Chrysanthemum (Chrysanthemum morifolium Ramat) is a food, which serves both as a medicinal and culinary resource in China; however, its active ingredients and mechanisms underlying its hepatoprotective effects remain elusive. This study aimed to investigate the protective effect of water extract from chrysanthemum flowers (WEFC) against metabolic dysfunction-associated fatty liver induced by thioacetamide (TAA) in zebrafish and its underlying mechanisms. The protective effect of WEFC against TAA-induced liver injury was investigated using the liver-specific transgenic zebrafish line, Tg(fabp10a:DsRed). Network pharmacology was used to analyze the potential targets and ingredients. Quantitative polymerase chain reaction was used to verify the associated mechanisms. Molecular protein docking was performed to identify the targets. WEFC and its component prunin attenuated TAA-induced liver injury and reversed the changes in lipid pathway-related gene expression induced by TAA. Therefore, prunin may play an important role in protecting the liver through RAC-alpha serine/threonine-protein kinase (AKT1) activation.

(1) Background: Atrial fibrillation (A Fib) is a common arrhythmia that affects millions of people worldwide and is characterized by irregular and often rapid heartbeats that can cause stroke. The aim of our study was to assess the importance of predictors for the occurrence of atrial fibrillation in patients with cardiac pacemakers and to analyze their impact on these patients, especially the impact of hepatic impairment. (2) Methods: This study is an observational, retrospective study, including 182 patients who were implanted with a dual-chamber pacemaker (DDD), with no known history of A Fib. (3) Results: We identified as predictors for the occurrence of atrial fibrillation in patients with cardiac pacemakers, DDD with rate response mode, NYHA class III of heart failure, as well as the presence of hepatic impairment (HI). Analysis of echocardiographic parameters of the left atrium revealed a larger left atrial volume as well as a larger left atrial area compared to patients who had a much smaller area at baseline and who did not experience any atrial fibrillation at follow-up. The fact that there were no statistically significant differences between the two groups of patients in terms of left atrial ejection fraction at baseline was very interesting. Patients in the A Fib group had a higher percentage of atrial pacing at the 9-month follow-up (86.23 ± 22.19%) compared to patients in the group without A Fib (44.92 ± 29.99%, p < 0.0001) and had a 9-month follow-up rate of A Fib of 25.806% vs. 2.247% in those with a low percentage of atrial pacing (p < 0.0001). The percentage of ventricular pacing at the 9-month follow-up, the observations were almost similar. (4) Conclusions: The importance of pacemakers in detecting subclinical episodes of atrial fibrillation remains crucial for the prevention of embolic events in these patients. Hepatic impairment may be a risk factor for the occurrence of atrial fibrillation in patients with pacemakers, but it can also create significant problems in stroke prevention.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality among LT candidates and accounts for up to 40% of the overall mortality within one month. It is influenced by traditional and nontraditional risk factors related to end-stage liver disease. A large proportion of CLD patients have underlying cardiovascular disease (CVD) especially if the etiology is metabolic associated steatohepatitis. Despite the large number of liver transplantations being conducted in India, there is a lack of an evidence-based guidelines for screening of CVD in this patient population. This consensus statement from Liver Transplant Society of India (LTSI) is the first attempt for developing an evidence-based document on preoperative cardiac evaluation from India. A task force consisting of transplant-anesthesiologists, transplant hepatologists, liver transplant surgeon and cardiologists from high volume centres was formed which reviewed the existing evidence and literature and formulated graded recommendations. The document focuses on identification of underlying cardiac pathologies, risk stratification and optimisation of modifiable cardiac diseases. Implementation of best practices and optimal strategies should be encouraged to improve cardiovascular outcomes in these populations.

Atrial fibrillation (AF) is a common arrhythmia often treated with cryoballoon ablation. The impact of Metabolic-associated fatty liver disease (MASLD), a condition newly defined by a fatty liver index ≥ 60, on AF recurrence post-ablation is unclear. We analyzed 303 patients undergoing cryoballoon ablation for AF. Cox proportional hazards models were used to assess the relationship between MASLD and AF recurrence. Paroxysmal atrial fibrillation was present in 61.1% of patients and 63% were male. Among the patients, 23.4% had MASLD. These patients exhibited larger left atrial diameter and left ventricular end-diastolic dimension. During a median follow-up of 14 months, AF recurrence was more frequent in MASLD patients (45.1% vs. 20.7%). MASLD independently predicted AF recurrence (HR, 2.24 [95% CI 1.35-3.74], P = 0.002), alongside persistent AF, longer AF duration, and larger left atrial diameter. MASLD consistently demonstrated a significant association with an increased risk of AF recurrence in both paroxysmal (HR, 2.38 [95% CI, 1.08-5.23], P = 0.031) and persistent AF (HR, 2.55 [95% CI, 1.23-5.26], P = 0.011). MASLD significantly increases the risk of AF recurrence after cryoballoon ablation, highlighting the importance of supporting targeted interventions of MASLD in the periprocedural management of AF.

The impact of metabolic dysfunction-associated steatotic liver disease (MASLD), the preferred nomenclature for NAFLD, on cardiovascular health and mortality among older adults is uncertain. As such, we aimed to identify whether MASLD increases the risk of Major Adverse Cardiovascular Events (MACE) (a composite of fatal coronary heart disease [excluding heart failure], nonfatal myocardial infarction, or fatal or nonfatal ischemic stroke), Atrial Fibrillation (AF), or all-cause mortality in older adults, and whether aspirin attenuates these risks in individuals with MASLD. This is a non-prespecified post-hoc analysis of the ASPREE (ASPirin in Reducing Events in the Elderly) randomized trial. Participants were community dwelling well adults aged ≥ 70 years without a history of atherosclerotic cardiovascular disease or AF. Fatty Liver Index (FLI) was used to identify MASLD at baseline. FLI is a composite of anthropometric and biochemical markers used in epidemiologic studies to rule in and rule out hepatic steatosis. MACE and cause of death were adjudicated by clinical experts; AF was assessed by previously defined algorithm in ASPREE. 9,097 participants were stratified into groups according to FLI. In univariate analysis, prevalent MASLD (FLI ≥ 60 with evidence of metabolic dysfunction; n = 2,998 [33.0%]) was associated with an increased risk of MACE (HR 1.47 [95% CI 1.22-1.78]) and AF (HR 1.50 [95% CI 1.19-1.88] but not all-cause mortality (HR 1.04 [95% CI 0.91-1.19]). After adjusting for cardiovascular disease risk factors, only the association between MASLD and AF remained significant (HR 1.46 [95% CI 1.11-1.93]). Aspirin did not reduce the risk of MACE, death, or AF in the MASLD group. MASLD was associated with an increased hazard of incident AF, but not of MACE or all-cause mortality, in community dwelling older adults. Primary prevention with aspirin does not ameliorate these risks in older adults with MASLD.

