Search Results (259)

Hypertension is one of the most common comorbidities in cardiometabolic diseases, affecting nearly one third of adults. As a result, its pathophysiological mechanisms have been studied extensively and are focused around pressure natriuresis, the renin–angiotensin system (RAS), the sympathetic nervous system, oxidative stress, and endothelial dysfunction. Additionally, hypertension secondary to other underlying etiologies also exists. While clinical evidence has clearly shown differences in hypertension development in males and females, relatively little is known about the pathophysiological mechanisms behind these differences. Sex hormones likely play a key role, as they modulate many factors related to hypertension development. In this review, we postulate the potential role for sexually dimorphic fat metabolism in the physiology of hypertension. In brief, estrogen promotes subcutaneous fat deposition over visceral fat and increases in mass via adaptive hyperplasia rather than pathogenic hypertrophy. This adipose tissue subsequently produces anti-inflammatory effects and inhibits metabolic dysfunction-associated fatty liver disease (MAFLD) and RAS activation, ultimately leading to decreased levels of hypertension in pre-menopausal females. On the other hand, androgens and the lack of estrogens promote visceral and ectopic fat deposition, including in the liver, and lead to increased circulating pro-inflammatory cytokines and potentially subsequent RAS activation and hypertension development in males and post-menopausal females. Understanding the sex-specific differences in fat metabolism may provide deeper insights into the patho-mechanisms associated with hypertension and lead to more comprehensive sex-specific care. Full article

The prevalence of metabolic syndrome has been exponentially increasing in recent decades. Thus, there is an increasing need for affordable and natural interventions for this disorder. We explored the effect of chrysin, a dietary polyphenol, on hepatic lipid and glycogen accumulation, metabolic dysfunction-associated fatty liver disease (MAFLD) activity score and oxidative stress and on hepatic and adipose tissue metabolism in rats presenting metabolic syndrome-associated conditions. Rats fed a chow diet were separated into four groups: Control (tap water), Fructose (tap water with 10% fructose), Chrysin (tap water+ chrysin (100 mg/kg body weight/d)), and Fructose + Chrysin (tap water with 10% fructose + chrysin (100 mg/kg body weight/d, daily)) (for 18 weeks). When associated with the chow diet, chrysin reduced hepatic lipid and glycogen storage, increased the hepatic antioxidant potential of glutathione and reduced de novo lipogenesis in the adipose tissue. When associated with the high fructose-diet, chrysin attenuated the increase in lipid and glycogen hepatic storage, improved the MAFLD activity score, decreased hepatic lipid peroxidation, increased the antioxidant potential of glutathione, and improved lipid and glucose metabolic markers in the liver and adipose tissue. In conclusion, our results suggest that chrysin is a beneficial addition to a daily diet for improvement of hepatic metabolic health, particularly for individuals suffering from metabolic syndrome. Full article

Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common cause of chronic liver disease worldwide, with a multifactorial etiology. This study aims to evaluate the associations between various sociodemographic variables, healthy habits, and stress with risk scale values for MAFLD. Materials and Methods: A descriptive, cross-sectional study was conducted on 16,708 Spanish workers to assess how sociodemographic variables (age, gender, and socioeconomic status), healthy habits (smoking, Mediterranean diet adherence, and physical activity), and stress correlate with values from three MAFLD risk scales: fatty liver index (FLI), hepatic steatosis index (HSI), and lipid accumulation product (LAP). Results: All analyzed variables were associated with the values of the three MAFLD risk scales. Among them, the variables showing the strongest associations (represented by odds ratio values) were age and physical activity. Conclusions: The profile of an individual at higher risk of elevated MAFLD risk scale values is a male, aged 50 or older, belonging to lower socioeconomic levels (manual laborers), a smoker, sedentary, with low adherence to the Mediterranean diet, and with high stress scale scores. Full article

