Search Results (46)

Insulin resistance (IR) describes impaired hormone signaling that triggers compensatory homeostatic responses resulting in hyperinsulinemia, increased accumulation of fatty substrates, lipotoxicity, oxidative stress, inflammation, cell death and fibrosis in target tissues. These processes ultimately lead to organ dysfunction and predispose certain individuals to various types of cancer. In this context, we will review the molecular pathogenesis and clinical significance of IR, its role in ‘metaflammation’, and the damage caused by IR in the pancreas, cardiovascular system, liver, and kidneys. Additionally, we will discuss principles of drug treatment for IR and outline a research agenda in this field. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is recognized as a systemic condition that is associated with an increased prevalence of chronic kidney disease (CKD), independent of classical risk factors. This review explores MASLD and metabolic kidney dysfunction, emphasizing lipotoxicity, emerging biomarkers, and liver–kidney fat imaging techniques. Renal fat is discussed as an ectopic lipid depot that may contribute to kidney vulnerability in the same cardiometabolic milieu as MASLD. In this context, lipotoxicity, a phenomenon intensively studied in MASLD, can affect multiple nephron segments, promoting fibrosis and, ultimately, CKD. Hepatokines may support the concept of a liver–kidney metabolic axis, but human data remain limited. Tubular biomarkers show promise for detecting early renal injury, but lack validation in large populations. Hepatic steatosis is quantified through multiple validated imaging techniques such as ultrasound, elastography, and magnetic resonance imaging (MRI). In contrast, renal fat imaging studies are limited and heterogeneous, and still lack standardization. In MASLD, an integrated hepatorenal assessment is warranted to capture the full burden of the disease. Full article

Excessive accumulation of lipid droplets (LDs), their dynamics, and lipotoxicity are critical factors in the progression of metabolic disorders, including diabetic nephropathy. This study investigates the effects of yomogi tea (Mugwort tea), specifically its leaf infusion (YL) and powdered infusion (YP), on lipid metabolism in human kidney proximal tubular epithelial HK-2 cells under lipotoxic conditions induced by palmitic acid (PA). Both YL and YP significantly reduced intracellular triglyceride (TG) and free fatty acid (FFA) levels, with YP showing a trend toward greater efficacy. Mechanistic analysis revealed that yomogi tea regulates lipid metabolism by significantly downregulating mRNA expression of FAS and upregulating that of the lipolytic ATGL, while SCD-1 mRNA expression remained largely unchanged. Furthermore, yomogi tea reduced LD size and neutral lipid content, potentially enhancing lipid hydrolysis efficiency and mitigating lipotoxic effects. These findings highlight the potential of yomogi tea as a natural agent for regulating lipid metabolism and reducing lipotoxicity, offering promise for managing lipid metabolism-related disorders. Full article

Metabolic dysfunction-associated fatty liver disease (MAFLD), a recently proposed term to replace non-alcoholic fatty liver disease (NAFLD), emphasizes the critical role of metabolic dysfunction and applies broader diagnostic criteria. Diagnosis of MAFLD requires evidence of hepatic steatosis combined with obesity, type 2 diabetes mellitus, or other metabolic dysregulation conditions, all of which significantly elevate the risk of chronic kidney disease (CKD). This review discusses the pathological mechanisms of lipid accumulation and insulin resistance in MAFLD and CKD, highlighting their mechanistic connections. Specifically, ectopic fat accumulation triggered by metabolic reprogramming, oxidative stress and inflammation induced by energy overload, modified lipids, uremic toxins, and senescence, as well as insulin resistance pathways activated by pro-inflammatory factors and lipotoxic products, collectively exacerbate simultaneous hepatic and renal injury. Moreover, interactions among hyperinsulinemia, the sympathetic nervous system, the renin–angiotensin system (RAS), and altered adipokine and hepatokine profiles further amplify insulin resistance, ectopic lipid deposition, and systemic damage. Finally, the review explores potential therapeutic strategies targeting lipid metabolism, insulin sensitivity, and RAS activity, which offer promise for dual-organ protection and improved outcomes in both hepatic and renal systems. Full article

