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A Multi-Ancestry Genome Wide Association Study and Evaluation of Polygenic Scores of LDL-C levels.
IF 5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-02-03 DOI: 10.1016/j.jlr.2025.100752
Umm-Kulthum Ismail Umlai, Salman M Toor, Yasser A Al-Sarraj, Shaban Mohammed, Moza S H Al Hail, Ehsan Ullah, Khalid Kunji, Ayman El-Menyar, Mohammed Gomaa, Amin Jayyousi, Mohamad Saad, Nadeem Qureshi, Jassim M Al Suwaidi, Omar M E Albagha

The genetic determinants of low-density lipoprotein cholesterol (LDL-C) levels in blood have been predominantly explored in European populations and remain poorly understood in Middle Eastern populations. We investigated the genetic architecture of LDL-C variation in Qatar by conducting a genome-wide association study (GWAS) on serum LDL-C levels using whole genome sequencing data of 13,701 individuals (discovery; n=5,939, replication; n=7,762) from the population-based Qatar Biobank (QBB) cohort. We replicated 168 previously reported loci from the largest LDL-C GWAS by the Global Lipids Genetics Consortium (GLGC), with high correlation in allele frequencies (R2=0.77) and moderate correlation in effect sizes (Beta; R2=0.53). We also performed a multi-ancestry meta-analysis with the GLGC study using MR-MEGA (Meta-Regression of Multi-Ethnic Genetic Association) and identified one novel LDL-C-associated locus; rs10939663 (SLC2A9; genomic control-corrected P=1.25×10-8). Lastly, we developed Qatari-specific polygenic score (PGS) panels and tested their performance against PGS derived from other ancestries. The multi-ancestry derived PGS (PGS000888) performed best at predicting LDL-C levels, whilst the Qatari-derived PGS showed comparable performance. Overall, we report a novel variant, which may be explored further to decipher its potential role in the etiopathogenesis of cardiovascular diseases. Our findings also highlight the importance of population-based genetics in developing PGS for clinical utilization.

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引用次数: 0
Efficacy of a novel PCSK9 inhibitory peptide alone and with evinacumab in a mouse model of atherosclerosis.
IF 5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-02-03 DOI: 10.1016/j.jlr.2025.100753
José A Inia, Anita van Nieuwkoop-van Straalen, J Wouter Jukema, Bidda Rolin, Ellen Marie Staarup, Christina K Mogensen, Hans M G Princen, Anita M van den Hoek

Atherosclerosis is the major cause of cardiovascular disease. This study evaluated the effect of lipid lowering using a novel peptide inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9) and a monoclonal antibody against angiopoietin-like 3 (evinacumab), either alone or in combination in APOE*3-Leiden.CETP mice fed a Western diet. Effects on body weight, plasma lipids, atherosclerotic lesion size, severity, composition and morphology were assessed. Treatment with PCSK9 inhibitory peptide significantly decreased both cholesterol and triglycerides (-69% and -68%, respectively). Similar reductions were seen in evinacumab-treated mice (-44% and -55%, respectively). The combination of evinacumab and PCSK9 inhibitory peptide lowered these levels to a larger extent than evinacumab alone (cholesterol: -74%; triglycerides: -81%). Reductions occurred in non-HDL-C without changes in HDL-C. Atherosclerotic lesion size was significantly reduced in all treatment groups compared to vehicle controls (evinacumab: -72%; PCSK9 inhibitory peptide: -97%; combination: -98%). Similarly, all interventions improved atherosclerotic lesion severity, with more undiseased segments and fewer severe lesions. Evaluation of the composition of severe atherosclerotic plaques revealed significant improvement in lesion stability in mice treated with both evinacumab and PCSK9 inhibitory peptide, attributable to decreased macrophage content and increased collagen content. Additionally, evaluation of lipid concentrations in cynomolgus monkeys revealed the beneficial effects of the PCSK9 inhibitory peptide on total cholesterol and LDL-C levels. Together these data demonstrate that treatment with evinacumab and PCSK9 inhibitory peptide alone and in combination reduces lipids, development of atherosclerosis and improves lesion composition, making it a promising approach for treatment of atherosclerosis.

