Sodium–Glucose Cotransporter Inhibitors: Cellular Mechanisms Involved in the Lipid Metabolism and the Treatment of Chronic Kidney Disease Associated with Metabolic Syndrome

Antioxidants, Journal Year: 2024, Volume and Issue: 13(7), P. 768 - 768

Published: June 26, 2024

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

Language: Английский

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Huangqi and Danshen improve the chronic nephrotoxicity of Cyclosporin A by regulating lipid metabolism

Phytomedicine, Journal Year: 2025, Volume and Issue: 140, P. 156582 - 156582

Published: Feb. 26, 2025

The clinical application of cyclosporine A (CsA) is limited due to nephrotoxicity. Lipid metabolism disorders play important roles in renal injury, but their role CsA nephrotoxicity not yet clear. Huangqi (Astragalus mongholicus Bunge) and Danshen (Salvia miltiorrhiza (HD) ameliorating the CsA, mechanisms still need be fully clarified. This study innovatively aimed analyse coexpression proteins serum metabolites for identification key pathways targets. provides novel insight into mechanism by which HD ameliorates CsA-induced We utilized intervene both vivo vitro models induced CsA. For experiments, we constructed a network metabolites, was used screen pathways. To validate these findings, knocked down vivo. studies, employed MTT, Transwell, flow cytometry, immunofluorescence assays monitor epithelial-mesenchymal transition (EMT) HK-2 cells. Additionally, electron microscopy Seahorse examine effects on mitochondrial structure function. Furthermore, overexpressed Ppara further confirm improves can improve pathological damage function; regulate blood lipids, inflammation oxidative stress indicators; reduce apoptosis tissues. Joint protein metabolomics analyses revealed that two lipid metabolism-related (the PPAR signalling pathway linoleic acid pathway) were coenriched, involving six differential (Cyp2e1, Cyp4a10, Gk, Lpl, Ppara, Pck1) differentially abundant (alpha-Dimorphecolic 12,13-EpOME). Western blot verify expressed proteins. improved accumulation, as demonstrated transmission (TEM) analysis Oil Red O staining. Knockdown affected expression ACOX1 exacerbated RF. In verification significantly inhibited EMT cells overexpression promoted HD-mediated regulation function, reduced apoptosis, ameliorate through protein-serum coexpression, pathway, metabolism. HD-induced upregulation metabolism, function are mechanisms. Ppara/ACOX1/TGF-β1 axis may an this process. These findings offer potential targets future development therapeutic strategies drugs.

Language: Английский

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Identification of a Pathogenic Mutation of the Lipase Maturation Factor 1 (LMF1) Gene Causing Recurrent Pancreatitis and Requiring Critical Care

Journal of Clinical Medicine, Journal Year: 2025, Volume and Issue: 14(6), P. 1827 - 1827

Published: March 8, 2025

Background: Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder characterized by extreme hypertriglyceridemia (>1000 mg/dL), recurrent pancreatitis, and lipoprotein lipase (LPL) deficiency. Mutations in the LMF1 gene, encoding chaperone protein required for LPL maturation, can lead to combined This study reports case of 33-year-old Ecuadorian mestizo woman presenting with pancreatitis secondary severe hypertriglyceridemia, whom two variants uncertain significance (VUS) were identified. Methods: Whole-exome sequencing (WES) was performed on patient her asymptomatic son using next-generation (NGS). Data analysis included computational pathogenicity predictors (REVEL, PolyPhen, SIFT, MutationTaster, etc.). Two variants—c.1142C>T (p.Pro381Leu) c.897G>A (p.Gln299Gln)—were Their pathogenic potential assessed based allele frequency (gnomAD), bioinformatics predictions, ACMG criteria. Results: Both classified as VUS, predicted affect splicing, potentially leading loss function. The c.1142C>T variant, despite its low frequency, remains unclassified due insufficient evidence. patient’s carried one variant but asymptomatic. phenotype suggested an intermediate form between monogenic polygenic hypertriglyceridemia. Conclusions: new report LMF1-related highlighting need functional studies confirm pathogenicity. Given classification both further research elucidate their clinical significance. underscores necessity genetic biochemical approach diagnosing managing

Language: Английский

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ANGPTL3/8 is an atypical unfoldase that regulates intravascular lipolysis by catalyzing unfolding of lipoprotein lipase

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(12)

Published: March 20, 2025

Lipoprotein lipase (LPL) carries out the lipolytic processing of triglyceride-rich lipoproteins (TRL) along luminal surface capillaries. LPL activity is regulated by angiopoietin-like proteins (ANGPTL3, ANGPTL4, ANGPTL8), which control delivery TRL-derived lipid nutrients to tissues in a temporal and spatial fashion. This regulation mediates partitioning adipose tissue striated muscle according nutritional status. A complex between ANGPTL3 ANGPTL8 (ANGPTL3/8) inhibits oxidative tissues, but its mode action has remained unknown. Here, we used biophysical techniques define how ANGPTL3/8 interact with they drive inactivation. We demonstrate, mass photometry, that heterotrimer 2:1 ANGPTL3:ANGPTL8 stoichiometry homotrimer. Hydrogen–deuterium exchange spectrometry (HDX-MS) studies revealed use proximal portion their N-terminal α-helices sequences surrounding catalytic pocket LPL. That binding event triggers unfolding LPL’s α/β -hydrolase domain irreversible loss activity. The endothelial transporter protein (GPIHBP1) or heparan-sulfate proteoglycans protects from inactivation, particularly against triggered ANGPTL3. Pulse-labeling HDX-MS catalyze an ATP-independent fashion, categorizes these inhibitors as atypical unfoldases. nature explains why low plasma concentrations are effective inhibiting molar excess

