its association with liver steatosis remains unclear. Here, we investigated the effect of sucrose-free soybean oil-and fish oilbased high fat diets (HFDs) (SF-Soy-HFD and SF-Fish-HFD, respectively) on gut dysbiosis, obesity, steatosis, hepatic inflammation, and insulin resistance. C57BL/6 mice were fed these HFDs for 24 weeks. Both diets had comparable effects on liver and total body weights. But 16S-rRNA sequencing of the gut content revealed induction of gut dysbiosis at different taxonomic levels. The microbial communities were clearly separated, showing differential dysbiosis between the two HFDs. Compared with the SF-Fish-HFD control group, the SF-Soy-HFD group had an increased abundance of Bacteroidetes, Firmicutes, and Deferribacteres, but a lower abundance of Verrucomicrobia. The Clostridia/Bacteroidia (C/B) ratio was higher in the SF-Soy-HFD group (3.11) than in the SF-Fish-HFD group (2.5). Conversely, the Verrucomicrobiacae/S24_7 (also known as Muribaculaceae family) ratio was lower in the SF-Soy-HFD group (0.02) than that in the SF-Fish-HFD group (0.75). The SF-Soy-HFD group had a positive association with S24_7, Clostridiales, Allobaculum, Coriobacteriaceae, Adlercreutzia, Christensenellaceae, Lactococcus, and Oscillospira, but was related to a lower abundance of Akkermansia, which maintains gut barrier integrity. The gut microbiota in the SF-Soy-HFD group had predicted associations with host genes related to fatty liver and inflammatory pathways. Mice fed the SF-Soy-HFD developed liver steatosis and showed increased transcript levels of genes associated with de novo lipogenesis (Acaca, Fasn, Scd1, Elovl6) and cholesterol synthesis (Hmgcr) pathways compared to those in the SF-Fish-HFDgroup. No differences were observed in the expression of fat uptake genes (Cd36 and Fabp1). The expression of the fat efflux gene (Mttp) was reduced in the SFSoy-HFD group. Moreover, hepatic inflammation markers (Tnfa and Il1b) were notably expressed in SF-Soy-HFD-fed mice. In conclusion, SF-Soy-HFD feeding induced gut dysbiosis in mice, leading to steatosis, hepatic inflammation, and impaired glucose homeostasis. [ABSTRACT FROM AUTHOR]

Amyloid beta (Aβ) plays a major role in the pathogenesis of Alzheimer's disease and, more recently, has been shown to protect against liver fibrosis. Therefore, we studied Aβ-42 levels and the expression of genes involved in the generation, degradation, and transport of Aβ proteins in liver samples from patients at different stages of metabolic dysfunction-associated liver disease (MASLD) and under steatotic conditions in vitro/in vivo. Amyloid precursor protein (APP), key Aβ-metabolizing proteins, and Aβ-42 were analyzed using RT-PCR, Western blotting, Luminex analysis in steatotic in vitro and fatty liver mouse models, and TaqMan qRT-PCR analysis in hepatic samples from patients with MASLD. Hepatocytes loaded with palmitic acid induced APP, presenilin, and neprilysin (NEP) expression, which was reversed by oleic acid. Increased APP and NEP, decreased BACE1, and unchanged Aβ-42 protein levels were found in the steatotic mouse liver compared to the normal liver. Aβ-42 concentrations were low in MASLD samples of patients with moderate to severe fibrosis compared to the livers of patients with mild or no MASLD. Consistent with the reduced Aβ-42 levels, the mRNA expression of proteins involved in APP degradation (ADAM9/10/17, BACE2) and Aβ-42 cleavage (MMP2/7/9, ACE) was increased. In the steatotic liver, the expression of APP- and Aβ-metabolizing proteins is increased, most likely related to oxidative stress, but does not affect hepatic Aβ-42 levels. Consistent with our previous findings, low Aβ-42 levels in patients with liver fibrosis appear to be caused by the reduced production and enhanced non-amyloidogenic processing of APP. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM), often featuring hyperglycemia or insulin resistance, is a global health concern that is increasing in prevalence in the United States and worldwide. A common complication is metabolic dysfunction-associated steatotic liver disease (MASLD), the hepatic manifestation of metabolic syndrome that is also rapidly increasing in prevalence. The majority of patients with T2DM will experience MASLD, and likewise, individuals with MASLD are at an increased risk for developing T2DM. These two disorders may act synergistically, in part due to increased lipotoxicity and inflammation within the liver, among other causes. However, the pathophysiological mechanisms by which this occurs are unclear, as is how the improvement of one disorder can ameliorate the other. This review aims to discuss the pathogenic interactions between T2D and MASLD, and will highlight novel therapeutic targets and ongoing clinical trials for the treatment of these diseases. [ABSTRACT FROM AUTHOR]