Consumption of phytosterols is a nutritional strategy employed to reduce cholesterol absorption, but recent research shows that their biological activity might go beyond cholesterol reduction for the treatment of metabolic dysfunction-associated fatty liver disease (MAFLD), and novel phytosterol formulations, such as submicron dispersions, could improve these effects. We explored the therapeutic activity of phytosterols, either formulated as submicron dispersions of phytosterols (SDPs) or conventional phytosterol esters (PEs), in a mouse model of MAFLD. MAFLD was induced in mice by atherogenic diet (AD) feeding. The reversion of distorted serum and liver parameter values after a period of AD feeding was investigated after supplementation of the AD with SDPs, PEs, or a placebo (PT). Additionally, the metabolic parameters of fatty acid synthesis, fatty acid oxidation, and inflammation were studied to understand the mechanism of action of phytosterols. AD supplementation with SDPs was shown to reduce liver fat, along with showing a significant improvement in liver triglycerides (TGs), free fatty acids (FFAs), and liver cholesterol levels. These results were reinforced by the analyses of the liver steatosis scores, and liver histologies, where SDP intervention showed a consistent improvement. Treatment with PEs showed slighter effects in the same analyses, and no effects were observed with the PT treatment. Additionally, SDP intervention reversed, with a higher efficacy than PEs, the effect of AD on the serum levels of TGs, total- and LDL-cholesterol levels, and glucose levels. And, exceptionally, while SDP improved HDL-cholesterol serum levels, PEs did not show any effect on this parameter. We provide evidence for the therapeutical activity of phytosterols in MAFLD beyond the regulation of cholesterol levels, which is increased when the phytosterols are formulated as submicron dispersions compared to ester formulations. Full article

Background/Objectives: Obesity and type 2 diabetes (T2D) are associated with significant alterations in various metabolic biomarkers. Isthmin-1 (Ism1) has recently emerged as a potential marker of metabolic health and was shown in animal studies to associate with metabolic-associated fatty liver disease (MAFLD). In this study, we aimed to investigate the circulatory levels of Ism1 in individuals with obesity compared to non-obese individuals and evaluate their association with insulin resistance, MAFLD, and T2D. The primary outcomes of this study are obesity, insulin resistance, MAFLD, and T2D, while the secondary outcome is hypertension; Methods: This is a cross-sectional study involving 450 participants, who were divided based on their obesity status into people with obesity (n = 182) and those without obesity (n = 265). Circulating Ism1 levels were measured by ELISA and were compared between the groups. Insulin resistance was assessed using the homeostasis model assessment of insulin resistance (HOMA-IR), and fatty liver was evaluated using Fibroscan; Results: Our results showed a significant reduction in circulating Ism1 levels in individuals with obesity (p-value = 0.002). Ism1 levels were negatively associated with the odds of T2D, possibly suggesting a protective role. Additionally, individuals with higher CAP scores demonstrated significantly lower Ism1 levels, and the Spearman’s rank correlation revealed a negative association between Ism1 and both CAP scores (r = −0.109, p-value = 0.025) and insulin resistance (r = −0.141, p-value = 0.004). Logistic regression analysis further supported Ism1 as an independent significant protective factor against obesity-related metabolic dysfunction. This significance persisted after adjusting for several confounders. Furthermore, our ROC results indicate that circulatory Ism1 levels possess significant diagnostic capability for identifying individuals with obesity-related metabolic imbalances with an area under the curve of 0.764 (95% CI = 0.718, 0.811). Finally, the adjusted multinomial analysis suggested that higher levels of Ism1 may play a protective role against pre-diabetes (AOR = 0.88, 95% CI = 0.838, 0.925) and T2D (AOR = 0.87, 95% CI = 0.814, 0.934); Conclusions: This study suggests that reduced Ism1 levels are linked to increased insulin resistance, MAFLD, and T2D in obese individuals. Our findings further corroborate the protective role of Ism1 and highlight its potential utility as a biomarker for monitoring obesity-related metabolic diseases. Full article

Nonalcoholic fatty liver disease (NAFLD), recently renamed metabolic-associated fatty liver disease (MAFLD), is the most prevalent liver disease worldwide. It is associated with an increased risk of developing hepatocellular carcinoma (HCC) in the background of cirrhosis or without cirrhosis. The prevalence of NAFLD-related HCC is increasing all over the globe, and HCC surveillance in NAFLD cases is not that common. In the present review, we attempt to summarize promising treatments and clinical trials focused on NAFLD, nonalcoholic steatohepatitis (NASH), and HCC in the past five to seven years. We categorized the trials based on the type of intervention. Most of the trials are still running, with only a few completed and with conclusive results. In clinical trial NCT03942822, 25 mg/day of milled chia seeds improved NAFLD condition. Completed trial NCT03524365 concluded that Rouxen-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) results in histological resolution of NASH without worsening of fibrosis, while NCT04677101 validated sensitivity/accuracy of blood biomarkers in predicting NASH and fibrosis stage. Moreover, trials with empagliflozin (NCT05694923), curcuvail (NCT06256926), and obeticholic acid (NCT03439254) were completed but did not provide conclusive results. However, trial NCT03900429 reported effective improvement in fibrosis by at least one stage, without worsening of NAFLD activity score (NAS), as well as improvement in lipid profile of the NASH patients by 80 or 100 mg MGL-3196 (resmetirom). Funded by Madrigal Pharmaceuticals, Rezdiffra (resmetirom), used in the clinical trial NCT03900429, is the first FDA-approved drug for the treatment of NAFLD/NASH. Full article

