Search Results (507)

Ceramides are central bioactive sphingolipids that regulate diverse cellular processes, including membrane organization, energy metabolism, and stress signaling. Emerging evidence has implicated that ceramide dysregulation is associated with the onset and progression of heart failure. This review introduces the understanding of ceramide metabolism, focusing on its biosynthesis, and functional roles in cardiomyocytes. In addition, the contribution of systemic ceramides derived from circulating lipoproteins and peripheral tissues to cardiovascular risk is also discussed. In parallel, it is highlighted that cardiomyocyte-intrinsic ceramide synthesis plays physiological and pathological roles in the heart. Particularly, excessive ceramide accumulation is detrimental for cardiac function, through multiple mechanisms, such as lipotoxic effects, mitochondrial impairment, inflammation, and cell death. The current review discusses the potential diagnostic and therapeutic strategies targeting ceramide metabolism, as well as the open questions about ceramide association with heart disease. Full article

Diabetic nephropathy and diabetic atherosclerosis often develop together and share similar metabolic disturbances. Lipid abnormalities are common in diabetes, yet their roles in kidney and vascular injury are not fully understood. In diabetic kidney disease, altered lipid uptake, reduced fatty acid oxidation, and accumulation of harmful lipid species contribute to cellular stress, mitochondrial injury, inflammation, and fibrosis. In parallel, disordered lipid handling in the vasculature promotes endothelial dysfunction and atherosclerotic plaque development. However, not all lipid accumulation appears to be detrimental, and some findings suggest adaptive or context-dependent effects, leading to inconsistent results across studies. In this review, we summarize current evidence on lipid metabolism in diabetic nephropathy and atherosclerosis, compare shared and distinct features, and discuss ongoing controversies. We also briefly address the therapeutic relevance of targeting lipid pathways and highlight areas that require further investigation. Compared with prior reviews that mainly discussed fatty kidney as an emerging concept in chronic kidney disease research, this review specifically focuses on diabetic kidney disease and integrates kidney-specific lipid trafficking, kidney–vessel crosstalk, conflicting evidence, and mechanism-based therapeutic implications. Full article

Hepatocellular carcinoma (HCC) represents a major global health challenge and the third leading cause of cancer-related mortality worldwide. Its epidemiological burden is rapidly increasing, largely driven by the rising prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), which is now recognized as the most common chronic liver disease globally. Notably, MASLD frequently coexists with type 2 diabetes mellitus (T2DM), sharing several features, including the interplay of common genetic, metabolic, and environmental factors, thus contributing to a complex multifactorial pathogenesis. Relevantly, patients affected by both conditions represent a subgroup at particularly high risk of liver disease progression and hepatocarcinogenesis. In this population, metabolic and inflammatory disturbances act synergistically to create a pro-tumorigenic hepatic environment where insulin resistance (IR) plays a crucial role, by driving hepatic lipotoxicity, mitochondrial dysfunction, and inflammatory signaling with oxidative stress, thereby establishing a permissive environment for worsening steatosis and malignant transformation. Increasing evidence supports the concept of MASLD as a multisystem disorder reflecting the systemic nature of metabolic dysfunction. Within this framework, beyond IR, extrahepatic factors have also emerged as important contributors to steatosis progression, worsening of T2DM, and modulation of HCC risk. In particular, the gut–liver axis has gained recognition as a key regulator of hepatic homeostasis, integrating signals from the intestinal microbiota, immune responses, and metabolic pathways. Dysregulation of this crosstalk promotes systemic inflammation and metabolic imbalance, exacerbating IR and fostering a pro-oncogenic hepatic environment. This review examines the interconnected metabolic and immune mechanisms linking IR and gut–liver axis dysfunction to HCC development in patients with MASLD and T2DM, highlighting their implications for risk stratification and precision-based therapeutic strategies. Full article

Diabetes and related metabolic disorders, including metabolic dysfunction-associated steatotic liver disease (MASLD), are increasingly recognized as diseases of inter-organ metabolic dysregulation rather than disorders of a single organ. The core of this process is the liver–pancreas axis, which integrates metabolic signals to maintain glucose and lipid homeostasis. Under physiological conditions, insulin and glucagon work together to regulate glucose production in the liver. The liver, in turn, regulates pancreatic β-cell function through hepatokines, metabolites and extracellular vesicles. Axis disorder driven by liver insulin resistance, lipid accumulation, inflammation or changes in hepatokine secretion exacerbates β-cell dysfunction, glucotoxicity and lipotoxic stress, thereby accelerating disease progression. This imbalance is involved in the pathogenesis of type 2 diabetes, type 1 diabetes, gestational diabetes, and monogenic diabetes, and makes MASLD a driving factor and early predictor of diabetes onset. This review summarizes the key molecular mechanisms behind liver–pancreas crosstalk and explores potential therapeutic strategies aimed at restoring coordinated metabolic regulation between the organs. Full article