This review explores the biological aspects of neutrophils, their contributions to the development of steatotic liver disease, and their potential as therapeutic targets for the disease. Although alcohol-associated and metabolic dysfunction-associated liver diseases originate from distinct etiological factors, the two diseases frequently share excessive lipid accumulation as a common contributor to their pathogenesis, thereby classifying them as types of steatotic liver disease. Dysregulated lipid deposition in the liver induces hepatic injury, triggering the activation of the innate immunity, partially through neutrophil recruitment. Traditionally recognized for their role in microbial clearance, neutrophils have recently garnered attention for their involvement in sterile inflammation, a pivotal component of steatotic liver disease pathogenesis. In conclusion, technological innovations, including single-cell RNA sequencing, have gradually disclosed the existence of various neutrophil subsets; however, how the distinct subsets of neutrophil population contribute differentially to the development of steatotic liver disease remains unclear. [ABSTRACT FROM AUTHOR]

The new nomenclature of metabolic dysfunction-associated steatotic liver disease (MASLD) emphasizes a positive diagnosis based on cardiometabolic risk factors. This definition is not only less stigmatizing but also allows for subclassification and stratification, thereby addressing the heterogeneity of what was historically referred to as nonalcoholic fatty liver disease. The heterogeneity within this spectrum is influenced by several factors which include but are not limited to demographic/dietary factors, the amount of alcohol use and drinking patterns, metabolic status, gut microbiome, genetic predisposition together with epigenetic factors. The net effect of this dynamic and intricate system-level interaction is reflected in the phenotypic presentation of MASLD. Therefore, the application of precision medicine in this scenario aims at complex phenotyping with consequent individual risk prediction, development of individualized preventive strategies, and improvements in the clinical trial designs. In this review, we aim to highlight the importance of precision medicine approaches in MASLD, including the use of novel biomarkers of disease, and its subsequent utilization in future study designs. [ABSTRACT FROM AUTHOR]

Objective Hypothyroidism has been proposed as a potential contributor to steatotic liver disease (SLD), but existing data shows conflicting results in euthyroid subjects. Therefore, we investigated the association between thyroid function and intrahepatic lipids (IHLs) during a 36-month randomized controlled trial evaluating a diet known to reduce liver fat. Design 502 eligible subjects (aged 50–80 years, ≥1 risk factor for unhealthy aging) were randomly assigned to either follow a diet rich in unsaturated fatty acids, plant protein, and fiber (intervention group, IG), or dietary recommendations of the German Nutrition Society (control group, CG). Methods Serum levels of thyroid hormones (THs) as well as IHLs, defined via magnetic resonance spectroscopy, were measured within an euthyroid subgroup without significant alcohol consumption at baseline (n = 332) and after 12 months (n = 243). A ratio of T3/T4 was used to assess whole-body deiodinase activity. Estimates of glucose and lipid metabolism were analyzed. Results Only fT3 and T3/T4 ratios showed a significant positive correlation with IHL at baseline. We observed a significant decline in fT3, T3, fT3/fT4 ratio, and T3/T4 ratio in CG and IG after 12 months without significant differences between groups. TSH, fT4, and T4 remained stable. A larger improvement of IHL during dietary intervention was seen in those subjects with a lower decline in T3 concentrations. Conclusions Altered TH balance indicates a possible compensatory upregulation of whole-body TH activity in subjects with increased liver fat. This might be also relevant during the improvement of hepatic steatosis. [ABSTRACT FROM AUTHOR]