Lipotoxicity, resulting from the buildup of excess lipids in non-adipose tissues, is increasingly recognized as a major contributor to the progression of kidney disease, highlighting the need for alternative models to assess its effects on renal cells. The main aim of this study was to investigate the usefulness of Caki-1, a human proximal tubule (PT) and renal cell carcinoma (RCC) representative cell line, as a 3D model system for studying free fatty acid-induced PT lipotoxicity. Caki-1 spheroids were generated and maintained on ultra-low attachment plates and characterized regarding time-dependent morphology changes. In optimal 3D culture conditions, Caki-1 cells formed well-defined large compact spheroids with uniform morphology, good circularity, and increased diameter from days 4–12. Chronic exposure to saturated palmitate resulted in dose- and time-dependent spheroid disintegration and cell death, including dispersed and flattened spheroid morphology, with increased dead cells in the peripheral layers and decreased spheroid core. Moreover, palmitate-treated spheroids showed a significant increase in cleaved poly(ADP-ribose) polymerase (PARP) and active caspase-3. Palmitate-induced PARP cleavage, as well as endoplasmic reticulum (ER) stress and autophagy dysfunction, were blunted by triacsin C, an inhibitor of long-chain acyl-CoA synthetases. In addition, co-incubation with unsaturated oleate prevented palmitate-induced spheroid disintegration and apoptotic cell death in Caki-1 3D culture. While fatty acid overload upregulated lipid droplet protein perilipin 2 in Caki-1 cells, knockdown of perilipin 2 by siRNAs resulted in an exacerbation of palmitate-induced cell death. Together, these results indicate that the 3D Caki-1 spheroid model is a simple and reproducible in vitro system for studying renal lipotoxicity and lipid metabolism that gives useful readouts at the molecular, cellular, and multicellular levels. Full article

Parathyroid hormone-related protein (PTHrP) and retinol-binding protein 4 (RBP4) have been associated with a worse prognosis of kidney disease. Recently, the direct interconnection between PTHrP and the peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear receptor whose activation is nephroprotective, has been discovered. The aim of this study was to analyze the relationship between PTHrP, PPARγ, and RBP4. For this purpose, we analyzed the levels of these proteins, which were studied in the kidneys of five experimental groups of mice at 6 weeks of age: controls, diabetics, insulin-treated diabetics, transgenic mice overexpressing PTHrP at the renal level, and the latter mice that were also induced with diabetes. In addition, we also analyzed the expression levels of these molecules in two mouse podocyte cell lines, controls and PPARγKO, subjected to a lipotoxic insult by palmitic acid. We found that RBP4 and PTHrP are increased in the kidney in pathological conditions and that insulin and PPARγ act regulating PTHrP and RBP4 expression, suggesting that the regulation of this system is critical for the maintenance of renal homeostasis and how it becomes imbalanced in different pathophysiological conditions. Full article

Obesity has emerged as a significant public health crisis, closely linked to the pathogenesis and progression of chronic kidney disease (CKD). This review explores the intricate relationship between obesity-induced lipid metabolism disorders and renal health. We discuss how excessive free fatty acids (FFAs) lead to lipid accumulation in renal tissues, resulting in cellular lipotoxicity, oxidative stress, and inflammation, ultimately contributing to renal injury. Key molecular mechanisms, including the roles of transcriptional regulators like PPARs and SREBP-1, are examined for their implications in lipid metabolism dysregulation. The review also highlights the impact of glomerular and tubular lipid overload on kidney pathology, emphasizing the roles of podocytes and tubular cells in maintaining kidney function. Various therapeutic strategies targeting lipid metabolism, including pharmacological agents such as statins and SGLT2 inhibitors, as well as lifestyle modifications, are discussed for their potential to mitigate CKD progression in obese individuals. Future research directions are suggested to better understand the mechanisms linking lipid metabolism to kidney disease and to develop personalized therapeutic approaches. Ultimately, addressing obesity-related lipid metabolism disorders may enhance kidney health and improve outcomes for individuals suffering from CKD. Full article