Gypenoside XLIX is a bioactive saponin with reported diverse biological activities, including antioxidant, regulation of cell growth, immune responses, and metabolic regulatory properties. The increasing global prevalence of non-alcoholic fatty liver disease (NAFLD) underscores the importance of exploring novel therapeutic agents such as Gypenoside XLIX. NAFLD pathogenesis involves lipotoxicity, oxidative stress, and mitochondrial dysfunction, in which mitochondria-associated endoplasmic reticulum membranes (MAMs) play a critical role in organelle communication, calcium signaling, and lipid metabolism. This narrative review summarizes current evidence indicating that Gypenoside XLIX may modulate oxidative stress, restore mitochondrial membrane potential, and regulate calcium homeostasis, thereby indirectly influencing MAM integrity and function. These effects can reduce lipid accumulation, improve hepatocellular metabolism, and attenuate inflammatory responses. This review evaluates the mechanistic impact and function of Gypenoside XLIX on MAM integrity and its effects on NAFLD. However, there is limited direct experimental evidence linking Gypenoside XLIX to MAM regulation, and further studies are required to validate its mechanisms and therapeutic potential in clinical settings. Full article

Background: Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality among individuals with type 2 diabetes mellitus (T2DM). Although women generally exhibit a more favorable cardiovascular risk profile than men in the general population, this protection is substantially reduced in the presence of diabetes, resulting in a disproportionately greater relative increase in CVD risk among women. Objective: This review aims to integrate the roles of metabolic phenotypes, dietary exposures, and genetic susceptibility in shaping cardiovascular risk in women with T2DM, with a focus on diet–gene and diet–epigenetic interactions across critical stages of the female life course. Methods: A narrative review of epidemiological, clinical, and mechanistic evidence from recent literature was conducted to synthesize current knowledge on sex-specific cardiometabolic pathways and nutritional determinants of vascular risk in T2DM. Results: Current evidence indicates that several interconnected mechanisms contribute to enhanced cardiovascular vulnerability in diabetic women, including (i) adipose tissue dysfunction and ectopic fat accumulation; (ii) insulin resistance with metabolic inflexibility and lipotoxicity; and (iii) endothelial and microvascular dysfunction driven by impaired nitric oxide signaling. Dietary patterns modulate these pathways through effects on inflammation, oxidative stress, postprandial lipid metabolism, and vascular function. Emerging evidence highlights that genetic variants (e.g., APOE; CETP; TCF7L2) significantly modify metabolic responses to dietary exposures in patients with T2DM; supporting a role for nutrigenetic interactions in shaping cardiovascular risk. In parallel, diet-related epigenetic mechanisms—including metabolic memory and early-life programming—may contribute to long-term and potentially intergenerational cardiometabolic risk. Conclusions: Integrating dietary patterns with genetic susceptibility and epigenetic regulation provides a mechanistic framework for understanding the disproportionate cardiovascular risk in diabetic women and supports the development of sex-specific, life-course-oriented precision nutrition strategies for cardiovascular risk reduction Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), is the most common chronic liver disease in the world. The disease progresses from steatosis to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, and hepatocellular carcinoma. The modern concept of “multiple parallel hits” interprets disease progression as the result of the synergistic action of lipotoxicity, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, proinflammatory signals, and gut–liver axis dysfunction. Against the background of the limited translation of preclinical data from animal models due to interspecies differences, the importance of human-oriented in vitro platforms compatible with controlled design and high-throughput screening is increasing. The current review analyzes MASLD models based on the HepG2 cell line, systematizing steatosis induction protocols, evaluating the metabolic characteristics and limitations of this cell, and comparing 2D monocultures, 3D systems, and co-cultures. HepG2 has been shown to demonstrate a predictable steatogenic response to free fatty acids (FFAs) and is convenient for reproducing early stages of pathogenesis and primary pharmacological selection of compounds. At the same time, key limitations of the model are highlighted, namely tumor origin, glycolytic shift (Warburg effect), reduced β-oxidation, impaired very-low-density lipoprotein (VLDL) assembly and secretion, and sharply reduced cytochrome P450 (CYP450) activity, as well as limited reproducibility of fructose-induced de novo lipogenesis (DNL). Comparative analysis demonstrates an increase in physiological relevance with the transition from 2D to 3D and multicomponent co-cultures, accompanied by increased complexity and cost, but allowing for the modeling of inflammation and fibrogenesis. The review justifies approaches to selecting the appropriate platform based on the specific research task. Full article