{"title":"Efficacy of a novel PCSK9 inhibitory peptide alone and with evinacumab in a mouse model of atherosclerosis.","authors":"José A Inia, Anita van Nieuwkoop-van Straalen, J Wouter Jukema, Bidda Rolin, Ellen Marie Staarup, Christina K Mogensen, Hans M G Princen, Anita M van den Hoek","doi":"10.1016/j.jlr.2025.100753","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100753","url":null,"abstract":"<p><p>Atherosclerosis is the major cause of cardiovascular disease. This study evaluated the effect of lipid lowering using a novel peptide inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9) and a monoclonal antibody against angiopoietin-like 3 (evinacumab), either alone or in combination in APOE*3-Leiden.CETP mice fed a Western diet. Effects on body weight, plasma lipids, atherosclerotic lesion size, severity, composition and morphology were assessed. Treatment with PCSK9 inhibitory peptide significantly decreased both cholesterol and triglycerides (-69% and -68%, respectively). Similar reductions were seen in evinacumab-treated mice (-44% and -55%, respectively). The combination of evinacumab and PCSK9 inhibitory peptide lowered these levels to a larger extent than evinacumab alone (cholesterol: -74%; triglycerides: -81%). Reductions occurred in non-HDL-C without changes in HDL-C. Atherosclerotic lesion size was significantly reduced in all treatment groups compared to vehicle controls (evinacumab: -72%; PCSK9 inhibitory peptide: -97%; combination: -98%). Similarly, all interventions improved atherosclerotic lesion severity, with more undiseased segments and fewer severe lesions. Evaluation of the composition of severe atherosclerotic plaques revealed significant improvement in lesion stability in mice treated with both evinacumab and PCSK9 inhibitory peptide, attributable to decreased macrophage content and increased collagen content. Additionally, evaluation of lipid concentrations in cynomolgus monkeys revealed the beneficial effects of the PCSK9 inhibitory peptide on total cholesterol and LDL-C levels. Together these data demonstrate that treatment with evinacumab and PCSK9 inhibitory peptide alone and in combination reduces lipids, development of atherosclerosis and improves lesion composition, making it a promising approach for treatment of atherosclerosis.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100753"},"PeriodicalIF":5.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Multi-layer regulation of postprandial triglyceride metabolism in response to acute cold exposure.
IF 5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-30 DOI: 10.1016/j.jlr.2025.100751
Yiliang Zhang, Shengyang Zhou, Runming Zhao, Chunyu Xiong, Yingzhen Huang, Minzhu Zhang, Yan Wang

Triglyceride-rich lipoproteins (TRLs) carry lipids in the bloodstream, where the fatty acid moieties are liberated by lipoprotein lipase (LPL) and taken up by peripheral tissues such as brown adipose tissue (BAT) and white adipose tissue (WAT), whereas the remaining cholesterol-rich remnant particles are cleared mainly by the liver. Elevated triglyceride (TG) levels and prolonged circulation of cholesterol-rich remnants are risk factors for cardiovascular diseases. Acute cold exposure decreases postprandial TG levels and is a potential therapeutic approach to treat hypertriglyceridemia. However, how acute cold exposure regulates TG metabolism remains incompletely understood. In the current study, we found that acute cold exposure simultaneously increases postprandial very-low-density lipoprotein (VLDL) production and TG clearance, with the latter playing a dominant role and resulting in decreased TG levels. Acute cold exposure increases LPL activity and TG uptake in BAT, while suppressing LPL activity and TG uptake in WAT. Mechanistically, acute cold exposure increases BAT LPL activity through transcriptional upregulation of Lpl and posttranscriptional regulation via inhibiting the hepatic insulin-ANGPTL8-ANGPTL3 axis, while suppressing WAT LPL activity through upregulation of ANGPTL4. Angptl8 knockout mice have dramatically decreased levels of circulating TG. In the absence of ANGPTL8, acute cold exposure increases rather than decreases circulating TG levels. Thus, our study reveals multi-layered regulation of acute cold response and postprandial TG metabolism, highlighting the key functions of ANGPTL3, 4, and 8 in response to acute cold exposure.

{"title":"Multi-layer regulation of postprandial triglyceride metabolism in response to acute cold exposure.","authors":"Yiliang Zhang, Shengyang Zhou, Runming Zhao, Chunyu Xiong, Yingzhen Huang, Minzhu Zhang, Yan Wang","doi":"10.1016/j.jlr.2025.100751","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100751","url":null,"abstract":"<p><p>Triglyceride-rich lipoproteins (TRLs) carry lipids in the bloodstream, where the fatty acid moieties are liberated by lipoprotein lipase (LPL) and taken up by peripheral tissues such as brown adipose tissue (BAT) and white adipose tissue (WAT), whereas the remaining cholesterol-rich remnant particles are cleared mainly by the liver. Elevated triglyceride (TG) levels and prolonged circulation of cholesterol-rich remnants are risk factors for cardiovascular diseases. Acute cold exposure decreases postprandial TG levels and is a potential therapeutic approach to treat hypertriglyceridemia. However, how acute cold exposure regulates TG metabolism remains incompletely understood. In the current study, we found that acute cold exposure simultaneously increases postprandial very-low-density lipoprotein (VLDL) production and TG clearance, with the latter playing a dominant role and resulting in decreased TG levels. Acute cold exposure increases LPL activity and TG uptake in BAT, while suppressing LPL activity and TG uptake in WAT. Mechanistically, acute cold exposure increases BAT LPL activity through transcriptional upregulation of Lpl and posttranscriptional regulation via inhibiting the hepatic insulin-ANGPTL8-ANGPTL3 axis, while suppressing WAT LPL activity through upregulation of ANGPTL4. Angptl8 knockout mice have dramatically decreased levels of circulating TG. In the absence of ANGPTL8, acute cold exposure increases rather than decreases circulating TG levels. Thus, our study reveals multi-layered regulation of acute cold response and postprandial TG metabolism, highlighting the key functions of ANGPTL3, 4, and 8 in response to acute cold exposure.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100751"},"PeriodicalIF":5.0,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Cholesterol affects the binding of proteins to phosphatidic acid without influencing its ionization properties.
IF 5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-27 DOI: 10.1016/j.jlr.2025.100749
Desmond Owusu Kwarteng, Alexander Wolf, Madisyn Langdon, Nawal Kassas, Nicolas Vitale, Edgar Eduard Kooijman