Language: Английский

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Leptin‐mediated suppression of lipoprotein lipase cleavage enhances lipid uptake and facilitates lymph node metastasis in gastric cancer

Cancer Communications, Journal Year: 2024, Volume and Issue: 44(8), P. 855 - 878

Published: July 3, 2024

Abstract Background Lymph node metastasis (LNM) is the primary mode of in gastric cancer (GC). However, precise mechanisms underlying this process remain elusive. Tumor cells necessitate lipid metabolic reprogramming to facilitate metastasis, yet role lipoprotein lipase (LPL), a pivotal enzyme involved exogenous uptake, remains uncertain tumor metastasis. Therefore, aim study was investigate presence during LNM GC as well LPL process. Methods Intracellular levels were quantified using oil red O staining, BODIPY 493/503 and flow cytometry. Lipidomics analysis employed identify alterations intracellular composition following knockdown. Protein expression assessed through immunohistochemistry, Western blotting, enzyme‐linked immunosorbent assays. The mouse popliteal model utilized differences LNM. Immunoprecipitation mass spectrometry examine protein associations. In vitro phosphorylation assays Phos‐tag sodium dodecyl‐sulfate polyacrylamide gel electrophoresis conducted detect angiopoietin‐like 4 (ANGPTL4) phosphorylation. Results We identified that an elevated level represents crucial characteristic node‐positive (N+) further demonstrated high‐fat diet can expedite found be significantly overexpressed N+ tissues shown by mediating dietary uptake within cells. Leptin, obesity‐related hormone, intercepted effect exerted ANGPTL4/Furin on cleavage. Circulating leptin binding receptor could induce activation inositol‐requiring enzyme‐1 (IRE1) kinase, leading ANGPTL4 at serine 30 residue subsequently reducing its affinity with LPL. Moreover, our research revealed disrupted homeostasis elevating arachidonic acid, which then triggered cyclooxygenase‐2/prostaglandin E2 (PGE2) pathway, thereby promoting lymphangiogenesis. Conclusions Leptin‐induced facilitates LPL‐mediated consequently stimulates production PGE2, ultimately facilitating GC.

Language: Английский

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Effect of life course body composition on lipids and coronary atherosclerosis mediated by inflammatory biomarkers

Free Radical Biology and Medicine, Journal Year: 2024, Volume and Issue: 227, P. 157 - 165

Published: Dec. 6, 2024

Language: Английский

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The Anti-obesity Effects of Lotus (Nelumbo nucifera Gaertn.) Seed Red Skin (Testa) Catechins by Regulating Lipoprotein Lipase Expression and Activity

Plant Foods for Human Nutrition, Journal Year: 2025, Volume and Issue: 80(1)

Published: Feb. 22, 2025

Language: Английский

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Angiopoietin-like Proteins and Lipoprotein Lipase: The Waltz Partners That Govern Triglyceride-Rich Lipoprotein Metabolism? Impact on Atherogenesis, Dietary Interventions, and Emerging Therapies

Journal of Clinical Medicine, Journal Year: 2024, Volume and Issue: 13(17), P. 5229 - 5229

Published: Sept. 4, 2024

Over 50% of patients who take statins are still at risk developing atherosclerotic cardiovascular disease (ASCVD) and do not achieve their goal LDL-C levels. This residual is largely dependent on triglyceride-rich lipoproteins (TRL) remnants. In essence, remnant cholesterol-rich chylomicron (CM) very-low-density lipoprotein (VLDL) particles play a role in atherogenesis. These remnants increase when lipase (LPL) activity inhibited. ApoCIII has been thoroughly studied as chief inhibitor therapeutic options to curb its effect available. On top apoCIII regulation LPL activity, there more precise control various tissues, which makes it easier physiologically divide the TRL burden according body’s requirements. general, oxidative tissues such skeletal cardiac muscle preferentially up lipids during fasting. Conversely, adipocytes increases significantly after feeding, while decreases concurrently. perspective addresses recent improvements our understanding circadian regulations implications. Three major tissue-specific lipolysis regulators have identified: ANGPTL3, ANGPTL4, ANGPTL8. Briefly, postprandial phase, liver ANGPTL8 acts ANGPTL3 (which released continuously from liver) inhibit heart through an endocrine mechanism. other hand, fasting, by adipocytes, inhibits adipose tissue paracrine manner. inhibitors may treatment hypertriglyceridemia. Several approaches under development. We look forward future studies clarify (a) nature hormonal nutritional factors that determine 4, 8 activities, along with what long-term impacts be expected if impaired pharmacologically; (b) quantitative hierarchy interaction regulatory actions apoCIII, apoAV, ANGPTL activity; (c) strategies for safe proper lipemia; (d) fructose restriction

Language: Английский

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Context-specific fatty acid uptake is a finely-tuned multi-level effort

Trends in Endocrinology and Metabolism, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 1, 2024

Language: Английский

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Adipocyte Angptl8 deletion improves glucose and energy metabolism and obesity associated inflammation in mice

iScience, Journal Year: 2024, Volume and Issue: 27(12), P. 111292 - 111292

Published: Nov. 9, 2024

Language: Английский

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