Drug-induced liver injury (DILI) represents a major issue for pharmaceutical companies, being a potential cause of black-box warnings on marketed pharmaceuticals, or drug withdrawal from the market. Lipid accumulation in the liver also referred to as steatosis, may be secondary to impaired mitochondrial fatty acid oxidation (mtFAO). However, an overall causal relationship between drug-induced mtFAO inhibition and the occurrence of steatosis in patients has not yet been established with a high number of pharmaceuticals. Hence, 32 steatogenic and 13 nonsteatogenic drugs were tested for their ability to inhibit mtFAO in isolated mouse liver mitochondria. To this end, mitochondrial respiration was measured with palmitoyl- l -carnitine, palmitoyl-CoA + l -carnitine, or octanoyl- l -carnitine. This mtFAO tri-parametric assay was able to predict the occurrence of steatosis in patients with a sensitivity and positive predictive value above 88%. To get further information regarding the mechanism of drug-induced mtFAO impairment, mitochondrial respiration was also measured with malate/glutamate or succinate. Drugs such as diclofenac, methotrexate, and troglitazone could inhibit mtFAO secondary to an impairment of the mitochondrial respiratory chain, whereas dexamethasone, olanzapine, and zidovudine appeared to impair mtFAO directly. Mitochondrial swelling, transmembrane potential, and production of reactive oxygen species were also assessed for all compounds. Only the steatogenic drugs amiodarone, ketoconazole, lovastatin, and toremifene altered all these 3 mitochondrial parameters. In conclusion, our tri-parametric mtFAO assay could be useful in predicting the occurrence of steatosis in patients. The combination of this assay with other mitochondrial parameters could also help to better understand the mechanism of drug-induced mtFAO inhibition. [ABSTRACT FROM AUTHOR]

INTRODUCTION: This study investigates the applicability of the new metabolic dysfunction-associated steatotic liver disease (MASLD) nomenclature to the real-world TARGET-NASH US adult cohort. METHODS: The new MASLD/metabolic steatohepatitis nomenclature was applied to patients enrolled with pragmatic diagnoses of nonalcoholic fatty liver and nonalcoholic steatohepatitis (NASH), and NASH cirrhosis and concordance were determined between the definitions. RESULTS: Approximately 99% of TARGET-NASH participants met the new MASLD diagnostic criteria. Approximately 1,484/1,541 (96.3%, kappa 0.974) nonalcoholic fatty liver patients (metabolic dysfunction-associated steatotic liver), 2,195/2,201 (99.7%, kappa 0.998) NASH patients (metabolic steatohepatitis), and 1,999/2,003 (99.8%, kappa 0.999) NASH cirrhosis patients met the new criteria. DISCUSSION: The new MASLD nomenclature is highly concordant with the previous TARGET-NASH pragmatic definitions. [ABSTRACT FROM AUTHOR]

Pediatric MASLD (previously referred to as NAFLD) incidence has continued to rise along with the obesity pandemic. Pediatric MASLD increases the risk of liver fibrosis and cirrhosis in adulthood. Early detection and intervention can prevent and reduce complications. Liver biopsy remains the gold standard for diagnosis, although imaging modalities are increasingly being used. We performed a retrospective study of 202 children seen in a pediatric gastroenterology clinic with a complaint of abdominal pain, elevated liver enzymes or MASLD, or a combination of the three to evaluate screening methods for MASLD. A total of 134 of the 202 patients included in the study underwent laboratory testing and abdominal ultrasound. Ultrasound images were reviewed with attention to liver size and echotexture by a fellowship-trained pediatric radiologist for liver size and echotexture. Overall, 76.2% of the initial radiology reports correctly identified hepatomegaly based on age and 75.4% of the initial radiology reports correctly described hepatic echogenicity that was consistent with increased hepatic fat deposition. Use of screening ultrasound in concert with other clinical evaluations can be helpful to identify children at risk of MASLD. Utilizing ranges for liver span according to age can help to diagnose hepatomegaly, and understanding how to identify hepatic echogenicity is important for identifying possible hepatic steatosis. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects 1 in 3–4 adult individuals and can progress to metabolic dysfunction-associated steatohepatitis (MASH) and cirrhosis. Insulin resistance plays a central role in MASLD/MASH pathophysiology with higher rates of MASLD (2 in 3) and MASH with fibrosis (1 in 5) in adults with obesity and diabetes. This review summarizes the role of glucagon-like peptide-1 receptor agonists in treating MASLD/MASH. Although not approved by the Food and Drug Administration for the treatment of MASLD, this class of medication is available to treat obesity and type 2 diabetes and has been shown to reverse steatohepatitis, reduce cardiovascular risk, and is safe to use across the spectrum of MASLD with or without fibrosis. [Display omitted] [ABSTRACT FROM AUTHOR]

