International Journal of Molecular Sciences

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Open AccessArticle

Leptin-Independent Association Between SNVs in the Leptin Gene and HDL-C and Apo-AI in Children

by Olga Pomares, Iris Pérez-Nadador, Francisco Javier Mejorado-Molano, Alejandro Parra-Rodríguez, Leandro Soriano-Guillén and Carmen Garcés

Int. J. Mol. Sci. 2025, 26(24), 11906; https://doi.org/10.3390/ijms262411906 - 10 Dec 2025

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Abstract

Polymorphisms in the leptin gene (LEP) have been associated with leptin levels and anthropometric variables; however, their association with lipid profiles remains under study. We aimed to determine the relationship between LEP single-nucleotide variants (SNVs) and body mass index (BMI), leptin [...] Read more.

Polymorphisms in the leptin gene (LEP) have been associated with leptin levels and anthropometric variables; however, their association with lipid profiles remains under study. We aimed to determine the relationship between LEP single-nucleotide variants (SNVs) and body mass index (BMI), leptin levels, and lipid profiles in prepubertal children. This cross-sectional study included a population-based sample of 1270 males and females aged 6-to-8 years. Lipid and leptin levels were quantified, and the SNVs G19A and G2548A were analyzed by real-time PCR using predesigned TaqMan™ Genotyping Assays. We found that both LEP SNVs were significantly associated with leptin levels after adjusting for sex. No significant associations between the studied SNVs and BMI were observed in our population. Additionally, both SNVs were associated with apolipoprotein AI (Apo-AI) levels in females, whereas G2548A was also associated with high-density lipoprotein cholesterol (HDL-C) levels after adjusting for sex. These associations remained statistically significant after adjusting for leptin levels. No association was found between SNVs and other lipid variable levels. Our results indicate that polymorphisms in the LEP gene influence not only leptin levels but also lipid metabolism, as evidenced by their association with Apo-AI and HDL-C, independent of plasma leptin concentrations. Full article

(This article belongs to the Special Issue The Role of Lipids in Health and Diseases)

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13 pages, 2101 KB

Open AccessArticle

Quantifying the Activation Barrier for Phospholipid Monolayer Fusion Governing Lipid Droplet Coalescence

by Rodion J. Molotkovsky, Zaret G. Denieva, Ivan N. Senchikhin, Ekaterina K. Urodkova, Petr V. Konarev, Georgy S. Peters, Timur R. Galimzyanov, Rais V. Pavlov and Pavel V. Bashkirov

Int. J. Mol. Sci. 2025, 26(23), 11664; https://doi.org/10.3390/ijms262311664 - 2 Dec 2025

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Abstract

Lipid droplet (LD) coalescence is a critical cellular process that reshapes lipid storage, drives metabolic disease progression, and dictates the stability of LD-mimetic drug carriers. However, the rate-limiting step—fusion of the phospholipid monolayers surrounding neutral-lipid cores—remains poorly quantified compared to bilayer fusion. Here, [...] Read more.

Lipid droplet (LD) coalescence is a critical cellular process that reshapes lipid storage, drives metabolic disease progression, and dictates the stability of LD-mimetic drug carriers. However, the rate-limiting step—fusion of the phospholipid monolayers surrounding neutral-lipid cores—remains poorly quantified compared to bilayer fusion. Here, we quantitatively determine the activation barrier for LD coalescence by tracking the kinetics in protein-free adiposome models. Using a multi-technique approach combining time-resolved dynamic light scattering and small-angle X-ray scattering, we reveal that monolayer fusion is the kinetic bottleneck. We demonstrate that lipid composition is a powerful regulator of this barrier: cone-shaped lipids (e.g., dioleoylphosphatidylethanolamine) lower the barrier and promote fusion, while phosphatidylcholine-rich monolayers enhance stability. A continuum fusion model, adapted for curved monolayers, explains these results through changes in spontaneous curvature, hydration repulsion, and stalk energetics. Our findings establish composition-dependent design rules for controlling LD dynamics in metabolic health and for engineering stable or triggerable lipid-based delivery vehicles. Full article

(This article belongs to the Special Issue The Role of Lipids in Health and Diseases)