Phosphatidic acid (PA) through its unique negatively charged phosphate headgroup binds to various proteins to modulate multiple cellular events. To perform such diverse signaling functions, the ionization and charge of PA's headgroup relies on the properties of vicinal membrane lipids and changes in cellular conditions. Cholesterol has conspicuous effects on lipid properties and membrane dynamics. In eukaryotic cells, its concentration increases along the secretory pathway, reaching its highest levels towards the plasma membrane. Moreover, membrane cholesterol levels are altered in certain diseases such as Alzheimer's disease, cancer and in erythrocytes of hypercholesteremia patients. Hence, those changing levels of cholesterol could affect PA's charge and alter binding to effector protein. However, no study has investigated the direct impact of cholesterol on the ionization properties of PA. Here, we used 31P MAS NMR to explore the effects of increasing cholesterol concentrations on the chemical shifts and pKa2 of PA. We find that, while the chemical shifts of PA change significantly at high cholesterol concentrations, surprisingly, the pKa2 and charge of PA under these conditions are not modified. Furthermore, using in vitro lipid binding assays we found that higher cholesterol levels increased PA binding of the Spo20p PA sensor. Finally, in cellulo experiments demonstrated that depleting cholesterol from neurosecretory cells halts the recruitment of this sensor upon PA addition. Altogether, these data suggest that the intracellular cholesterol gradient may be an important regulator of proteins binding to PA and that a disruption of those levels in certain pathologies may also affect PA binding to its target proteins and subsequent signaling pathways.

{"title":"Cholesterol affects the binding of proteins to phosphatidic acid without influencing its ionization properties.","authors":"Desmond Owusu Kwarteng, Alexander Wolf, Madisyn Langdon, Nawal Kassas, Nicolas Vitale, Edgar Eduard Kooijman","doi":"10.1016/j.jlr.2025.100749","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100749","url":null,"abstract":"<p><p>Phosphatidic acid (PA) through its unique negatively charged phosphate headgroup binds to various proteins to modulate multiple cellular events. To perform such diverse signaling functions, the ionization and charge of PA's headgroup relies on the properties of vicinal membrane lipids and changes in cellular conditions. Cholesterol has conspicuous effects on lipid properties and membrane dynamics. In eukaryotic cells, its concentration increases along the secretory pathway, reaching its highest levels towards the plasma membrane. Moreover, membrane cholesterol levels are altered in certain diseases such as Alzheimer's disease, cancer and in erythrocytes of hypercholesteremia patients. Hence, those changing levels of cholesterol could affect PA's charge and alter binding to effector protein. However, no study has investigated the direct impact of cholesterol on the ionization properties of PA. Here, we used <sup>31</sup>P MAS NMR to explore the effects of increasing cholesterol concentrations on the chemical shifts and pKa2 of PA. We find that, while the chemical shifts of PA change significantly at high cholesterol concentrations, surprisingly, the pKa2 and charge of PA under these conditions are not modified. Furthermore, using in vitro lipid binding assays we found that higher cholesterol levels increased PA binding of the Spo20p PA sensor. Finally, in cellulo experiments demonstrated that depleting cholesterol from neurosecretory cells halts the recruitment of this sensor upon PA addition. Altogether, these data suggest that the intracellular cholesterol gradient may be an important regulator of proteins binding to PA and that a disruption of those levels in certain pathologies may also affect PA binding to its target proteins and subsequent signaling pathways.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100749"},"PeriodicalIF":5.0,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Cadmium-cardiolipin disruption of respirasome assembly and redox balance through mitochondrial membrane rigidification.
IF 5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-27 DOI: 10.1016/j.jlr.2025.100750
Nadiya Romanova, Kevin Sule, Travis Issler, Daniel Hebrok, Marcus Persicke, Frank Thévenod, Elmar J Prenner, Wing-Kee Lee