Nutrient-sensing nuclear receptors (NSNRs), including PPARs, FXR, LXRs, RAR/RXR, VDR, and related orphan receptors, integrate a molecular interface that allows diet to communicate directly with the genome. By binding fatty acids, bile acids, sterols, vitamins, polyphenols, and other food-derived metabolites, NSNRs translate qualitative and quantitative features of the diet into coordinated transcriptional programmes across metabolically active organs. This ligand-dependent signalling network integrates dietary information to orchestrate inter-organ lipid and glucose metabolism, mitochondrial function, thermogenesis, and immune response, thereby enabling the organism to adapt dynamically to fasting–feeding cycles. In this review, we synthesise current evidence on the integrated roles of major NSNRs in the liver, skeletal muscle, white and brown adipose tissue, and kidney, emphasising how receptor networks within and between metabolic organs collectively govern energy expenditure, substrate partitioning, and systemic metabolic flexibility. We propose a conceptual framework in which diet functions as an “external endocrine organ”, acting as the primary source of chemically diverse NSNR ligands, while metabolic tissues serve as secondary signal amplifiers and integrators. Through circulating lipid species, bile acids, oxysterols, and other metabolites, these organs engage in continuous bidirectional communication that reprograms NSNR activity across tissues. We then examine how the global shift from minimally processed, nutrient-rich foods to nutrient-poor, energy-dense ultra-processed diets leads to a reduction in NSNR ligand diversity, promoting hepatic steatosis, muscle metabolic inflexibility, adipose tissue dysfunction, renal lipotoxicity, and chronic low-grade inflammation, ultimately causing obesity, type 2 diabetes, and cardiometabolic disease. Finally, we explore strategies to restore NSNR function, including Mediterranean and plant-based dietary patterns, as well as diets enriched with ω-3 polyunsaturated fatty acids, monounsaturated fats, and polyphenols. By integrating molecular, physiological, and clinical evidence, this review aims to clarify how NSNR networks translate dietary cues into coordinated inter-organ metabolism and how nutrient-poor diets lead to metabolic diseases trough a loss of metabolic information, rather than merely by energy excess. This framework supports a paradigm shift from calorie-centred nutrition to diet quality as the main therapeutic target for preventing metabolic diseases and promoting health. Full article

Background: Metabolic syndrome (MetS) and alcohol-related liver disease (ALD) are increasingly recognized as interconnected disorders linked by shared mechanisms of lifestyle-driven metabolic reprogramming. Alterations in systemic and hepatic metabolic pathways—including insulin signaling, lipid metabolism, mitochondrial bioenergetics, and redox homeostasis—reduce hepatic resilience to alcohol exposure and accelerate liver disease progression. Objective: This narrative review aims to integrate clinical, epidemiological, and mechanistic evidence published over the past two decades to examine how modifiable lifestyle factors contribute to metabolic reprogramming linking metabolic syndrome and alcohol-related liver disease with prioritization of high-level clinical evidence (cohort studies, meta-analyses, and guidelines). Key Findings: Modifiable lifestyle exposures such as alcohol consumption, cigarette smoking, unhealthy dietary patterns, and physical inactivity converge on common metabolically mediated pathways, including insulin resistance, dysregulated lipid metabolism and lipotoxicity, mitochondrial dysfunction, oxidative stress, chronic low-grade inflammation, and gut–liver axis perturbations. These processes are reflected in altered metabolite profiles involving lipid species, bile acids, tricarboxylic acid cycle intermediates, and microbiota-derived metabolites, shaping a metabolic–hepatic continuum. Among these, alcohol consumption and metabolic dysfunction show the strongest and most consistent associations with liver disease progression, with evidence supporting synergistic rather than additive effects. Conclusions: The coexistence of metabolic dysfunction and alcohol exposure is consistently associated with synergistic worsening of liver-related outcomes, including fibrosis progression, cirrhosis, and hepatocellular carcinoma. Recognition of metabolic alcohol-related liver disease (MetALD) underscores the need for integrated lifestyle-based strategies targeting alcohol consumption, smoking cessation, dietary quality, and physical activity to modulate shared metabolic and inflammatory pathways. A metabolically informed, systems-level approach may improve risk stratification, prevention, and management across the metabolic–hepatic continuum. Full article