Liver fibrosis scores, such as the fibrosis-4 index (FIB-4I), a representative index of liver fibrosis, have recently been linked to heart failure, coronary artery disease (CAD), and atrial fibrillation (AF). We investigated the association between FIB-4I and AF in patients who underwent coronary computed tomography angiography (CCTA). This study included 1525 patients clinically suspected of having CAD or about to undergo treatment for AF, such as catheter ablation. FIB-4I and the presence or absence of AF were the primary endpoints. FIB-4I was higher in the AF group than in the sinus rhythm group (1.93 ± 0.94 versus [vs.] 1.75 ± 1.03, p = 0.001). No significant difference was observed in the FIB-4I between the paroxysmal AF and persistent AF groups (1.93 ± 0.99 vs. 1.94 ± 0.78, p = 0.922). Furthermore, FIB-4I was higher in the hypertension (HTN) group than in the non-HTN group (1.84 ± 1.04 vs. 1.62 ± 0.91, p < 0.001). Low FIB-4I (≤1.29) was proven to be a contributing factor for the absence of AF in all patients (odds ratio [OR]: 0.55, 95% confidence interval [CI]: 0.39-0.78, p < 0.001) as well as the HTN and non-HTN (OR: 0.53, 95% CI: 0.37-0.78, p < 0.001 and OR: 0.39, 95% CI: 0.23-0.68, p < 0.001, respectively) groups. Thus, FIB-4I may serve as a diagnostic indicator of the absence of AF in patients undergoing CCTA. The liver fibrosis-4 index as a diagnostic indicator of the absence of atrial fibrillation in patients undergoing coronary computed tomography angiography.

Cardiovascular disease (CVD) is a common cause of death in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Therefore, CVD surveillance is important, but it is not well established. We evaluated the association between liver fibrosis, carotid artery atherosclerosis, and coronary artery stenosis in patients with MASLD.

Overall, 153 patients with MASLD who underwent carotid artery ultrasound were enrolled. Maximum intima-media thickness including plaques (Max-IMT) was measured by ultrasound. To predict liver fibrosis, liver stiffness was measured by vibration-controlled transient elastography and the fibrosis 4 (FIB-4) index was calculated. Coronary computed tomography angiography was performed to detect coronary artery stenosis based on a Max-IMT of ≥ 1.1 mm.

The median Max-IMT was 1.3 mm, and 63 patients (41.2%) had a Max-IMT of ≥ 1.5 mm. FIB-4 index and liver stiffness was significantly correlated with Max-IMT, respectively (ρ=0.356, p＜0.001, ρ=0.25, p=0.002). Liver stiffness was significantly associated with a Max-IMT of ≥1.5 mm, independent of age. Individuals with higher FIB-4 index had moderate or severe coronary artery stenosis more frequently. Individuals with higher LSM level also had moderate or severe coronary artery stenosis more frequently, especially severe stenosis.

Liver fibrosis parameters were associated with carotid artery atherosclerosis and coronary artery stenosis. Evaluation of liver fibrosis may be useful to identify significant atherosclerosis and coronary artery stenosis in patients with MASLD.

Fatty liver disease or steatotic liver disease (SLD) affects 25% of the global population and has been associated with heart disease. However, there is a lack of postmortem studies in the context of sudden cardiac death (SCD).

To investigate the relationship between SLD and SCD.

A post-mortem case-case study was conducted in victims of SCD from an ongoing community-based study in Southern California (Ventura, CA, 2015-2023). Diagnosis of SLD was determined from post-mortem liver histopathology reports. For each patient, demographic variables, laboratory values, and presence of co-morbidities were ascertained from medical records and were compared between patients with and without SLD.

Of 162 individuals with SCD, there were 101 SLD cases and 61 without SLD. Individuals with SLD were found to have higher BMI (31.6 ± 7.6 vs. 26.7 ± 5.7, p < 0.001), higher prevalence of heavy drinking (28 % vs. 12 %, p = 0.008), heavier liver weights (2433.6 g ± 940.6 vs 1934.7 g ± 505.3, p < 0.001), and were more often Hispanic (37 vs. 18 %, p = 0.01). Patients with SLD had lower prevalence of coronary artery disease (CAD) (49 % vs. 70 %). Multivariable logistic regression analysis showed that CAD was a negative predictor of SCD with SLD (OR = 0.35, 95 % CI 0.14 - 0.83).

Among adults with SCD, SLD was associated with higher prevalence of Hispanic ethnicity and lower prevalence of CAD. Given the major rise in SLD burden, these ethnicity-based differences as well as the specific nature of non-ischemic SCD etiologies warrant urgent further investigation.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is correlated with an increased cardiovascular risk, independent of other traditional risk factors. The mechanisms underlying this pathogenic link are complex yet remain incompletely elucidated. Among these, the most significant are visceral adiposity, low-grade inflammation and oxidative stress, endothelial dysfunction, prothrombotic status, insulin resistance, dyslipidemia and postprandial hyperlipemia, gut dysbiosis, and genetic mutations. Cardiovascular diseases are the leading cause of death in patients with MASLD. These patients have an increased incidence of coronary artery disease, carotid artery disease, structural and functional cardiac abnormalities, and valvulopathies, as well as arrhythmias and cardiac conduction disorders. In this review, we present the latest data on the association between MASLD and cardiovascular risk, focusing on the pathogenic mechanisms that explain the correlation between these two pathologies. Given the high rates of cardiovascular morbidity and mortality among patients with MASLD, we consider it imperative to raise awareness of the risks associated with this condition within the general population. Further research is essential to clarify the mechanisms underlying the increased cardiovascular risk linked to MASLD. This understanding may facilitate the identification of new diagnostic and prognostic biomarkers for these patients, as well as novel therapeutic targets.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic liver disease characterized by hepatic steatosis. Ubiquitin-specific protease 29 (USP29) plays pivotal roles in hepatic ischemiareperfusion injury and hepatocellular carcinoma, but its role in MASLD remains unexplored. Therefore, the aim of this study was to reveal the effects and underlying mechanisms of USP29 in MASLD progression.