Mitochondrial dysfunction is a critical factor in the pathogenesis of Alport syndrome (AS), contributing to podocyte injury and disease progression. Ezetimibe, a lipid-lowering drug, is known to inhibit cholesterol and fatty acid uptake and to reduce triglyceride content in the kidney cortex of mice with AS. However, its effects on lipid droplet (LD) utilization by mitochondria have not been explored. Transmission electron microscopy (TEM) and mitochondrial functional assays (ATP production, mitochondrial membrane potential, and citrate synthase activity) were used to investigate the impact of ezetimibe on LD–mitochondria contact formation and mitochondrial function in Col4a3KO (AS) and wildtype (WT) podocytes. TEM analysis revealed significant mitochondrial abnormalities in AS podocytes, including swollen mitochondria and reduced cristae density, while mitochondrial function assays showed decreased ATP production and lowered mitochondrial membrane potential. AS podocytes also demonstrated a higher content of LD but with reduced LD–mitochondria contact sites. Ezetimibe treatment significantly increased the number of LD–mitochondria contact sites, enhanced fatty acid transfer efficiency, and reduced intracellular lipid accumulation. These changes were associated with a marked reduction in the markers of lipotoxicity, such as apoptosis and oxidative stress. Mitochondrial function was significantly improved, evidenced by increased basal respiration, ATP production, maximal respiration capacity, and the restoration of mitochondrial membrane potential. Additionally, mitochondrial swelling was significantly reduced in ezetimibe-treated AS podocytes. Our findings reveal a novel role for ezetimibe in enhancing LD–mitochondria contact formation, leading to more efficient fatty acid transfer, reduced lipotoxicity, and improved mitochondrial function in AS podocytes. These results suggest that ezetimibe could be a promising therapeutic agent for treating mitochondrial dysfunction and lipid metabolism abnormalities in AS. Full article

Metabolic syndrome (MetS) is a multifactorial condition that significantly increases the risk of cardiovascular disease and chronic kidney disease (CKD). Recent studies have emphasized the role of lipid dysregulation in activating cellular mechanisms that contribute to CKD progression in the context of MetS. Sodium–glucose cotransporter 2 inhibitors (SGLT2i) have demonstrated efficacy in improving various components of MetS, including obesity, dyslipidemia, and insulin resistance. While SGLT2i have shown cardioprotective benefits, the underlying cellular mechanisms in MetS and CKD remain poorly studied. Therefore, this review aims to elucidate the cellular mechanisms by which SGLT2i modulate lipid metabolism and their impact on insulin resistance, mitochondrial dysfunction, oxidative stress, and CKD progression. We also explore the potential benefits of combining SGLT2i with other antidiabetic drugs. By examining the beneficial effects, molecular targets, and cytoprotective mechanisms of both natural and synthetic SGLT2i, this review provides a comprehensive understanding of their therapeutic potential in managing MetS-induced CKD. The information presented here highlights the significance of SGLT2i in addressing the complex interplay between metabolic dysregulation, lipid metabolism dysfunction, and renal impairment, offering clinicians and researchers a valuable resource for developing improved treatment strategies and personalized approaches for patients with MetS and CKD. Full article

Kidney diseases, including chronic kidney disease (CKD), diabetic nephropathy, and acute kidney injury (AKI), represent a significant global health burden. The kidneys are metabolically very active organs demanding a large amount of ATP. They are composed of highly specialized cell types in the glomerulus and subsequent tubular compartments which fine-tune metabolism to meet their numerous and diverse functions. Defective renal cell metabolism, including altered fatty acid oxidation or glycolysis, has been linked to both AKI and CKD. Mitochondria play a vital role in renal metabolism, and emerging research has identified mitochondrial sirtuins (SIRT3, SIRT4 and SIRT5) as key regulators of renal cell metabolic adaptation, especially SIRT3. Sirtuins belong to an evolutionarily conserved family of mainly NAD⁺-dependent deacetylases, deacylases, and ADP-ribosyl transferases. Their dependence on NAD⁺, used as a co-substrate, directly links their enzymatic activity to the metabolic status of the cell. In the kidney, SIRT3 has been described to play crucial roles in the regulation of mitochondrial function, and the antioxidative and antifibrotic response. SIRT3 has been found to be constantly downregulated in renal diseases. Genetic or pharmacologic upregulation of SIRT3 has also been associated with beneficial renal outcomes. Importantly, experimental pieces of evidence suggest that SIRT3 may act as an important energy sensor in renal cells by regulating the activity of key enzymes involved in metabolic adaptation. Activation of SIRT3 may thus represent an interesting strategy to ameliorate renal cell energetics. In this review, we discuss the roles of SIRT3 in lipid and glucose metabolism and in mediating a metabolic switch in a physiological and pathological context. Moreover, we highlight the emerging significance of other mitochondrial sirtuins, SIRT4 and SIRT5, in renal metabolism. Understanding the role of mitochondrial sirtuins in kidney diseases may also open new avenues for innovative and efficient therapeutic interventions and ultimately improve the management of renal injuries. Full article