Background/Objectives: This study builds on previous findings from mouse models, which showed that maternal overnutrition induced by a high-fat diet (HFD) promotes metabolic-associated fatty liver disease (MAFLD) in offspring, linked to global DNA hypermethylation. We explored whether epigenetic modulation with 5-Aza-CdR, a DNA methylation inhibitor, could prevent MAFLD in offspring exposed to maternal overnutrition. Methods: The offspring mice from dams of maternal overnutrition were fed either a chow diet or a high-fat diet (HFD) for 10 weeks. These mice were randomly divided into two groups: HFD, and AZA + HFD. Mice assigned to the AZA group were given 5-Aza-CdR during the last three weeks. Results: Our findings show that 5-Aza-CdR treatment in HFD-fed offspring effectively countered weight gain, improved glucose regulation, and minimized hepatic fat buildup along with serum lipid imbalances. Additionally, it boosted AMPK signaling and raised PPAR-α expression, pointing to enhanced fatty acid oxidation. We also detected an increase in JNK signaling, affecting the gene expression associated with cell death and proliferation. Notably, treated mice displayed more hepatic inflammation than the HFD group alone, suggesting a complex, dual impact on MAFLD management. Significant apoptotic and inflammatory gene changes were identified, along with corresponding differentially methylated regions triggered by 5-Aza-CdR, marking potential therapeutic targets. Conclusions: 5-Aza-CdR was shown to mitigate MAFLD features in offspring of maternal overnutrition by reversing DNA hypermethylation and improving metabolic pathways, though its dual impact on inflammation highlights the need for further research to optimize its therapeutic potential. Full article

The majority of drugs are typically orally administered. The journey from drug discovery to approval is often long and expensive, involving multiple stages. A major challenge in the drug development process is drug-induced liver injury (DILI), a condition that affects the liver, the organ responsible for metabolizing most drugs. Traditionally, identifying DILI risk has been difficult due to the poor correlation between preclinical animal models and in vitro systems. Differences in physiology between humans and animals or cell lines contribute to the failure of many drug programs during clinical trials. The use of advanced in vitro systems that closely mimic human physiology, such as organ-on-a-chip models like gut–liver-on-a-chip, can be crucial in improving drug efficacy while minimizing toxicity. Additionally, the adaptation of these technologies has the potential to significantly reduce both the time and cost associated with obtaining safe drug approvals, all while adhering to the 3Rs principle (replacement, reduction, refinement). In this review, we discuss the significance, current status, and future prospects of advanced platforms, specifically organ-on-a-chip models, in supporting preclinical drug discovery. Full article

Obesity and its related diseases, such as type 2 diabetes (T2DM), cardiovascular disease (CVD), and metabolic fatty liver disease (MAFLD), require new diagnostic markers for earlier detection and intervention. The aim of this study is to demonstrate the potential of metabolomics as a tool for identifying biomarkers associated with obesity and its comorbidities in every age group. The presented systematic review makes an important contribution to the understanding of the potential of metabolomics in identifying biomarkers of obesity and its complications, especially considering the influence of branched-chain amino acids (BCAAs), amino acids (AAs) and adipokines on the development of T2DM, MAFLD, and CVD. The unique element of this study is the combination of research results from the last decade in different age groups and a wide demographic range. The review was based on the PubMed and Science Direct databases, and the inclusion criterion was English-language original studies conducted in humans between 2014 and 2024 and focusing on the influence of BCAAs, AAs or adipokines on the above-mentioned obesity complications. Based on the PRISMA protocol, a total of 21 papers were qualified for the review and then assigned to a specific disease entity. The collected data reveal that elevated levels of BCAAs and some AAs strongly correlate with insulin resistance, leading to T2DM, MAFLD, and CVD and often preceding conventional clinical markers. Valine and tyrosine emerge as potential markers of MAFLD progression, while BCAAs are primarily associated with insulin resistance in various demographic groups. Adipokines, although less studied, offer hope for elucidating the metabolic consequences of obesity. The review showed that in the case of CVDs, there is still a lack of studies in children and adolescents, who are increasingly affected by these diseases. Moreover, despite the knowledge that adipokines play an important role in the pathogenesis of obesity, there are no precise findings regarding the correlation between individual adipokines and T2DM, MAFLD, or CVD. In order to be able to introduce metabolites into the basic diagnostics of obesity-related diseases, it is necessary to develop panels of biochemical tests that will combine them with classical markers of selected diseases. Full article