USP29 expression was assessed in liver samples from MASLD patients and mice. The role and molecular mechanism of USP29 in MASLD were assessed in high-fat diet-fed and high-fat/high-cholesterol diet-fed mice and palmitic acid and oleic acid treated hepatocytes.

USP29 protein levels were significantly reduced in mice and humans with MASLD. Hepatic steatosis, inflammation and fibrosis were significantly exacerbated by USP29 deletion and relieved by USP29 overexpression. Mechanistically, USP29 significantly activated the expression of genes related to fatty acid β-oxidation (FAO) under metabolic stimulation, directly interacted with long-chain acyl-CoA synthase 5 (ACSL5) and repressed ACSL5 degradation by increasing ACSL5 K48-linked deubiquitination. Moreover, the effect of USP29 on hepatocyte lipid accumulation and MASLD was dependent on ACSL5.

USP29 functions as a novel negative regulator of MASLD by stabilizing ACSL5 to promote FAO. The activation of the USP29-ACSL5 axis may represent a potential therapeutic strategy for MASLD.

Non-alcoholic fatty liver disease (NAFLD), now known as metabolic-associated steatotic liver disease (MASLD), is the most common liver disease worldwide, with a prevalence of 38%. In these patients, cardiovascular disease (CVD) is the number one cause of mortality rather than liver disease. Liver abnormalities per se due to MASLD contribute to risk factors such as dyslipidemia and obesity and increase CVD incidents. In this review we discuss hepatic pathophysiological changes the liver of MASLD leading to cardiovascular risks, including liver sinusoidal endothelial cells, insulin resistance, and oxidative stress with a focus on glutathione metabolism and function. In an era where there is an increasingly robust recognition of what causes CVD, such as the factors included by the American Heart Association in the recently developed PREVENT equation, the inclusion of liver disease may open doors to how we approach treatment for MASLD patients who are at risk of CVD.

Non-alcoholic fatty liver disease (NAFLD) and heart failure (HF) are related conditions with an increasing incidence. However, the mechanism underlying their association remains unclear. This study aimed to explore the shared pathogenic mechanisms and common biomarkers of NAFLD and HF through bioinformatics analyses and experimental validation.

NAFLD and HF-related transcriptome data were extracted from the Gene Expression Omnibus (GEO) database (GSE126848 and GSE26887). Differential analysis was performed to identify common differentially expressed genes (co-DEGs) between NAFLD and HF. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) were conducted to explore the functions and regulatory pathways of co-DEGs. Protein-protein interaction (PPI) network and support vector machine-recursive feature elimination (SVM-RFE) methods were used to screen common key DEGs. The diagnostic value of common key DEGs was assessed by receiver operating characteristic (ROC) curve and validated with external datasets (GSE89632 and GSE57345). Finally, the expression of biomarkers was validated in mouse models.

A total of 161 co-DEGs were screened out in NAFLD and HF patients. GO, KEGG, and GSEA analyses indicated that these co-DEGs were mainly enriched in immune-related pathways. PPI network revealed 14 key DEGs, and SVM-RFE model eventually identified two genes (CD163 and CCR1) as common key DEGs for NAFLD and HF. Expression analysis revealed that the expression levels of CD163 and CCR1 were significantly down-regulated in HF and NAFLD patients. ROC curve analysis showed that CD163 and CCR1 had good diagnostic values for HF and NAFLD. Single-gene GSEA suggested that CD163 and CCR1 were mainly engaged in immune responses and inflammation. Experimental validation indicated unbalanced macrophage polarization in HF and NAFLD mouse models, and the expression of CD163 and CCR1 were significantly down-regulated.

This study identified M2 polarization impairment characterized by decreased expression of CD163 and CCR1 as a common pathogenic pathway in NAFLD and HF. The downregulation of CD163 and CCR1 may reflect key pathological changes in the development and progression of NAFLD and HF, suggesting their potential as diagnostic and therapeutic targets.

The aims of our study were to evaluate whether point-of-care β-hydroxybutyrate (BHB) measurement can be used to identify patients with adequate cardiac glucose metabolism suppression for cardiac [18F]-fluoro-2-deoxy-d-glucose-positron emission tomography with computerized tomography (FDG-PET/CT) and to develop a pretest probability calculator of myocardial suppression using other metabolic factors attainable before imaging.

We recruited 193 patients with any clinical indication for whole body [18F]-FDG-PET/CT. BHB level was measured with a point-of-care device. Maximal myocardial standardized uptake value using lean body mass (SULmax) was measured from eight circular regions of interest with 1 cm circumference and background from left ventricular blood pool. Correlations SULmax and point-of-care measured BHB were analysed. The ability of BHB test to predict adequate suppression was evaluated with receiver operating characteristic analysis. Liver and spleen attenuation in computed tomography were measured to assess the presence of fatty liver. BHB level correlated with myocardial uptake and, using a cut-off value of 0.35 mmol/L to predict adequate myocardial suppression, we reached specificity of 90% and sensitivity of 56%. Other variables to predict adequate suppression were diabetes, obesity, ketogenic diet and fatty liver. Using information attainable before imaging, we created a pretest probability calculator of inadequate myocardial glucose metabolism suppression. The area under the curve for BHB test alone was 0.802 and was 0.857 for the pretest calculator (p = 0.319).

BHB level measured with a point-of-care device is useful in predicting adequate myocardial glucose metabolism suppression. More detailed assessment of other factors potentially contributing to cardiac metabolism is needed.

Atrial cardiomyopathy (ACM) is responsible for atrial fibrillation (AF) and thromboembolic events. Diabetes mellitus (DM) is an important risk factor for ACM. However, the potential mechanism between ACM and DM remains elusive.

Atrial tissue samples were obtained from patients diagnosed with AF or sinus rhythm (SR) to assess alterations in NR4A3 expression, and then two distinct animal models were generated by subjecting Nr4a3-/- mice and WT mice to a high-fat diet (HFD) and Streptozotocin (STZ), while db/db mice were administered AAV9-Nr4a3 or AAV9-ctrl. Subsequently, in vivo and in vitro experiments were conducted to assess the impact of NR4A3 on diabetes-induced atrial remodeling through electrophysiological, biological, and histological analyses. RNA sequencing (RNA-seq) and metabolomics analysis were employed to unravel the downstream mechanisms.