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27 pages, 1802 KB

Open AccessArticle

The Functional Interaction Between PRDM16 and the SREBP Pathway Controls Lipid Metabolism

by Hafiz Majid Mahmood, Maria Teresa Bengoechea-Alonso, Dana E. Al-Ansari, Khaled Machaca and Johan Ericsson

Int. J. Mol. Sci. 2025, 26(21), 10246; https://doi.org/10.3390/ijms262110246 - 22 Oct 2025

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Abstract

Dysregulated lipid metabolism is associated with cardiovascular disease, obesity and type 2 diabetes. In the current report, we explore the functional interactions between two important regulators of lipid metabolism, sterol regulatory element-binding protein 1 and 2 (SREBP1/2), and PRDI-BF1 and RIZ homology domain [...] Read more.

Dysregulated lipid metabolism is associated with cardiovascular disease, obesity and type 2 diabetes. In the current report, we explore the functional interactions between two important regulators of lipid metabolism, sterol regulatory element-binding protein 1 and 2 (SREBP1/2), and PRDI-BF1 and RIZ homology domain containing 16 (PRDM16). The SREBP family of transcription factors regulate cholesterol and fatty acid synthesis and metabolism, primarily in liver but also in white adipose tissue. PRDM16 is a major regulator of brown adipose tissue (BAT) biogenesis and function as well as an inhibitor of white adipogenesis. We find that PRDM16 interacts with the nuclear forms of SREBP1/2 and inhibits their transcriptional activities. Consequently, inactivation of PRDM16 enhances the expression of well-established SREBP target genes involved in fatty acid and cholesterol synthesis/metabolism. Importantly, PRDM16 inactivation increases the expression of LDL receptor mRNA (1.6-fold) and protein (1.7-fold) and augments the cellular uptake of LDL particles (2.3-fold). Supporting these findings, PRDM16-deficient cells accumulate more neutral lipids in a SREBP1/2-dependent manner. Inactivation of PRDM16 in white and brown preadipocyte cell lines and human adipose-derived stem cells enhances the expression of SREBP target genes. In addition, the expression of adipogenic markers was increased in mature white adipocytes generated from PRDM16-knockdown preadipocytes (1.8- to 3.9-fold). Thus, our study identifies PRDM16 as a novel inhibitor of SREBP-dependent lipid metabolism with implications for adipose biology and metabolic disease. Full article

(This article belongs to the Special Issue The Role of Lipids in Health and Diseases)

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16 pages, 49683 KB

Open AccessArticle

Niemann-Pick C-like Endolysosomal Dysfunction in DHDDS Patient Cells, a Congenital Disorder of Glycosylation, Can Be Treated with Miglustat

by Hannah L. Best, Sophie R. Cook, Helen Waller-Evans and Emyr Lloyd-Evans

Int. J. Mol. Sci. 2025, 26(4), 1471; https://doi.org/10.3390/ijms26041471 - 10 Feb 2025

Cited by 2 | Viewed by 2045

Abstract

DHDDS (dehydrodolichol diphosphate synthetase) and NgBR (Nogo-B Receptor) collectively form an enzymatic complex important for the synthesis of dolichol, a key component of protein N-glycosylation. Mutations in DHDDS and the gene encoding NgBR (NUS1) are associated with neurodevelopmental disorders that clinically present [...] Read more.

DHDDS (dehydrodolichol diphosphate synthetase) and NgBR (Nogo-B Receptor) collectively form an enzymatic complex important for the synthesis of dolichol, a key component of protein N-glycosylation. Mutations in DHDDS and the gene encoding NgBR (NUS1) are associated with neurodevelopmental disorders that clinically present with epilepsy, motor impairments, and developmental delay. Previous work has demonstrated both DHDDS and NgBR can also interact with NPC2 (Niemann-Pick C (NPC) type 2), a protein which functions to traffic cholesterol out of the lysosome and, when mutated, can cause a lysosomal storage disorder (NPC disease) characterised by an accumulation of cholesterol and glycosphingolipids. Abnormal cholesterol accumulation has also been reported in cells from both individuals and animal models with mutations in NUS1, and suspected lipid storage has been shown in biopsies from individuals with mutations in DHDDS. Our findings provide further evidence for overlap between NPC2 and DHDDS disorders, showing that DHDDS patient fibroblasts have increased lysosomal volume, store cholesterol and ganglioside GM1, and have altered lysosomal Ca²⁺ homeostasis. Treatment of DHDDS cells, with the approved NPC small molecule therapy, miglustat, improves these disease-associated phenotypes, identifying a possible therapeutic option for DHDDS patients. These data suggest that treatment options currently approved for NPC disease may be translatable to DHDDS/NUS1 patients. Full article