Background/Objectives: Type 2 diabetes mellitus (T2DM) is considered a serious risk to public health since its prevalence is rapidly increasing worldwide despite numerous therapeutics. Insulin resistance in T2DM contributes to chronic inflammation and other metabolic abnormalities that generate fat accumulation in the liver, eventually leading to the progression of metabolic dysfunction-associated fatty liver disease (MAFLD). Recently, the possibility that microbial-derived metabolites may alleviate MAFLD through enterohepatic circulation has emerged, but the underlying mechanism remains unclear. In this research, we utilized metabolites obtained from the fermentation of guava leaf extract, which is well-known for its antidiabetic activity, to investigate their effects and mechanisms on MAFLD. Methods: Diabetes was induced by a high-fat diet and streptozotocin injection (80 mg/kg body weight) twice in mice. Subsequently, mice whose fasting blood glucose levels were measured higher than 300 mg/dL were administered with metabolites of Limosilactobacillus fermentum (LF) (50 mg/kg/day) or guava leaf extract fermented by L. fermentum (GFL) (50 mg/kg/day) by gavage for 15 weeks. Results: GFL supplementation mitigated hyperglycemia and hepatic insulin resistance. Moreover, GFL regulated abnormal hepatic histological changes and lipid profiles in diabetic mice. Furthermore, GFL enhanced energy metabolism by activating the sirtuin1 (SIRT1)/proliferator-activated receptor γ coactivator 1α (PGC1α)/peroxisome proliferator-activated receptor (PPAR)-α pathway in diabetic mice. Meanwhile, GFL supplementation suppressed hepatic inflammation in diabetic mice. Conclusions: Taken together, the current study elucidated that GFL could be a potential therapeutic to ameliorate hyperglycemia and hepatic steatosis by improving SIRT1/PGC-1α/ PPAR-α-related energy metabolism in T2DM. Full article

Background: Metabolic-associated fatty liver disease (MAFLD) is a spectrum of liver diseases linked to insulin resistance (IR), type 2 diabetes, and metabolic disorders. IR accelerates fat accumulation in the liver, worsening MAFLD. Regular physical activity and weight loss can improve liver function, reduce fat, and lower cardiovascular risk. This study examines the role of sex hormone-binding globulin (SHBG) in MAFLD, focusing on its potential as a biomarker and its relationship with insulin resistance. Methods: The study included 98 male patients (ages 30–55) with MAFLD, identified through systematic examinations, and 74 healthy male controls. All participants underwent abdominal ultrasound and blood tests after fasting, assessing markers such as glucose, liver enzymes (AST, ALT, γGT), lipids (cholesterol, triglycerides), insulin, SHBG, estradiol, and testosterone. SHBG levels were analyzed in relation to body mass index (BMI) and age. Results: A significant association was found between low SHBG levels and the presence of fatty liver. Individuals with MAFLD had lower SHBG levels compared to controls. BMI and age were key factors influencing SHBG, with higher BMI linked to lower SHBG in younger men, while SHBG remained stable in older individuals regardless of BMI. Conclusion: SHBG may serve as a valuable biomarker for early detection and risk assessment of MAFLD. The complex relationship between SHBG, BMI, and age highlights the importance of considering both hormonal and metabolic factors when assessing fatty liver risk. Our findings support the need for comprehensive metabolic evaluations in clinical practice. Full article

Lipid accumulation and oxidative stress, which could be improved by autophagy, are the “hits” of metabolic-associated fatty liver disease (MAFLD). Ganoderma lucidum spore powder (GLSP) has the effect of improving liver function. However, there are few reports about its effects on and mechanisms impacting MAFLD alleviation. This study investigated the effect of GLSP on hepatic lipid accumulation and oxidative stress and explored the role that autophagy played in this effect. The results showed that GLSP effectively reduced lipid accumulation and activated autophagy in the livers of mice with high-fat-diet-induced disease and palmitic acid-induced hepatocytes. GLSP reduced the lipid accumulation by reducing lipogenesis and promoting lipid oxidation in HepG2 cells. It decreased the production of ROS, increased the activity of SOD and CAT, and improved the mitochondrial membrane potential via the Keap1/Nrf2 pathway. The alleviating effects of GLSP on the lipid accumulation and oxidative stress was reversed by 3-methyladenine (3-MA), an autophagy inhibitor. GLSP activated autophagy via the AMPK pathway in HepG2 cells. In conclusion, GLSP could attenuate MAFLD by the improvement of lipid accumulation and oxidative stress via autophagy. This paper is the first to report the improvement of MAFLD through autophagy promotion. It will shed novel light on the discovery of therapeutic strategies targeting autophagy for MAFLD. Full article