Obesity is one of the main causes of chronic kidney disease; however, the precise molecular mechanisms leading to the onset of kidney injury and dysfunction in obesity-associated nephropathy remain unclear. The present study aimed to unveil the kidney microRNA (miRNA) expression profile in a model of obesity-induced kidney disease in C57BL/6J mice using next-generation sequencing (NGS) analysis. High-fat diet (HFD)-induced obesity led to notable structural alterations in tubular and glomerular regions of the kidney, increased renal expression of proinflammatory and profibrotic genes, as well as an elevated renal expression of genes involved in cellular lipid metabolism. The miRNA sequencing analysis identified a set of nine miRNAs differentially expressed in the kidney upon HFD feeding, with miR-5099, miR-551b-3p, miR-223-3p, miR-146a-3p and miR-21a-3p showing the most significant differential expression between standard diet (STD) and HFD mice. A validation analysis showed that the expression levels of miR-5099, miR-551b-3p and miR-146a-3p were consistent with NGS results, while Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses revealed that these three validated miRNAs modulated target genes involved in metabolic and adipocytokine pathways, fatty acid and lipid metabolism, and inflammatory, senescence and profibrotic pathways. Our results suggest that differentially expressed miRNAs play pivotal roles in the intricate pathophysiology of obesity-associated kidney disease and could potentially create novel treatment strategies to counteract the deleterious effects of obesity on kidney function. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its advanced subtype, metabolic dysfunction-associated steatohepatitis (MASH), have emerged as the most common chronic liver disease worldwide, yet there is no targeted pharmacotherapy presently available. This study aimed to investigate the possible in vivo function of STE20-type protein kinase MST4, which was earlier implicated in the regulation of hepatocellular lipotoxic milieu in vitro, in the control of the diet-induced impairment of systemic glucose and insulin homeostasis as well as MASLD susceptibility. Whole-body and liver-specific Mst4 knockout mice were generated by crossbreeding conditional Mst4^fl/fl mice with mice expressing Cre recombinase under the Sox2 or Alb promoters, respectively. To replicate the environment in high-risk subjects, Mst4^–/– mice and their wild-type littermates were fed a high-fat or a methionine–choline-deficient (MCD) diet. Different in vivo tests were conducted in obese mice to describe the whole-body metabolism. MASLD progression in the liver and lipotoxic damage to adipose tissue, kidney, and skeletal muscle were analyzed by histological and immunofluorescence analysis, biochemical assays, and protein and gene expression profiling. In parallel, intracellular fat storage and oxidative stress were assessed in primary mouse hepatocytes, where MST4 was silenced by small interfering RNA. We found that global MST4 depletion had no effect on body weight or composition, locomotor activity, whole-body glucose tolerance or insulin sensitivity in obese mice. Furthermore, we observed no alterations in lipotoxic injuries to the liver, adipose, kidney, or skeletal muscle tissue in high-fat diet-fed whole-body Mst4^–/– vs. wild-type mice. Liver-specific Mst4^–/– mice and wild-type littermates displayed a similar severity of MASLD when subjected to an MCD diet, as evidenced by equal levels of steatosis, inflammation, hepatic stellate cell activation, fibrosis, oxidative/ER stress, and apoptosis in the liver. In contrast, the in vitro silencing of MST4 effectively protected primary mouse hepatocytes against ectopic lipid accumulation and oxidative cell injury triggered by exposure to fatty acids. In summary, these results suggest that the genetic ablation of MST4 in mice does not mitigate the initiation or progression of MASLD and has no effect on systemic glucose or insulin homeostasis in the context of nutritional stress. The functional compensation for the genetic loss of MST4 by yet undefined mechanisms may contribute to the apparent discrepancy between in vivo and in vitro phenotypic consequences of MST4 silencing. Full article