The expression of NR4A3 was significantly decreased in atrial tissues of both AF patients and diabetic mice compared to their respective control groups. NR4A3 deficiency exacerbated atrial hypertrophy and atrial fibrosis, and increased susceptibility to pacing-induced AF. Conversely, overexpression of NR4A3 alleviated atrial structural remodeling and reduced AF induction rate. Mechanistically, we confirmed that NR4A3 improves mitochondrial energy metabolism and reduces oxidative stress injury by preserving the transcriptional expression of Sdha, thereby exerting a protective influence on atrial remodeling induced by diabetes.

Our data confirm that NR4A3 plays a protective role in atrial remodeling caused by diabetes, so it may be a new target for treating ACM.

This study was supported by the major research program of National Natural Science Foundation of China (NSFC) No: 82370316 (to Q-S. W.), No. 81974041 (to Y-P. W.), and No. 82270447 (to Y-P. W.) and Fundation of Shanghai Hospital Development Center (No. SHDC2022CRD044 to Q-S. W.).

Metabolic Dysfunction-Associated Fatty Liver Disease and Diabetes Mellitus are two prevalent metabolic disorders that often coexist and synergistically contribute to the progression of each other. Several pathophysiological pathways are involved in the association, including insulin resistance, inflammation, and lipotoxicity, providing a foundation for understanding the complex interrelationships between these conditions. The presence of MASLD has a significant impact on diabetes risk and the development of microvascular and macrovascular complications, and diabetes significantly contributes to an increased risk of liver fibrosis progression in MASLD and the development of hepatocellular carcinoma. Moreover, both pathologies have a synergistic effect on cardiovascular events and mortality. Therapeutic interventions targeting MASLD and diabetes are discussed, considering lifestyle modifications, pharmacological agents, and emerging treatment modalities. The review also addresses the challenges in managing these comorbidities, such as the need for personalized approaches and the potential impact on cardiovascular health. The insights gleaned from this analysis can inform clinicians, researchers, and policymakers in developing integrated strategies for preventing, diagnosing, and managing these metabolic disorders.

The metabolic syndrome, characterized by type 2 diabetes mellitus (T2DM), hypertension, hyperlipidemia, and obesity, collectively increases the risk of cardiovascular diseases. Nonalcoholic fatty liver disease (NAFLD) is a prominent manifestation, affecting over a third of the global population with a concerning annual increase in prevalence. Nearly 70 % of overweight individuals have NAFLD, and NAFLD-related deaths are predicted to rise, especially among young adults. The association of T2DM and NAFLD has led to the proposal of "metabolic dysfunction-associated steatotic liver disease" (MASLD) terminology, encompassing individuals with T2DM, overweight/obesity, hypertension, hypertriglyceridemia, or low HDL-cholesterol. Patients with MASLD will likely have double the risk of developing T2DM, and the combination of insulin resistance, overweight/obesity, and MASLD significantly elevates the risk of T2DM. Cardiovascular diseases remain the leading cause of mortality in the MASLD and T2DM population, with MASLD directly associated with coronary artery disease, compounded by coexisting insulin resistance and T2DM. Urgency lies in early detection of subclinical cardiovascular diseases among patients with T2DM and MASLD. Novel strategies targeting multiple pathways offer hope for effectively improving cardiometabolic health. Understanding and addressing the intertwined factors contributing to these disorders can pave the way towards better management and prevention of cardiometabolic complications.

Atrial cardiomyopathy is defined as any complex of structural, architectural, contractile or electrophysiological changes affecting atria, with the potential to produce clinically relevant manifestations. Most of our knowledge about the mechanistic aspects of atrial cardiomyopathy is derived from studies investigating animal models of atrial fibrillation and atrial tissue samples obtained from individuals who have a history of atrial fibrillation. Several noninvasive tools have been reported to characterize atrial cardiomyopathy in patients, which may be relevant for predicting the risk of incident atrial fibrillation and its related outcomes, such as stroke. Here, we provide an overview of the pathophysiological mechanisms involved in atrial cardiomyopathy, and discuss the complex interplay of these mechanisms, including aging, left atrial pressure overload, metabolic disorders and genetic factors. We discuss clinical tools currently available to characterize atrial cardiomyopathy, including electrocardiograms, cardiac imaging and serum biomarkers. Finally, we discuss the clinical impact of atrial cardiomyopathy, and its potential role for predicting atrial fibrillation, stroke, heart failure and dementia. Overall, this review aims to highlight the critical need for a clinically relevant definition of atrial cardiomyopathy to improve treatment strategies.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formally known as nonalcoholic fatty liver disease, is the most common chronic liver disease in the United States. Patients with MASLD have been reported to be at a higher risk of developing severe coronavirus disease 2019 (COVID-19) and death. However, most studies are single-center studies, and nationwide data in the United States is lacking.

To study the influence of MASLD on COVID-19 hospitalizations during the initial phase of the pandemic.

We retrospectively analyzed the 2020 National Inpatient Sample (NIS) database to identify primary COVID-19 hospitalizations based on an underlying diagnosis of MASLD. A matched comparison cohort of COVID-19 hospitalizations without MASLD was identified from NIS after 1: N propensity score matching based on gender, race, and comorbidities, including hypertension, heart failure, diabetes, and cirrhosis. The primary outcomes included inpatient mortality, length of stay, and hospitalization costs. Secondary outcomes included the prevalence of systemic complications.

A total of 2210 hospitalizations with MASLD were matched to 2210 hospitalizations without MASLD, with a good comorbidity balance. Overall, there was a higher prevalence of severe disease with more intensive care unit admissions (9.5% vs 7.2%, P = 0.007), mechanical ventilation (7.2% vs 5.7%, P = 0.03), and septic shock (5.2% vs 2.7%, P <0.001) in the MASLD cohort than in the non-MASLD cohort. However, there was no difference in mortality (8.6% vs 10%, P = 0.49), length of stay (5 d vs 5 d, P = 0.25), and hospitalization costs (42081.5 $ vs 38614$, P = 0.15) between the MASLD and non-MASLD cohorts.

The presence of MAFLD with or without liver cirrhosis was not associated with increased mortality in COVID-19 hospitalizations; however, there was an increased incidence of severe COVID-19 infection. This data (2020) predates the availability of COVID-19 vaccines, and many MASLD patients have since been vaccinated. It will be interesting to see if these trends are present in the subsequent years of the pandemic.