Objectives: To assess whether meal or water intake may affect the measurement of the ultrasound (US) attenuation coefficient (AC) imaging, a parameter that is directly related to liver fat content. Methods: The study was performed in two centers (Italy and USA). AC was obtained using the ATI algorithm implemented in the Aplio i‐series US systems (Canon Medical Systems, Japan) by one operator at each center. Measurements were performed at baseline and 5, 15, 30, 45 minutes after drinking 500 mL of water (group 1), or 30, 45, 60, 90, 120 minutes after eating a meal of about 600 kcal (group 2). Multilevel generalized estimating equations for repeated measures were used for the statistical analysis to consider the clustered nature of the data. Results: Twenty‐six individuals were enrolled: 11 (10 females; age, 43.7 ± 12.5 years) in Italy and 15 (10 females; age, 60.7 ± 6.3 years) in USA. At B‐mode US, 10 (38.5%) had liver steatosis. The baseline AC values, in decibel/centimeter/megahertz, were 0.64 (0.12) in group 1 and 0.66 (0.13) in group 2. There was not any significant difference in AC values at every time‐point after water or meal intake either in group 1 or group 2. This result did not change including sex, age, and skin‐to‐liver capsule into the models. Conclusions: The measurement of the AC, which is a biomarker of liver steatosis, does not require a fasting state and drinking water does not affect the result. [ABSTRACT FROM AUTHOR]

Purpose: The need to investigate the pathogenesis and treatment of nonalcoholic fatty liver disease (NAFLD) has led to the development of multiple mouse models. The aim of this study was to validate a fast food diet (FFD) mouse model that is introduced as being close to the human disease. Methods: Eight to nine weeks old male and female C57BL/6 J mice were randomly allocated to a FFD group or to a chow diet (CD) group. Every four weeks, mice were weighed, and blood samples were collected for the measurement of glucose, alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglycerides (TGs) and total cholesterol. After 25 weeks, mice were sacrificed, and liver tissue was histologically evaluated. Results: FFD mice gained more weight (p = 0.049) and presented a higher liver-to-body weight ratio (p < 0.001) compared to CD mice. FFD group presented with greater steatosis, hepatocellular ballooning and NAFLD activity score (NAS), whereas lobular inflammation and fibrosis were not significantly different compared to CD. When stratified by sex, NAS was different between FFD and CD groups in both male and female mice. Group by time interaction was significant for weight, ALT and cholesterol, but not for glucose, AST and TGs. Conclusion: FFD mice presented with morphologic and biochemical features of NAFLD and with greater hepatic steatosis, hepatocellular ballooning and NAS, but not lobular inflammation and fibrosis, compared to CD mice. These results only partly validate the FFD mouse model for NAFLD, at least for a 6-month feeding period. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is one of the liver illnesses that may be affected by mitophagy, which is the selective removal of damaged mitochondria. RNF31, an E3 ubiquitin ligase, is carcinogenic in many malignancies. However, the influence of RNF31 on mitochondrial homeostasis and NAFLD development remains unknown. Oleic-palmitic acid treated hepatocytes and high-fat diet (HFD)-fed mice were established to observe the effect of RNF31 on hepatocyte mitophagy and steatosis. Mitophagy processes were comprehensively assessed by mt-Keima fluorescence imaging, while global changes in hepatic gene expression were measured by RNA-seq. The present study discovered a reduction in RNF31 expression in lipotoxic hepatocytes with mitochondrial dysfunction. The observed decrease in RNF31 expression was associated with reduced mitochondrial membrane potential, disturbed mitophagy, and increased steatosis. Additionally, the findings indicated that RNF31 is a pivotal factor in the initiation of mitophagy and the facilitation of mitochondrial homeostasis, resulting in a decrease in steatosis in lipotoxic hepatocytes. Mechanistically, RNF31 enhanced p53 ubiquitination and subsequent proteasomal degradation. Down-regulation of p53 led to increased expression of the mitophagy receptor protein BCL2 and adenovirus E1B 19 kDa-interacting protein 3 (BNIP3), thereby promoting mitophagy in hepatocytes. Furthermore, it was demonstrated that the transportation of RNF31 via small extracellular vesicles derived from mesenchymal stem cells (referred to as sEV) had a substantial influence on reducing hepatic steatosis and restoring liver function in HFD-fed mice. The findings highlight RNF31's essential role in the regulation of mitochondrial homeostasis in hepatocytes, emphasizing its potential as a therapeutic target for NAFLD. A high-fat diet (HFD)-induced state of liver steatosis can lead to a reduction in hepatocyte RING finger protein 31 (RNF31) expression. This decline disrupts the ubiquitination process of p53, which RNF31 regulates. As a result, BCL2 and adenovirus E1B 19 kDa-interacting protein 3 (BNIP3)-related mitophagy is suppressed, leading to impaired mitochondrial homeostasis in hepatocytes. RNF31 is transported into liver tissue by mesenchymal stem cell-derived small extracellular vesicles (MSC-sEV) in mice fed an HFD. This process promotes hepatocyte mitophagy and lowers hepatic steatosis. [Display omitted] • RNF31 is a BNIP3-dependent active factor in regulating mitophagy and inhibiting lipid deposition in hepatocytes. • RNF31-mediated ubiquitination of p53 enhances mitochondrial homeostasis through BNIP3-related mitophagy. • MSC-sEV transported RNF31 effectively reduce hepatic lipid deposition in HFD-fed mice. [ABSTRACT FROM AUTHOR]