This narrative review aims to illustrate the notion that nonalcoholic steatohepatitis (NASH), recently renamed metabolic dysfunction-associated steatohepatitis (MASH), is a systemic metabolic disorder featuring both adverse hepatic and extrahepatic outcomes. In recent years, several NASH trials have failed to identify effective pharmacological treatments and, therefore, lifestyle changes are the cornerstone of therapy for NASH. with this context, we analyze the epidemiological burden of NASH and the possible pathogenetic factors involved. These include genetic factors, insulin resistance, lipotoxicity, immuno-thrombosis, oxidative stress, reprogramming of hepatic metabolism, and hypoxia, all of which eventually culminate in low-grade chronic inflammation and increased risk of fibrosis progression. The possible explanations underlying the failure of NASH trials are also accurately examined. We conclude that the high heterogeneity of NASH, resulting from variable genetic backgrounds, exposure, and responses to different metabolic stresses, susceptibility to hepatocyte lipotoxicity, and differences in repair-response, calls for personalized medicine approaches involving research on noninvasive biomarkers. Future NASH trials should aim at achieving a complete assessment of systemic determinants, modifiers, and correlates of NASH, thus adopting a more holistic and unbiased approach, notably including cardiovascular–kidney–metabolic outcomes, without restricting therapeutic perspectives to histological surrogates of liver-related outcomes alone. Full article

Oxidative stress, a hallmark pathophysiological feature in diabetic kidney disease (DKD), arises from the intricate interplay between pro-oxidants and anti-oxidants. While hyperglycemia has been well established as a key contributor, lipotoxicity emerges as a significant instigator of oxidative stress. Lipotoxicity encompasses the accumulation of lipid intermediates, culminating in cellular dysfunction and cell death. However, the mechanisms underlying lipotoxic kidney injury in DKD still require further investigation. The key role of cell metabolism in the maintenance of cell viability and integrity in the kidney is of paramount importance to maintain proper renal function. Recently, dysfunction in energy metabolism, resulting from an imbalance in oxygen levels in the diabetic condition, may be the primary pathophysiologic pathway driving DKD. Therefore, we aim to shed light on the pivotal role of oxidative stress related to lipotoxicity and renal hypoxia in the initiation and progression of DKD. Multifaceted mechanisms underlying lipotoxicity, including oxidative stress with mitochondrial dysfunction, endoplasmic reticulum stress activated by the unfolded protein response pathway, pro-inflammation, and impaired autophagy, are delineated here. Also, we explore potential therapeutic interventions for DKD, targeting lipotoxicity- and hypoxia-induced oxidative stress. These interventions focus on ameliorating the molecular pathways of lipid accumulation within the kidney and enhancing renal metabolism in the face of lipid overload or ameliorating subsequent oxidative stress. This review highlights the significance of lipotoxicity, renal hypoxia-induced oxidative stress, and its potential for therapeutic intervention in DKD. Full article

Abnormal lipid metabolism increases the relative risk of kidney disease in patients with a single kidney. Using transcriptome analysis, we investigated whether a high-fat diet leads to abnormalities in lipid metabolism and induces kidney cell-specific damage in unilateral nephrectomy mice. Mice with unilateral nephrectomy fed a high-fat diet for 12 weeks exhibited progressive renal dysfunction in proximal tubules, including lipid accumulation, vacuolization, and cell damage. Ring finger protein 20 (RNF20) is a ligase of nuclear receptor corepressor of peroxisome proliferator-activated receptors (PPARs). The transcriptome analysis revealed the involvement of RNF20-related transcriptome changes in PPAR signaling, lipid metabolism, and water transmembrane transporter under a high-fat diet and unilateral nephrectomy. In vitro treatment of proximal tubular cells with palmitic acid induced lipotoxicity by altering RNF20, PPARα, and ATP-binding cassette subfamily A member 1 (ABCA1) expression. PPARγ and aquaporin 2 (AQP2) expression decreased in collecting duct cells, regulating genetic changes in the water reabsorption process. In conclusion, a high-fat diet induces lipid accumulation under unilateral nephrectomy via altering RNF20-mediated regulation and causing functional damage to cells as a result of abnormal lipid metabolism, thereby leading to structural and functional kidney deterioration. Full article