Nonalcoholic fatty liver (NAFL) remains relatively benign, but high-risk to end-stage liver diseases become highly prevalent when it progresses into nonalcoholic steatohepatitis (NASH). Our current understanding of the development of NAFL to NASH remains insufficient. In this study, we revealed MAP kinase (MAPK) activation as the most notable molecular signature associated with NASH progression across multiple species. Furthermore, we identified suppressor of IKKε (SIKE) as a conserved and potent negative controller of MAPK activation. Hepatocyte-specific overexpression of Sike prevented NASH progression in diet- and toxin-induced mouse NASH models. Mechanistically, SIKE directly interacted with TGF-β-activated kinase 1 (TAK1) and TAK1-binding protein 2 (TAB2) to interrupt their binding and subsequent TAK1-MAPK signaling activation. We found that indobufen markedly up-regulated SIKE expression and effectively improved NASH features in mice and macaques. These findings identify SIKE as a MAPK suppressor that prevents NASH progression and provide proof-of-concept evidence for targeting the SIKE-TAK1 axis as a potential NASH therapy.

Metabolic dysfunction-associated steatotic liver disease (MASLD) typically presents with hepatic fibrosis in advanced disease, resulting in increased liver stiffness. A subset of patients further develops liver cirrhosis and hepatocellular carcinoma. Cardiovascular disease is a common comorbidity in patients with MASLD and its prevalence is increasing in parallel. Recent evidence suggests that especially liver stiffness, whether or not existing against a background of MASLD, is associated with heart diseases. We conducted a narrative review on the role of liver stiffness in the prediction of highly prevalent heart diseases including heart failure, cardiac arrhythmias (in particular atrial fibrillation), coronary heart disease, and aortic valve sclerosis. Research papers were retrieved from major scientific databases (PubMed, Web of Science) until September 2023 using 'liver stiffness' and 'liver fibrosis' as keywords along with the latter cardiac conditions. Increased liver stiffness, determined by vibration-controlled transient elastography or hepatic fibrosis as predicted by biomarker panels, are associated with a variety of cardiovascular diseases, including heart failure, atrial fibrillation, and coronary heart disease. Elevated liver stiffness in patients with metabolic liver disease should lead to considerations of cardiac workup including N-terminal pro-B-type natriuretic peptide/B-type natriuretic peptide determination, electrocardiography, and coronary computed tomography angiography. In addition, patients with MASLD would benefit from heart disease case-finding strategies in which liver stiffness measurements can play a key role. In conclusion, increased liver stiffness should be a trigger to consider a cardiac workup in metabolically compromised patients.

It is uncertain if there is a link between non-alcoholic fatty liver disease (NAFLD) and cardiovascular diseases (CVD) in young adults and children. To evaluate the potential link between these two conditions, we conducted a systematic review and meta-analysis of cohort studies.

A comprehensive search was conducted in PubMed, Web of Science and Embase in order to locate all relevant cohort studies published until August 2023. Random effects meta-analyses were conducted using the generic inverse variance method, with additional subgroup and sensitivity analyses. The Newcastle-Ottawa Scale was employed to evaluate the methodological quality.

Four cohort studies (eleven datasets) involving 10,668,189 participants were included in this meta-analysis. This meta-analysis demonstrated that NAFLD increases the risk of CVD in young adults and children (HR = 1.63, 95% CI: 1.46-1.82, P < 0.00001). Further subgroup analyses showed that individuals with NAFLD were at a heightened risk of coronary heart disease (CHD) (HR = 3.10, 95% CI: 2.01-4.77, P < 0.00001), myocardial infarction (MI) (HR = 1.69, 95% CI: 1.61-1.78, P < 0.00001), atrial fibrillation (AF) (HR = 2.00, 95% CI: 1.12-3.57, P = 0.02), congestive heart failure (CHF) (HR = 3.89, 95% CI: 1.20-12.61, P = 0.02), and stroke (HR = 1.47, 95% CI: 1.39-1.55, P < 0.00001). The results of subgroup analyses based on the study location, NAFLD definition, and follow-up time also showed consistency with the overall results. Sensitivity analyses showed that our results were robust. All of the included studies were judged to be of medium to high quality.

Current evidence reveals that NAFLD is linked to an increased risk of major CVD (including CHD, MI, AF, CHF and stroke) in young adults and children. Further research is needed to strengthen this association and provide stronger evidence for primary prevention of CVD in young adults and children with NAFLD.

https://www.crd.york.ac.uk/PROSPERO/, PROSPERO registration number: CRD42023457817.

Accumulating epidemiological and experimental evidence indicates that nonalcoholic fatty liver disease (NAFLD) has an intrauterine origin. Fetuses exposed to adverse prenatal environments (e.g., maternal malnutrition and xenobiotic exposure) are more susceptible to developing NAFLD after birth. Glucocorticoids are crucial triggers of the developmental programming of fetal-origin diseases. Adverse intrauterine environments often lead to fetal overexposure to maternally derived glucocorticoids, which can program fetal hepatic lipid metabolism through epigenetic modifications. Adverse intrauterine environments program the offspring's glucocorticoid-insulin-like growth factor 1 (GC-IGF1) axis, which contributes to postnatal catch-up growth and disturbs glucose and lipid metabolism. These glucocorticoid-driven programming alterations increase susceptibility to NAFLD in the offspring. Notably, after delivery, offspring often face an environment distinct from their in utero life. The mismatch between the intrauterine and postnatal environments can serve as a postnatal hit that further disturbs the programmed endocrine axes, accelerating the onset of NAFLD. In this review, we summarize the current epidemiological and experimental evidence demonstrating that NAFLD has an intrauterine origin and discuss the underlying intrauterine programming mechanisms, focusing on the role of overexposure to maternally derived glucocorticoids. We also briefly discuss potential early life interventions that may be beneficial against fetal-originated NAFLD.

The objective of this manuscript is to examine the current literature on non-alcoholic fatty liver disease (NAFLD) biomarkers and their correlation with cardiovascular disease (CVD) outcomes and cardiovascular risk scores.

There has been a growing appreciation for an independent link between NAFLD and CVD, culminating in a scientific statement by the American Heart Association in 2022. More recently, studies have begun to identify biomarkers of the three NAFLD phases as potent predictors of cardiovascular risk. Despite the body of evidence supporting a connection between hepatic biomarkers and CVD, more research is certainly needed, as some studies find no significant relationship. If this relationship continues to be robust and readily reproducible, NAFLD and its biomarkers may have an exciting role in the future of cardiovascular risk prediction, possibly as risk-enhancing factors or as components of novel cardiovascular risk prediction models.