Atherosclerosis (AS) is the leading cause of cardiovascular disease worldwide, yet its clinical heterogeneity and close association with metabolic disorders are not fully explained by the classical “endothelial injury–lipid deposition–inflammatory amplification” paradigm. In this review, we introduce the PVAT–MAMs axis as a hypothesis-driven, cross-scale conceptual framework linking extravascular metabolic dysfunction to intracellular stress signaling in vascular cells. We propose that, under metabolic stress, dysfunctional perivascular adipose tissue (PVAT) may influence mitochondria-associated endoplasmic reticulum membranes (MAMs) via the release of inflammatory, lipotoxic, and oxidative mediators. Accumulating experimental and associative evidence suggests that perturbation of MAMs is associated with dysregulated calcium handling, lipid metabolism, inflammatory signaling, and redox imbalance, processes implicated in AS progression. Although direct causal relationships remain to be fully established. By synthesizing current findings, this framework provides an integrative perspective on disease heterogeneity and highlights testable pathogenic nodes spanning from PVAT to subcellular MAMs. Finally, we discuss how this conceptual axis may inform hypothesis-driven therapeutic strategies. Importantly, the PVAT–MAMs axis is presented as a hypothesis-driven conceptual model rather than an established signaling pathway, and its mechanistic architecture requires rigorous experimental and translational validation. Full article

Background: Visceral adipose tissue (VAT) and epicardial adipose tissue (EAT) are increasingly recognized as relevant contributors to cardiometabolic alterations and subclinical myocardial dysfunction, independently of overall obesity. Their pathogenic role extends beyond simple fat accumulation, encompassing inflammatory activation, lipotoxicity, and altered myocardial metabolism. Objective: This narrative review synthesizes current evidence on the relationships between VAT/EAT and myocardial strain parameters, with emphasis on subclinical cardiovascular risk detection and nutritional interventions. Methods: We conducted a comprehensive review of studies published between 2003–2025, focusing on imaging-based assessments of adipose tissue distribution and strain parameters using echocardiography, computed tomography, and cardiac magnetic resonance. Results: Increased EAT and, to a lesser extent, VAT showed significant associations with impaired global longitudinal strain (GLS) across imaging-based studies. In patients with type 2 diabetes, VAT mediated a substantial proportion of the association between insulin resistance and left ventricular dysfunction. Mediterranean diet adherence was associated with lower epicardial adipose tissue burden, while higher EAT was associated with persistent atrial fibrillation among patients with atrial fibrillation undergoing catheter ablation. Speckle-tracking echocardiography consistently showed superior prognostic value compared to ejection fraction for detecting subclinical dysfunction. Conclusions: VAT and EAT represent important mechanistic links between body composition and early myocardial dysfunction, identifiable through advanced strain imaging before clinical disease becomes apparent. These findings support the integration of multimodal cardiac imaging and nutritional interventions into cardiovascular prevention strategies, providing novel opportunities for early risk stratification and personalized treatment approaches. Full article

Diabetes mellitus is a rapidly escalating worldwide health issue that involves intricate molecular, metabolic, and systemic dysregulation. In addition to hyperglycemia, disease pathogenesis involves β-cell dysfunction, insulin resistance, mitochondrial dysfunction, endoplasmic reticulum stress (ER stress), redox imbalance, lipotoxicity, chronic inflammation, and inappropriate epigenetic modifications. New evidence also emphasizes the participation of mechanotransduction, ion channel signaling, circadian regulation, and organ cross-talk among the pancreas, liver, adipose tissue, skeletal muscle, heart, brain, and gut in modulating disease heterogeneity and progression. This review highlights updates of molecular mechanisms in diabetes, focusing on the β-cell response to stress, the AMPK–Sirtuin 1 (or PGC-1α) signaling pathway, mitochondrial quality control, mechanosensitive ion channels, immunometabolic crosstalk, and epigenetic regulation. We consider the increasing importance of multi-omics methods for early identification of pathogenic signatures and integration of artificial intelligence to enable precision stratification and therapeutic tailoring. Finally, we highlight novel experimental and translational tools, such as iPSC-derived β-cells or organoids, CRISPR-based gene editing, sophisticated metabolic imaging, and electrophysiology. Taken together, this review shifts the paradigm of diabetes as a system-level network disease and emphasizes the importance of data-driven multi-target strategies for prevention and reduction in long-term complications. Full article