Background: The performance and reliability criteria for Aixplorer MACH30 (SS) in chronic liver diseases (CLD) have not been validated. Aims: The objectives were to define the optimal procedure, the accuracy for fibrosis and steatosis diagnosis, and the reliability criteria using SS. Methods: Patients had 2D-shear wave elastography (SWE) and ultraSound-guided controlled attenuation parameter (SCAP) performed in triplicate at the mid-axillary line (MAL), posterior axillary line (PAL), and anterior axillary line (AAL). Performances of SWE and SCAP were defined using transient elastography (TE ≥ 9.5 kPa) and CAP (≥ 275 dB/m) using Fibroscan (FS) as reference and validated with liver biopsy (LB). Results: FS and SS data from 203 CLD patients were analyzed (55 ± 14 years; 59% male; MASLD 58%). Median TE and CAP were 6.4 kPa (2.5–66.9) and 270 dB/m (141–400). The best technique for the diagnosis of advanced fibrosis and significant steatosis was the median of three SWE values and three SCAP values at MAL, PAL, and AAL with an AUROC of 0.96 [95% CI 0.93–0.98] and 0.91 [95% CI 0.86–0.95]. Only skin-to-liver distance ≥ 2.4 cm (p = 0.012, 95% CI 1.37–13.38) was independently associated with discordance. The accuracy of SWE (≥ 8.5 kPa) and SCAP (≥ 0.44) was analyzed in 58 patients with LB. The PPV and NPV were 50% and 94%, and 71% and 88% for fibrosis and steatosis, respectively. Conclusion: A reliable diagnosis of advanced fibrosis and significant steatosis can be obtained with the median of three measurements in different liver portions using SS. The only non-reliable criterion is skin-to-liver distance ≥ 2.4 cm. [ABSTRACT FROM AUTHOR]

The incidence of nonalcoholic fatty liver disease (NAFLD), or metabolic dysfunction-associated fatty liver disease (MAFLD), is increasing in adults and children. Unfortunately, effective pharmacological treatments remain unavailable. Single nucleotide polymorphisms (SNPs) in the patatin-like phospholipase domain-containing protein (PNPLA3 I148M) have the most significant genetic association with the disease at all stages of its progression. A roadblock to identifying potential treatments for PNPLA3-induced NAFLD is the lack of a human cell platform that recapitulates the PNPLA3 I148M-mediated onset of lipid accumulation. Hepatocyte-like cells were generated from PNPLA3−/− and PNPLA3I148M/M-induced pluripotent stem cells (iPSCs). Lipid levels were measured by staining with BODIPY 493/503 and were found to increase in PNPLA3 variant iPSC-derived hepatocytes. A small-molecule screen identified multiple compounds that target Src/PI3K/Akt signaling and could eradicate lipid accumulation in these cells. We found that drugs currently in clinical trials for cancer treatment that target the same pathways also reduced lipid accumulation in PNPLA3 variant cells. [ABSTRACT FROM AUTHOR]

