Tatjana Ábel

Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized as a disorder of hepatic lipid metabolic reprogramming rather than a consequence of passive triglyceride accumulation. Chronic nutrient excess, insulin resistance, adipose tissue dysfunction, and altered nutrient-sensing pathways disrupt the balance among hepatic fatty acid uptake, de novo lipogenesis, β-oxidation, lipid storage, and lipoprotein export. These changes promote the accumulation of bioactive lipid species, including saturated fatty acids, ceramides, diacylglycerols, oxidized phospholipids, and free cholesterol. Unlike triglycerides, which may serve an adaptive buffering role under conditions of preserved lipid-storage capacity, these bioactive lipids function as metabolic stress signals that impair insulin signaling, disrupt mitochondrial and endoplasmic reticulum homeostasis, activate PKC, JNK, MAPK, NF-κB, and NLRP3 pathways, and promote hepatocyte death, immune activation, and fibrogenesis. Emerging lipidomic and multi-omic approaches further demonstrate that the molecular composition and subcellular distribution of hepatic lipids may be more closely associated with disease progression than total lipid content. This review critically integrates current evidence on hepatic lipid metabolic reprogramming, lipid-mediated signaling, organelle dysfunction, fibrosis, and molecular heterogeneity in MASLD. It also evaluates the translational potential and limitations of lipidomic biomarkers and mechanism-based therapies targeting lipogenesis, nuclear receptors, ceramide metabolism, inflammatory signaling, and fibrosis. A deeper understanding of disease-specific lipid signatures and signaling networks may support molecular endotyping, mechanism-based therapeutic strategies, and precision hepatology in patients with metabolic dysfunction-associated steatohepatitis (MASH) and progressive fibrosis.

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

Type 2 diabetes mellitus (T2DM) is characterized not only by chronic hyperglycemia but also by profound adipose tissue dysfunction, including impaired lipid handling, low-grade inflammation, mitochondrial dysfunction, and extracellular matrix (ECM) remodeling. These adipose tissue alterations play a central role in the development of systemic insulin resistance, ectopic lipid accumulation, and cardiometabolic complications. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), particularly semaglutide, have emerged as highly effective therapies for T2DM and obesity. While their glucose-lowering and appetite-suppressive effects are well established, accumulating evidence indicates that semaglutide exerts pleiotropic metabolic actions that extend beyond glycemic control, with adipose tissue representing a key target organ. This review synthesizes current preclinical and clinical evidence on the molecular and cellular mechanisms through which semaglutide modulates adipose tissue biology in T2DM. We discuss depot-specific effects on visceral and subcutaneous adipose tissue, regulation of adipocyte lipid metabolism and lipolysis, enhancement of mitochondrial biogenesis and oxidative capacity, induction of beige adipocyte programming, modulation of adipokine and cytokine secretion, immunometabolic remodeling, and attenuation of adipose tissue fibrosis and ECM stiffness. Collectively, available data indicate that semaglutide promotes a functional shift in adipose tissue from a pro-inflammatory, lipid-storing phenotype toward a more oxidative, insulin-sensitive, and metabolically flexible state. These adipose-centered adaptations likely contribute to improvements in systemic insulin sensitivity, reduction in ectopic fat deposition, and attenuation of cardiometabolic risk observed in patients with T2DM. Despite compelling mechanistic insights, much of the current evidence derives from animal models or in vitro systems. Human adipose tissue-focused studies integrating molecular profiling, advanced imaging, and longitudinal clinical data are therefore needed to fully elucidate the extra-glycemic actions of semaglutide and to translate these findings into adipose-targeted therapeutic strategies.

Purpose of review: Chronic kidney disease (CKD) significantly increases the risk of atherosclerotic cardiovascular disease (ASCVD), with dyslipidemia—particularly elevated low-density lipoprotein cholesterol (LDL-C)—being a shared risk factor. While statin-based therapies are effective in early-stage CKD, their benefits in dialysis and kidney transplant patients remain inconclusive. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of lipid metabolism. This review aims to summarize the factors influencing PCSK9 levels in CKD patients and evaluate the safety and efficacy of PCSK9 inhibitors across different stages of CKD. Recent findings: Multiple factors have been associated with variations in plasma PCSK9 concentrations in CKD, including glycemic status, proteinuria, renal function, dialysis modality, lipid-lowering therapy, and circadian rhythms. PCSK9 inhibitors, such as alirocumab, evolocumab, and inclisiran, effectively reduce LDL-C and ASCVD risk in patients with mild-to-moderate CKD. However, evidence is limited in patients with advanced CKD (stages 4–5, end stage renal disease (ERSD)), particularly those undergoing dialysis. Summary: Elevated PCSK9 levels may not independently predict ASCVD risk in CKD populations. Nonetheless, PCSK9 inhibitors provide a well-tolerated and effective lipid-lowering option in early CKD. Large-scale prospective studies are warranted to clarify their role in patients with ESRD.

Previously published studies have shown that women with type 2 diabetes have a higher risk of atherosclerotic cardiovascular disease than men with type 2 diabetes. The exact reason for this is not yet known. The association between metabolic dysfunction-associated steatotic liver disease and type 2 diabetes appears to be bidirectional, meaning that the onset of one may increase the risk of the onset and progression of the other. Dyslipidemia is common in both diseases. Our aim was therefore to investigate whether there is a sex difference in the pathogenesis and management of dyslipidemia in patients with type 2 diabetes and steatotic liver disease with metabolic dysfunction. While the majority of published studies to date have found no difference between men and women in statin treatment, some studies have shown reduced effectiveness in women compared to men. Statin treatment is under-prescribed for both type 2 diabetics and patients with dysfunction-associated steatotic liver disease. No sex differences were found for ezetimibe treatment. However, to the best of our knowledge, no such study was found for fibrate treatment. Conflicting results on the efficacy of newer cholesterol-lowering PCSK9 inhibitors have been reported in women and men. Results from two real-world studies suggest that up-titration of statin dose improves the efficacy of PCSK9 inhibitors in women. Bempedoic acid treatment has been shown to be effective and safe in patients with type 2 diabetes and more effective in lipid lowering in women compared to men, based on phase 3 results published to date. Further research is needed to clarify whether the sex difference in dyslipidemia management shown in some studies plays a role in the risk of ASCVD in patients with type 2 diabetes and steatotic liver disease with metabolic dysfunction.