In traditional Chinese medicine (TCM), the liver is the "general organ" that is responsible for governing/maintaining the free flow of qi over the entire body and storing blood. According to the classic five elements theory, zang-xiang theory, yin-yang theory, meridians and collaterals theory, and the five-viscera correlation theory, the liver has essential relationships with many extrahepatic organs or tissues, such as the mother-child relationships between the liver and the heart, and the yin-yang and exterior-interior relationships between the liver and the gallbladder. The influences of the liver to the extrahepatic organs or tissues have been well-established when treating the extrahepatic diseases from the perspective of modulating the liver by using the ancient classic prescriptions of TCM and the acupuncture and moxibustion. In modern medicine, as the largest solid organ in the human body, the liver has the typical functions of filtration and storage of blood; metabolism of carbohydrates, fats, proteins, hormones, and foreign chemicals; formation of bile; storage of vitamins and iron; and formation of coagulation factors. The liver also has essential endocrine function, and acts as an immunological organ due to containing the resident immune cells. In the perspective of modern human anatomy, physiology, and pathophysiology, the liver has the organ interactions with the extrahepatic organs or tissues, for example, the gut, pancreas, adipose, skeletal muscle, heart, lung, kidney, brain, spleen, eyes, skin, bone, and sexual organs, through the circulation (including hemodynamics, redox signals, hepatokines, metabolites, and the translocation of microbiota or its products, such as endotoxins), the neural signals, or other forms of pathogenic factors, under normal or diseases status. The organ interactions centered on the liver not only influence the homeostasis of these indicated organs or tissues, but also contribute to the pathogenesis of cardiometabolic diseases (including obesity, type 2 diabetes mellitus, metabolic [dysfunction]-associated fatty liver diseases, and cardio-cerebrovascular diseases), pulmonary diseases, hyperuricemia and gout, chronic kidney disease, and male and female sexual dysfunction. Therefore, based on TCM and modern medicine, the liver has the bidirectional interaction with the extrahepatic organ or tissue, and this established bidirectional interaction system may further interact with another one or more extrahepatic organs/tissues, thus depicting a complex "pan-hepatic network" model. The pan-hepatic network acts as one of the essential mechanisms of homeostasis and the pathogenesis of diseases.

Atrial fibrillation (AF) and related cardiovascular complications pose a heavy burden to patients and society. Mounting evidence suggests a close association between nonalcoholic fatty liver disease (NAFLD) and AF. NAFLD and AF transcriptomic datasets were obtained from GEO database and analyzed using several bioinformatics approaches. We established a NAFLD-AF associated gene diagnostic signature (NAGDS) using protein-protein interaction analysis and machine learning, which was further quantified through RT-qPCR. Potential miRNA targeting NAGDS were predicted. Gene modules highly correlated with NAFLD liver pathology or AF occurrence were identified by WGCNA. Enrichment analysis of the overlapped genes from key module revealed that T-cell activation plays essential roles in NAFLD and AF, which was further confirmed by immune infiltration. Furthermore, an integrated SVM-RFE and LASSO algorithm was used to identify CCL4, CD48, ITGB2, and RNASE6 as NAGDS, all of which were found to be upregulated in NAFLD and AF mouse tissues. Patients with higher NAGDS showed augmented T cell and macrophage immunity, more advanced liver pathological characteristics, and prolonged AF duration. Additionally, hsa-miR-26a-5p played a central role in the regulation of NAGDS. Our findings highlight the central role of T-cell immune response in linking NAFLD to AF, and established an accurate NAGDS diagnostic model, which could serve as potential targets for immunoregulatory therapy.

Type 2 diabetes mellitus, nonalcoholic fatty liver disease (NAFLD), cardio-cerebrovascular diseases (CCVDs), hyperuricemia and gout, and metabolic-related sexual dysfunction are metabolic diseases that affect human health in modern society. Scientists have made great efforts to investigate metabolic diseases using cell models in vitro or animal models in the past. However, the findings from cells or animals are difficult to translate into clinical applications due to factors such as the in vitro and in vivo differences; the differences in anatomy, physiology, and genetics between humans and animals; and the differences in microbiome-host interaction. The Chinese have extensively used the medicated diet of traditional Chinese medicine (TCM) (also named as Yao-Shan of TCM, Chinese Yao-Shan et al.) to maintain or improve cardiometabolic health for more than 2,200 years. These ancient classic diets of TCM are essential summaries of long-term life and clinical practices. Over the past 5 years, our group has made every effort to collect and sort out the classic Yao-Shan of TCM from the ancient TCM literature since Spring and Autumn and Warring States Period, especially these are involved in the prevention and treatment of metabolic diseases, such as diabetes, NAFLD, CCVDs, hyperuricemia and gout, and sexual dysfunction. Here, we summarized and discussed the classic Yao-Shan of TCM for metabolic diseases according to the time recorded in the ancient literature, and revised the Latin names of the raw materials in these Yao-Shan of TCM. Moreover, the modern medicine evidences of some Yao-Shan of TCM on metabolic diseases have also been summarized and emphasized in here. However, the exact composition (in terms of ratios), preparation process, and dosage of many Yao-Shan are not standardized, and their main active ingredients are vague. Uncovering the mystery of Yao-Shan of TCM through modern biological and chemical strategies will help us open a door, which is ancient but now looks new, to modulate metabolic homeostasis and diseases.

Metabolic-associated fatty liver disease (MAFLD) is a condition of fat accumulation in the liver that occurs in the majority of patients in combination with metabolic dysfunction in the form of overweight or obesity. In this review, we highlight the cardiovascular complications in MAFLD patients as well as some potential mechanisms linking MAFLD to the development of cardiovascular disease and highlight potential therapeutic approaches to treating cardiovascular diseases in patients with MAFLD.

MAFLD is associated with an increased risk of cardiovascular diseases (CVD), including hypertension, atherosclerosis, cardiomyopathies, and chronic kidney disease. While clinical data have demonstrated the link between MAFLD and the increased risk of CVD development, the mechanisms responsible for this increased risk remain unknown. MAFLD can contribute to CVD through several mechanisms including its association with obesity and diabetes, increased levels of inflammation, and oxidative stress, as well as alterations in hepatic metabolites and hepatokines. Therapies to potentially treat MAFLD-induced include statins and lipid-lowering drugs, glucose-lowering agents, antihypertensive drugs, and antioxidant therapy.