(This article belongs to the Special Issue The Role of Lipids in Health and Diseases)

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Review

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17 pages, 1124 KB

Open AccessReview

St. John’s Wort for Depression: From Neurotransmitters to Membrane Plasticity

by Verena M. Merk, Georg Boonen and Veronika Butterweck

Int. J. Mol. Sci. 2025, 26(24), 11925; https://doi.org/10.3390/ijms262411925 - 10 Dec 2025

Viewed by 418

Abstract

Depression is a multifactorial disorder shaped by genetic, psychosocial, and biological influences, with hypotheses ranging from monoamine deficiency and neuroplasticity deficits to inflammation and stress-induced dysregulation. St. John’s wort (Hypericum perforatum L.) has long been used as an herbal antidepressant and is [...] Read more.

Depression is a multifactorial disorder shaped by genetic, psychosocial, and biological influences, with hypotheses ranging from monoamine deficiency and neuroplasticity deficits to inflammation and stress-induced dysregulation. St. John’s wort (Hypericum perforatum L.) has long been used as an herbal antidepressant and is supported by clinical evidence for efficacy and safety in mild-to-moderate depression. While its multimodal mechanisms have been linked to neurotransmitter reuptake inhibition, neuroendocrine regulation, and modulation of neuroplasticity, recent findings suggest an additional role at the membrane level. Emerging lipidomic studies highlight that Ze 117, a low-hyperforin H. perforatum extract, counteracts stress- and glucocorticoid-induced increases in membrane fluidity by modulating lipid composition and cholesterol metabolism. These effects normalize receptor mobility and signal transduction, particularly of β1-adrenoceptors, and modulate glycerophospholipid metabolism in both cellular and animal models. Such membrane-stabilizing properties may represent a novel mechanistic pathway complementing classical neurochemical actions. This review revisits the mechanisms of St. John’s wort with a special focus on its impact on membrane lipids, positioning lipidomics as a promising tool for elucidating antidepressant activity. These insights may open avenues toward personalized therapeutic strategies in depression. Full article

(This article belongs to the Special Issue The Role of Lipids in Health and Diseases)

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49 pages, 10722 KB

Open AccessReview

Triglycerides, Glucose Metabolism, and Type 2 Diabetes

by Yutang Wang

Int. J. Mol. Sci. 2025, 26(20), 9910; https://doi.org/10.3390/ijms26209910 - 11 Oct 2025

Cited by 2 | Viewed by 5081

Abstract

Type 2 diabetes is a major global health burden, causing approximately 2 million deaths annually. Recent studies have revealed a strong positive correlation between elevated triglyceride levels and plasma glucose, as well as increased prevalence, incidence, and mortality of type 2 diabetes, suggesting [...] Read more.

Type 2 diabetes is a major global health burden, causing approximately 2 million deaths annually. Recent studies have revealed a strong positive correlation between elevated triglyceride levels and plasma glucose, as well as increased prevalence, incidence, and mortality of type 2 diabetes, suggesting a potential causal link. This review explores the metabolic interconversion between triglycerides and glucose, emphasizing how excess carbohydrate intake leads to ectopic triglyceride accumulation, which in turn enhances hepatic gluconeogenesis. It highlights key signaling pathways through which ectopic triglyceride deposition drives insulin resistance, hyperinsulinemia, β-cell dysfunction and apoptosis, and increased glucose production—central mechanisms in diabetes pathogenesis. Evidence from clinical interventions, such as the reversal of type 2 diabetes through bariatric surgery and dietary energy restriction, supports the hypothesis that ectopic triglyceride accumulation is a driving factor. Furthermore, this review explains why omega-3 fatty acids and niacin, in contrast to fibrates, do not protect against type 2 diabetes, despite lowering triglycerides. Overall, this review emphasizes the contribution of ectopic triglyceride accumulation—driven by obesity, hypertriglyceridemia, excessive consumption of carbohydrates and fats, and physical inactivity—to the onset and progression of type 2 diabetes, offering valuable insights into potential therapeutic strategies. Full article