High accumulation of lipids in hepatocytes can trigger an increase in the production of radical compounds, leading to fatty liver disease. This condition induces histological changes in the liver, especially in hepatocytes, and affects the surrounding structures. Mahogany seeds have the potential to act as a hypolipidemic agent in treating fatty liver. Mahogany seeds are known to contain phytochemical compounds which act as antioxidants. This study aimed to determine liver histopathology of rats by inducing high-fat diet after giving mahogany seeds ethanol extract which was observed through the percentage of steatosis, hepatocyte diameter, and hepatosomatic index. This study involved thirty male Sprague Dawley rats, divided into 6 groups: P0 (given commercial feed), P1 (given high-fat diet), P2 (given high-fat diet and simvastatin at a dose of 8 mg/200 g BW), P3, P4, and P5 (given high-fat diet and mahogany seeds ethanol extract at a dose of 14, 28, and 56 mg/200 g BW). The results showed that the hepatosomatic index among all treatment groups did not differ significantly; however, the percentage of steatosis and hepatocyte diameter in the groups given mahogany seeds ethanol extract significantly differed from the group given only high-fat feed. Based on these results, it can be concluded that mahogany seed ethanol extract can maintain the histological structure of the liver in male Sprague Dawley rats with fatty liver. [ABSTRACT FROM AUTHOR]

Activation of pregnane X receptor (PXR) by xenobiotics has been associated with metabolic diseases. This study aimed to reveal the impact of PXR activation on hepatic metabolome and explore novel mechanisms underlying PXR-mediated lipid metabolism disorder in the liver. Wild-type and PXR-deficient male C57BL/6 mice were used as in vivo models, and hepatic steatosis was induced by pregnenolone-16α-carbonitrile, a typical rodent PXR agonist. Metabolomic analysis of liver tissues showed that PXR activation led to significant changes in metabolites involved in multiple metabolic pathways previously reported, including lipid metabolism, energy homeostasis, and amino acid metabolism. Moreover, the level of hepatic all- trans retinoic acid (ATRA), the main active metabolite of vitamin A, was significantly increased by PXR activation, and genes involved in ATRA metabolism exhibited differential expression following PXR activation or deficiency. Consistent with previous research, the expression of downstream target genes of peroxisome proliferator-activated receptor α (PPARα) was decreased. Analysis of fatty acids by Gas Chromatography-Mass Spectrometer further revealed changes in polyunsaturated fatty acid metabolism upon PXR activation, suggesting inhibition of PPARα activity. Taken together, our findings reveal a novel metabolomic signature of hepatic steatosis induced by PXR activation in mice. [Display omitted] • PXR activation and deficiency have different impact on hepatic metabolomics in mice. • PXR activation increased hepatic all- trans -retinoic acid by affecting the expression of genes involved in ATRA metabolism. • PXR activation inhibited PPARα-target genes involved in lipid metabolism and altered the composition of hepatic fatty acids. [ABSTRACT FROM AUTHOR]

Background/Aim: Depression is associated with metabolic disorders, including non-alcoholic fatty liver disease (NAFLD). However, the mechanisms underlying the interaction between them are still poorly known. Materials and Methods: In this study, mice on a choline deficiency, L-amino acid-defined, high-fat diet (CDAHFD) developing steatosis were challenged with chronic restraint stress (CRS), a protocol widely used to induce depression. The development of depression and steatosis was evaluated using histopathology analysis, ELISA, q-PCR and Western Blot. Results: The contribution of the activated HPA axis to hepatic steatosis progress was fully established, which was validated using a hepatocyte model. Histopathological and biochemical analysis indicated that steatosis was exacerbated by CRS challenge, and behavioral tests indicated that the mice developed depression. Among the screened endocrinal pathways, the hypothalamic-pituitary-adrenal (HPA) axis was significantly activated and the synergistic effect of CDAHFD and CRS in activating the HPA axis was observed. In the hypothalamus, expression of corticotropin-releasing hormone (CRH) was increased by 86% and the protein levels of hypothalamic CRH were upregulated by 25% to 33% by CRS treatment. Plasma CRH levels were elevated by 45-56% and plasma adrenocorticotropic hormone (ACTH) levels were elevated by 29-58% by CRS treatment. In the liver, target genes of the HPA axis were activated, accompanied by disruption of the lipid metabolism and progression of steatohepatitis. The lipid metabolism in the Hepa1-6 cell line treated with endogenous corticosterone (CORT) was in accordance with the aforementioned in vivo responses. Conclusion: Depression aggravated hepatic steatosis in CDAHFD-fed mice by activating the HPA axis. The risk of NAFLD development should be fully considered in depressive patients and improvement of psychotic disorders could be an etiological treatment strategy for them. [ABSTRACT FROM AUTHOR]