Background: Insulin resistance (IR) is central to the progression of non-alcoholic fatty liver disease (MAFLD). While aerobic exercise reduces hepatic fat and enhances insulin sensitivity, the specific mechanisms—particularly those involving exosomal pathways—are not fully elucidated. Method: Exosomes were isolated from 15 MAFLD patients’ plasma following the final session of a 12-week aerobic exercise intervention. Liver fat content was measured using MRI-PDFF, and metabolic parameters were assessed via OGTT, HOMA-IR, QUICKI, and VO₂ max. Co-culture experiments evaluated the effects of exercise-derived exosomes on IR signaling pathways. miRNA microarray analysis identified miR-324, which was quantified in high-fat diet (HFD) mice with and without exercise and compared between athletes and sedentary controls. Functional assays assessed miR-324’s role in glucose and lipid metabolism, while luciferase reporter and Western blot assays confirmed ROCK1 as its direct target. Result: Aerobic exercise significantly reduced liver fat and improved insulin sensitivity in both MAFLD patients and HFD mice. Notably, exosomal miR-324 levels were lower in athletes than sedentary controls, indicating an inverse association with insulin sensitivity. Post-exercise, precursor and mature miR-324 increased in adipose tissue and decreased in muscle, suggesting its adipose origin and inverse regulation. Functional assays demonstrated that miR-324 modulates insulin resistance by targeting ROCK1. Conclusion: Exercise-induced exosomal miR-324 from adipose tissue targets ROCK1, revealing a novel mechanism by which aerobic exercise confers hepatoprotection against insulin resistance in MAFLD. These findings enhance our understanding of how exercise influences metabolic health and may inform future therapeutic strategies for managing MAFLD and related conditions. Full article

Long regarded as illicit substances with no clinical value, N-dimethylated tryptamines—such as N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, and bufotenine—have been found to produce naturally in a wide variety of species, including humans. Known for their psychoactive effects through serotonin receptors (5-HTRs), N-dimethylated tryptamines are currently being reinvestigated clinically for their long-term benefits in mental disorders. Endogenous tryptamine is methylated by indolethylamine-N-methyltransferase (INMT), which can then serve as an agonist to pro-survival pathways, such as sigma non-opioid intracellular receptor 1 (SIGMAR1) signaling. Fibrogenic diseases, like metabolic-associated fatty liver disease (MAFLD), steatohepatitis (MASH), and chronic kidney disease (CKD) have shown changes in INMT and SIGMAR1 activity in the progression of disease pathogenesis. At the cellular level, endothelial cells and fibroblasts have been found to express INMT in various tissues; however, little is known about tryptamines in endothelial injury and fibrosis. In this review, I will give an overview of the biochemistry, molecular biology, and current evidence of INMT’s role in hepatic fibrogenesis. I will also discuss current pre-clinical and clinical findings of N-methylated tryptamines and highlight new and upcoming therapeutic strategies that may be adapted for mitigating fibrogenic diseases. Finally, I will mention recent findings for mutualistic gut bacteria influencing endogenous tryptamine signaling and metabolism. Full article

An ellagitannin-derived metabolite, Urolithin A (UA), has emerged as a potential therapeutic agent for metabolic disorders due to its antioxidant, anti-inflammatory, and mitochondrial function-improving properties, but its efficacy in protecting against ER stress remains underexplored. The endoplasmic reticulum (ER) is a cellular organelle involved in protein folding, lipid synthesis, and calcium regulation. Perturbations in these functions can lead to ER stress, which contributes to the development and progression of metabolic disorders such as metabolic-associated fatty liver disease (MAFLD). In this study, we identified a novel target protein of UA and elucidated its mechanism for alleviating palmitic acid (PA)-induced ER stress. Cellular thermal shift assay (CETSA)-LC-MS/MS analysis revealed that UA binds directly to the sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase (SERCA), an important regulator of calcium homeostasis in mitochondria-associated ER membranes (MAMs). As an agonist of SERCA, UA attenuates abnormal calcium fluctuations and ER stress in PA-treated liver cells, thereby contributing to cell survival. The lack of UA activity in SERCA knockdown cells suggests that UA regulates cellular homeostasis through its interaction with SERCA. Collectively, our results demonstrate that UA protects against PA-induced ER stress and enhances cell survival by regulating calcium homeostasis in MAMs through SERCA. This study highlights the potential of UA as a therapeutic agent for metabolic disorders associated with ER stress. Full article