Lipids are the major energy reservoir, but excessive fat accumulation drives immune cell trapping, chronic inflammation, autoimmunity, and cancer. Lipid synthesis, secretion, degradation, and the shuttling to cellular organelles and compartments are still poorly investigated in all cell types of the mammalian body. The major routes of FA uptake are dietary uptake, lipolysis, and de novo synthesis. We highlight disease associations zooming in on the Signal Transducer and Activator of Transcription 1/3/5 (STAT1/3/5) molecules in association with cytokine, growth factors, and hormone action, steering lipid metabolism. We compare STAT-lipid crosstalk from nuclear and mitochondrial perspectives, highlighting roles in immunity, metabolic diseases, and cancer, and providing insights into key regulatory mechanisms of lipid metabolism. A high degree of cellular flexibility in metabolic adaptation explains the need for fine-tuning, in which STAT molecules can function as rheostats to maintain energy equilibrium within cellular compartments. This concept bridges, e.g., high-energy flux or the Warburg effect, with the Hydride Transfer Complex upon low-energy provision. Another interesting STAT1/3/5 aspect is their Lipid droplet (LD) association and LD formation. LDs play key roles in disease initiation or progression, including autoimmunity or cancer, as well as chronic inflammatory diseases due to their role in (1) lipotoxicity, (2) cell death regulation, (3) immune system amelioration, and (4) energy provision. Finally, the therapeutic consequences of the angles are outlined, along with future research directions. Full article

Diabetic cardiomyopathy (DbCM) is an important contributor to heart failure (HF) in diabetes, occurring independently of other cardiovascular risk factors. Accumulating evidence demonstrates that cardiac lipotoxicity is a key driver of the onset and progression of DbCM and HF. Myocardial lipid homeostasis is coordinated by multiple transcriptional regulations, signaling pathway activation, and endoplasmic reticulum-mediated management involved in lipid metabolism. In DbCM, unbalanced fatty acid (FA) influx, handling, storage, and utilization initiates lipid overload, accumulation of toxic lipid intermediates (e.g., diacylglycerols and ceramides), and activation of maladaptive response. Notably, these lipid intermediates amplify reactive oxygen species (ROS) generation, which serves as a critical link between lipotoxic signaling and mitochondrial dysfunction by promoting electron leak, mitochondrial damage, and activation of inflammatory and cell-death pathways. These processes converge on adverse remodeling and contractile impairment, accelerating DbCM progression. This review integrates mechanistic and translational evidence linking dysregulated lipid handling to DbCM and discusses the potential therapeutic strategies that target lipid abnormalities. Full article

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease worldwide. During the last few years, remarkable advances have been made in the treatment of DN. Sodium–glucose cotransporter type 2 inhibitors (SGLT2i) consistently prevent or delay albuminuria and renal failure in patients with DN. Prior research from our group highlights the Janus kinase/signal transducers and activators of transcription axis as a critical target in DN. Specifically, the administration of suppression of cytokine signaling 1 (SOCS1) mimetic peptides (MiS1) modulates aberrant signaling, resulting in profound beneficial effects on renal function and structural integrity in experimental DN. The aim of this study was to evaluate the effect of empagliflozin and MiS1 on kidney damage and its associated inflammatory, oxidative stress and lipotoxic mechanisms in an advanced type 2 DN mouse model BTBR ob/ob. Mice were treated for 7 weeks with empagliflozin and MiS1, alone or in combination, and monitored for glycemia, body weight, albuminuria, histopathological damage, podocyte loss, and gene expression related to inflammation, redox balance, and lipid metabolism. Empagliflozin or MiS1 monotherapies significantly reduced albuminuria and structural renal injury, preserved podocyte number, and downregulated genes involved in inflammatory, oxidative, and mitochondrial–lipid metabolic dysregulation, with empagliflozin additionally improving metabolic parameters. Notably, the combined therapy achieved the greatest reduction in albuminuria and histological damage with enhanced suppression of pathogenic inflammatory and metabolic pathways, resulting in superior renoprotection compared with monotherapy. These findings suggested that add-on therapy with SOCS1 peptidomimetics and SGLT2i may help mitigate residual albuminuria and renal damage in type 2 DN. Full article