Heart failure with reduced ejection fraction (HFrEF) and nonalcoholic fatty liver disease (NAFLD) are two common comorbidities that share similar pathophysiological mechanisms. There is a growing interest in the potential of targeted therapies to improve outcomes in patients with coexisting HFrEF and NAFLD. This manuscript reviews current and potential therapies for patients with coexisting HFrEF and NAFLD. Pharmacological therapies, including angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, mineralocorticoids receptor antagonist, and sodium-glucose cotransporter-2 inhibitors, have been shown to reduce fibrosis and fat deposits in the liver. However, there are currently no data showing the beneficial effects of sacubitril/valsartan, ivabradine, hydralazine, isosorbide nitrates, digoxin, or beta blockers on NAFLD in patients with HFrEF. This study highlights the importance of considering HFrEF and NAFLD when developing treatment plans for patients with these comorbidities. Further research is needed in patients with coexisting HFrEF and NAFLD, with an emphasis on novel therapies and the importance of a multidisciplinary approach for managing these complex comorbidities.

The association between atrial fibrillation (AF) and non-alcoholic fatty liver disease (NAFLD) or metabolic-associated fatty liver disease (MAFLD) has been explored in recent cohort studies, however, the results have been controversial and inconclusive. This meta-analysis aimed to explore this potential association.

We systematically searched PubMed, Embase, and Web of Science databases to identify all relevant cohort studies investigating the association between NAFLD/MAFLD and AF published from database inception to October 30, 2022. Random-effects models were utilized to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) for summary purposes. Additionally, subgroup and sensitivity analyses were performed.

A total of 13 cohort studies with 14 272 735 participants were included. Among these, 12 cohort studies with 14 213 289 participants (median follow-up of 7.8 years) showed a significant association between NAFLD and an increased risk of incident AF (HR = 1.18, 95% CI: 1.12-1.23, P < 0.00001). Our subgroup analyses mostly yielded similar results, and the results of sensitivity analyses remained unchanged. However, meta-analysis of data from 2 cohort studies with 59 896 participants (median follow-up of 2.15 years) showed that MAFLD was not linked to incident AF (HR = 1.36, 95% CI: 0.63-2.92, P = 0.44).

Current evidence shows that NAFLD may be linked to a slightly higher risk of developing AF, particularly among Asian populations and those diagnosed with NAFLD using FLI criteria. Nevertheless, there is not enough evidence to support the proposed association between MAFLD and an increased risk of AF. To better understand this relationship, future studies should consider factors such as specific population, the severity of NAFLD/MAFLD, diagnostic methods of NAFLD and AF, and cardiometabolic risk factors.

https://www.crd.york.ac.uk/prospero, identifier CRD42022371503.

The aim of the study was to depict the global death burden of atrial fibrillation and/or flutter (AFF) between 1990 and 2019 and predict this burden in the next decade.

We retrieved annual death data on cases and rates of AFF between 1990 and 2019 from the Global Burden of Disease (GBD) Study 2019 and projected the trends for 2020-2029 by developing the Bayesian age-period-cohort model.

The global number of deaths from AFF increased from 117,038.00 in 1990 to 315,336.80 in 2019. This number is projected to reach 404,593.40 by 2029. The age-standardized mortality rates (ASMRs) of AFF have increased significantly in low- to middle-sociodemographic index (SDI) regions, which will surpass that in high SDI regions and reach above 4.60 per 100,000 by 2029. Globally, women have a higher ASMR than men, which is largely attributed to disproportionately higher mortality in women than men in lower SDI regions. Notably, AFF-related premature mortality continues to worsen worldwide. A pandemic of high systolic blood pressure and high body mass index (BMI) largely contributes to AFF-associated death. In particular, low- to middle-SDI regions and younger populations are increasingly affected by the rapidly growing current and future risk of high BMI.

The global death burden of AFF in low-income countries and younger generations have not been sufficiently controlled in the past and will continue growing in the future, which is largely attributed to metabolic risks, particularly for high BMI. There is an urgent need to implement effective measures to control AFF-related mortality.

Immune cells play an integral role in the development and progression of non-alcoholic fatty liver disease (NAFLD). This study was to identify immune-cell-related biomarkers for the diagnosis and treatment of NAFLD.

First, we introduced human liver transcriptome data from the GEO database (GSE48452 and GSE126848) and performed a weighted gene co-expression network analysis (WGCNA) to screen out the modules related to immune cell infiltration and to identify immune-cell-related differentially expressed genes (ICR-DEGs) associated with NAFLD progression. Further, the protein-protein interaction (PPI) network of ICR-DEGs was established to obtain hub genes and subsequently, the expression trend analysis was conducted to identify immune-cell-related biomarkers of NAFLD. Finally, the mRNA expression of biomarkers was validated in a NAFLD mouse model induced by high-fat diet (HFD) feeding. In total, we identified 66 ICR-DEGs and 13 hub genes associated with NAFLD. Among them, 9 hub genes (CD247, CD74, FCGR2B, IL2RB, INPP5D, MRPL16, RPL35, RPS3A, RPS8) were correlated with the infiltrating immune cells by the Pearson correlation analysis. Subsequently, 4 immune-cell-related biomarkers (RPL35, RPS3A, RPS8, and MRPL16) with the same expression trends in GSE48452 and GSE126848 datasets were identified. These biomarkers were enriched in immune-related pathways and had a good ability to distinguish between NASH and healthy samples. Moreover, we constructed a competing endogenous RNA (ceRNA) network of biomarkers and predicted twenty potential therapeutic drugs targeting RPS3A such as taxifolin and sitagliptin. Finally, experimental validation indicated that the hepatic mRNA expression of Rpl35, Rps3A, and Rps8 was significantly decreased in NAFLD mice.

This study identified four ribosomal protein genes (RPL35, RPS3A, RPS8, and MRPL16) as immune-cell-related biomarkers of NAFLD, which may actively participate in the immune processes during NAFLD progression and could serve as potential targets for the diagnosis and treatment of NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is associated with atrial fibrillation (AF). Insulin resistance (IR) is the main cause of the high prevalence of AF in NAFLD patients. The triglyceride-glucose index (TyG) is a novel IR-related indicator implicated in the incidence and severity of NAFLD. However, the role of TyG in determining the risk for AF in patients with NAFLD remains unclear.