(This article belongs to the Special Issue The Role of Lipids in Health and Diseases)

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17 pages, 1628 KB

Open AccessReview

Crosstalk Between Dietary Fatty Acids and MicroRNAs in the Regulation of Hepatic ApoB-Containing Lipoprotein Synthesis in Humans

by Joanna Karbowska and Zdzislaw Kochan

Int. J. Mol. Sci. 2025, 26(10), 4817; https://doi.org/10.3390/ijms26104817 - 17 May 2025

Cited by 2 | Viewed by 1535

Abstract

Enhanced hepatic synthesis, assembly, and secretion of apolipoprotein B (ApoB)-containing lipoproteins elevate their plasma levels and—like their impaired clearance from the circulation—can increase cardiovascular risk. Both dietary fatty acids and microRNAs contribute to the nutrient-dependent regulation of hepatic gene expression. Together, these factors [...] Read more.

Enhanced hepatic synthesis, assembly, and secretion of apolipoprotein B (ApoB)-containing lipoproteins elevate their plasma levels and—like their impaired clearance from the circulation—can increase cardiovascular risk. Both dietary fatty acids and microRNAs contribute to the nutrient-dependent regulation of hepatic gene expression. Together, these factors may modulate lipid and ApoB-containing lipoprotein synthesis in the liver, either exacerbating or mitigating dyslipidemia. Research continues to reveal the complexity of fatty acid–microRNA networks and highlights differences in regulating hepatic ApoB-containing lipoprotein synthesis between humans and rodents. Consequently, this review focuses on studies conducted in humans or human-derived hepatocytes. Full article

(This article belongs to the Special Issue The Role of Lipids in Health and Diseases)

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19 pages, 742 KB

Open AccessReview

The Multifaceted Impact of Bioactive Lipids on Gut Health and Disease

by Joseph P. Sullivan and Melissa K. Jones

Int. J. Mol. Sci. 2024, 25(24), 13638; https://doi.org/10.3390/ijms252413638 - 20 Dec 2024

Cited by 6 | Viewed by 3493

Abstract

Bioactive lipids have a multifaceted role in health and disease and are recognized to play an important part in gut immunity and disease conditions such as inflammatory bowel disease and colon cancer. Advancements in lipidomics, enabled by mass spectrometry and chromatographic techniques, have [...] Read more.

Bioactive lipids have a multifaceted role in health and disease and are recognized to play an important part in gut immunity and disease conditions such as inflammatory bowel disease and colon cancer. Advancements in lipidomics, enabled by mass spectrometry and chromatographic techniques, have enhanced our understanding of lipid diversity and functionality. Bioactive lipids, including short-chain fatty acids, saturated fatty acids, omega-3 fatty acids, and sphingolipids, exhibit diverse effects on inflammation and immune regulation. Short-chain fatty acids like butyrate demonstrate anti-inflammatory properties, enhancing regulatory T cell function, gut barrier integrity, and epigenetic regulation, making them promising therapeutic targets for inflammatory bowel disease and colon cancer. Conversely, saturated fatty acids promote inflammation by disrupting gut homeostasis, triggering oxidative stress, and impairing immune regulation. Omega-3 lipids counteract these effects, reducing inflammation and supporting immune balance. Sphingolipids exhibit complex roles, modulating immune cell trafficking and inflammation. They can exert protective effects or exacerbate colitis depending on their source and context. Additionally, eicosanoids can also prevent pathology through prostaglandin defense against damage to epithelial barriers. This review underscores the importance of dietary lipids in shaping gut health and immunity and also highlights the potential use of lipids as therapeutic strategies for managing inflammatory conditions and cancer. Full article

(This article belongs to the Special Issue The Role of Lipids in Health and Diseases)

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