Mono‐(2‐ethylhexyl) phthalate (MEHP) can accumulate in the liver and then lead to hepatic steatosis, while the underlying mechanism remains unclear. Inflammation plays an important role in the disorder of hepatic lipid metabolism. This study aims to clarify the role of the inflammatory response mediated by formyl peptide receptor 2 (FPR2) in steatosis of L02 cells exposed to MEHP. L02 cells were exposed to MEHP of different concentrations and different time. A steatosis model of L02 cells was induced with oleic acid and the cells were exposed to MEHP simultaneously. In addition, L02 cells were incubated with FPR2 antagonist and then exposed to MEHP. Lipid accumulation was determined by oil red O staining and extraction assay. The indicators related to lipid metabolism and inflammatory response were measured with appropriate kits. The relative expression levels of FPR2 and its ligand were determined by Western blot, and the interaction of them was detected by co‐immunoprecipitation. As a result, MEHP exposure could promote the occurrence and progression of steatosis and the secretion of chemokines and inflammatory factors in L02 cells. MEHP could also affect the expression and activation of FPR2 and the secretion of FPR2 ligands. In addition, the promotion effect of MEHP on the secretion of total cholesterol and interleukin 1β in L02 cells could be significantly inhibited by the FPR2 antagonist. We concluded that FPR2 might affect the promotion effect of MEHP on steatosis of L02 cells by mediating inflammatory response. [ABSTRACT FROM AUTHOR]

Plant-based diets (PBDs) are gaining attention as a sustainable and health-conscious alternative for managing various chronic conditions, including metabolic dysfunction-associated steatotic liver disease (MASLD). In the absence of pharmacological treatments, exploring the potential of lifestyle modifications to improve biochemical and pathological outcomes becomes crucial. The adoption of PBDs has demonstrated beneficial effects such as weight control, increased metabolic health and improved coexisting diseases. Nonetheless, challenges persist, including adherence difficulties, ensuring nutritional adequacy, and addressing potential deficiencies. The aim of this review is to provide a comprehensive overview of the impact of PBDs on MASLD, emphasizing the need for tailored dietary interventions with professional support to optimize their effectiveness in preventing and treating metabolic diseases. [ABSTRACT FROM AUTHOR]

Although aspirin is deeply rooted in the most ancient history of medicine, the mechanism of action of this drug was only identified a few decades ago. Aspirin has several indications ranging from its long-known analgesic and antipyretic properties to the more recently discovered antithrombotic, chemopreventive and anti-eclampsia actions. In addition, a recent line of research has identified aspirin as a drug with potential hepatologic indications. This article specifically focuses on the nonalcoholic fatty liver disease/nonalcoholic metabolic dysfunction fatty liver disease/metabolic dysfunction-associated steatotic liver disease (NAFLD/MAFLD/MASLD) field. To this end, the most recently published randomized controlled trial on aspirin for non-cirrhotic MASLD is summarized and discussed. Moreover, previous epidemiologic evidence supporting the notion that aspirin exerts antisteatotic and antifibrotic hepatic effects, which may result in the primary prevention of hepatocellular carcinoma, is also addressed. Next, the putative mechanisms involved are examined, with reference to the effects on adipose tissue and liver and sex differences in the action of aspirin. It is concluded that these novel findings on aspirin as a "hepatologic drug" deserve additional in-depth evaluation. Plain Language Summary: Although aspirin is part of the history of medicine, its mechanism of action was only discovered a few decades ago. Aspirin can be used to treat pain, fever, inflammation and conditions where the blood tends to clot excessively (hypercoagulate) as well as for the prevention of certain types of cancer. Additionally, recent research has identified potential hepatologic indications and beneficial actions of aspirin among the so-called fatty liver disorders owing to conditions which disrupt the body's regular metabolic functions and disorders (such as obesity and diabetes). This article discusses a recently published study while also addressing previous studies supporting the notion that aspirin might have pharmacologic action against fatty liver and its progression to scarring tissue (liver fibrosis and hepatic cirrhosis) and prevent the most common type of primary liver cancer. Aspirin not only acts on the blood cells that protect against hemorrhage (i.e., the platelets) but also targets other tissues such as adipose tissue and the liver. Importantly, biologic sex may affect the pharmacologic action of aspirin. Collectively, the discoveries summarized in our article justify additional investigations into aspirin as a "novel" drug in the hepatologic field. [ABSTRACT FROM AUTHOR]