A retrospective study was conducted on 912 patients diagnosed with NAFLD via ultrasonography. These patients were divided into two groups: (1) NAFLD+ AF and (2) NAFLD+ non-AF. Least Absolute Shrinkage and Selection Operator (LASSO) regression was used to assess the correlation between the TyG index and the high risk for AF. A receiver operating characteristic (ROC) curve was constructed to evaluate the predictive value for the TyG index for AF. Restricted cubic splines (RCS) were used to test the linear correlation between TyG and the risk for AF.

A total of 204 patients with AF and 708 patients without AF were included in this study. The LASSO logistic regression analysis showed that TyG was an independent risk factor for AF (odds ratio [OR] = 4.84, 95% confidence interval [CI] 2.98-7.88, P < 0.001). The RCS showed that the risk for AF increased linearly with TyG over the entire TyG range; this risk was also evident when the patients were analyzed based on sex (P for nonlinear > 0.05). In addition, the correlation between TyG and AF was a consistent finding in subgroup analysis. Furthermore, ROC curve analysis showed that TyG levels combined with traditional risk factors improved the predictive value for atrial fibrillation.

The TyG index is useful in assessing the risk for atrial fibrillation in patients with NAFLD. Patients with NAFLD and increased TyG indices have higher risks for atrial fibrillation. Therefore, TyG indices should be assessed when managing patients with NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is a chronic metabolic disease characterized by an excessive accumulation of fat in the liver, which is becoming a major global health problem, affecting about a quarter of the population. In the past decade, mounting studies have found that 25%-40% of NAFLD patients have cardiovascular disease (CVD), and CVD is one of the leading causes of death in these subjects. However, it has not attracted enough awareness and emphasis from clinicians, and the underlying mechanisms of CVD in NAFLD patients remain unclear. Available research reveals that inflammation, insulin resistance, oxidative stress, and glucose and lipid metabolism disorders play indispensable roles in the pathogenesis of CVD in NAFLD. Notably, emerging evidence indicates that metabolic organ-secreted factors, including hepatokines, adipokines, cytokines, extracellular vesicles, and gut-derived factors, are also involved in the occurrence and development of metabolic disease and CVD. Nevertheless, few studies have focused on the role of metabolic organ-secreted factors in NAFLD and CVD. Therefore, in this review, we summarize the relationship between metabolic organ-secreted factors and NAFLD as well as CVD, which is beneficial for clinicians to comprehensive and detailed understanding of the association between both diseases and strengthen management to improve adverse cardiovascular prognosis and survival.

One of the most prevalent cardiac diseases is cardiac arrhythmia, however the underlying causes are not entirely understood. There is a lot of proof that gut microbiota (GM) and its metabolites have a significant impact on cardiovascular health. In recent decades, intricate impacts of GM on cardiac arrythmia have been identified as prospective approaches for its prevention, development, treatment, and prognosis. In this review, we discuss about how GM and its metabolites might impact cardiac arrhythmia through a variety of mechanisms. We proposed to explore the relationship between the metabolites produced by GM dysbiosis including short-chain fatty acids(SCFA), Indoxyl sulfate(IS), trimethylamine N-oxide(TMAO), lipopolysaccharides(LPS), phenylacetylglutamine(PAGln), bile acids(BA), and the currently recognized mechanisms of cardiac arrhythmias including structural remodeling, electrophysiological remodeling, abnormal nervous system regulation and other disease associated with cardiac arrythmia, detailing the processes involving immune regulation, inflammation, and different types of programmed cell death etc., which presents a key aspect of the microbial-host cross-talk. In addition, how GM and its metabolites differ and change in atrial arrhythmias and ventricular arrhythmias populations compared with healthy people are also summarized. Then we introduced potential therapeutic strategies including probiotics and prebiotics, fecal microbiota transplantation (FMT) and immunomodulator etc. In conclusion, the GM has a significant impact on cardiac arrhythmia through a variety of mechanisms, offering a wide range of possible treatment options. The discovery of therapeutic interventions that reduce the risk of cardiac arrhythmia by altering GM and metabolites is a real challenge that lies ahead.

Over the past 100 years, cardiovascular disease (CVD) has become a leading cause of mortality and morbidity in developed countries, and similar trends have occurred for chronic liver disease. Subsequent research also indicated that people with non-alcoholic fatty liver disease (NAFLD) had a twofold increased risk of CV events and that this risk was doubled in those with liver fibrosis. However, no validated CVD risk score specific for NAFLD patients has yet been validated, as traditional risk scores tend to underestimate the CV risk in NAFLD patients. From a practical perspective, identifying NAFLD patients and assessing severity of liver fibrosis when concurrent atherosclerotic risk factors are already established may serve as an important criterion in new CV risk scores. The current review aims to assess current risk scores and their utility for the prediction of CV events among patients with NAFLD.

Non-alcoholic fatty liver (NAFLD) and its related metabolic syndrome have become major threats to human health, but there is still a need for effective and safe drugs to treat these conditions. Here we aimed to identify potential drug candidates for NAFLD and the underlying molecular mechanisms.

A drug repositioning strategy was used to screen an FDA-approved drug library with approximately 3000 compounds in an in vitro hepatocyte model of lipid accumulation, with honokiol identified as an effective anti-NAFLD candidate. We systematically examined the therapeutic effect of honokiol in NAFLD and metabolic syndrome in multiple in vitro and in vivo models. Transcriptomic examination and biotin-streptavidin binding assays were used to explore the underlying molecular mechanisms, confirmed by rescue experiments.

Honokiol significantly inhibited metabolic syndrome and NAFLD progression as evidenced by improved hepatic steatosis, liver fibrosis, adipose inflammation, and insulin resistance. Mechanistically, the beneficial effects of honokiol were largely through AMPK activation. Rather than acting on the classical upstream regulators of AMPK, honokiol directly bound to the AMPKγ1 subunit to robustly activate AMPK signaling. Mutation of honokiol-binding sites of AMPKγ1 largely abolished the protective capacity of honokiol against NAFLD.

These findings clearly demonstrate the beneficial effects of honokiol in multiple models and reveal a previously unappreciated signaling mechanism of honokiol in NAFLD and metabolic syndrome. This study also provides new insights into metabolic disease treatment by targeting AMPKγ1 subunit-mediated signaling activation.