The environmental pollutant cadmium (Cd) poses a threat to human health through consumption of contaminated foodstuffs culminating in chronic nephrotoxicity. Mitochondrial dysfunction and excessive reactive oxygen species (ROS) are key to Cd cellular toxicity. Cd-lipid interactions have been less considered. We hypothesized Cd binding to the inner mitochondrial membrane (IMM) phospholipid cardiolipin (CL) and membrane rigidification underlies defective electron transfer by disrupted respiratory supercomplexes (SCs). In Cd-treated rat kidney cortex (rKC) mitoplasts, laurdan (lipid-water interface) and diphenylhexatriene (hydrophobic core) revealed increased and decreased membrane fluidity, respectively. Laurdan-loaded pure CL or IMM biomimetic (40mol% POPC, 35mol% DOPE, 20mol% TOCL, 5mol% SAPI) nanoliposomes were rigidified by 25μM Cd, which was confirmed in live-cell imaging of laurdan or di-4-ANEPPDHQ loaded human proximal convoluted tubule (HPCT) cells. Blue native gel electrophoresis evidenced ∼30% loss of I+III2+IVn SC formation after 5μM Cd for 6h in HPCTs, which was reversed by CL-binding drug MTP-131/SS-31/elamipretide (0.1μM), yet α-tocopherol-insensitive. Moreover, MTP131 attenuated Cd-induced H2O2 (∼30%) and cytochrome c release (∼25%), but not osmotic swelling, in rKC mitochondria as well as Cd-induced ROS (∼25%) in HPCTs. MTP-131 binding to IMM biomimetic nanoliposomes decreased zeta potential, prevented Cd-induced liposome size increase, and membrane rigidification reported by laurdan. Heterologous CRLS1 expression reversed Cd (5μM, 24h) cytotoxicity (∼25%) by MTT assay, Cd (5μM, 3h)-induced ROS and mitochondrial membrane rigidification by Cd (1μM, 1h) in HPCT cells. In summary, we report a novel mechanism for Cd toxicity in which Cd-CL interactions cause IMM rigidification, thereby disrupting correct SC assembly and increasing ROS.

{"title":"Cadmium-cardiolipin disruption of respirasome assembly and redox balance through mitochondrial membrane rigidification.","authors":"Nadiya Romanova, Kevin Sule, Travis Issler, Daniel Hebrok, Marcus Persicke, Frank Thévenod, Elmar J Prenner, Wing-Kee Lee","doi":"10.1016/j.jlr.2025.100750","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100750","url":null,"abstract":"<p><p>The environmental pollutant cadmium (Cd) poses a threat to human health through consumption of contaminated foodstuffs culminating in chronic nephrotoxicity. Mitochondrial dysfunction and excessive reactive oxygen species (ROS) are key to Cd cellular toxicity. Cd-lipid interactions have been less considered. We hypothesized Cd binding to the inner mitochondrial membrane (IMM) phospholipid cardiolipin (CL) and membrane rigidification underlies defective electron transfer by disrupted respiratory supercomplexes (SCs). In Cd-treated rat kidney cortex (rKC) mitoplasts, laurdan (lipid-water interface) and diphenylhexatriene (hydrophobic core) revealed increased and decreased membrane fluidity, respectively. Laurdan-loaded pure CL or IMM biomimetic (40mol% POPC, 35mol% DOPE, 20mol% TOCL, 5mol% SAPI) nanoliposomes were rigidified by 25μM Cd, which was confirmed in live-cell imaging of laurdan or di-4-ANEPPDHQ loaded human proximal convoluted tubule (HPCT) cells. Blue native gel electrophoresis evidenced ∼30% loss of I+III<sub>2</sub>+IV<sub>n</sub> SC formation after 5μM Cd for 6h in HPCTs, which was reversed by CL-binding drug MTP-131/SS-31/elamipretide (0.1μM), yet α-tocopherol-insensitive. Moreover, MTP131 attenuated Cd-induced H<sub>2</sub>O<sub>2</sub> (∼30%) and cytochrome c release (∼25%), but not osmotic swelling, in rKC mitochondria as well as Cd-induced ROS (∼25%) in HPCTs. MTP-131 binding to IMM biomimetic nanoliposomes decreased zeta potential, prevented Cd-induced liposome size increase, and membrane rigidification reported by laurdan. Heterologous CRLS1 expression reversed Cd (5μM, 24h) cytotoxicity (∼25%) by MTT assay, Cd (5μM, 3h)-induced ROS and mitochondrial membrane rigidification by Cd (1μM, 1h) in HPCT cells. In summary, we report a novel mechanism for Cd toxicity in which Cd-CL interactions cause IMM rigidification, thereby disrupting correct SC assembly and increasing ROS.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100750"},"PeriodicalIF":5.0,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Taurine alleviates dysfunction of cholesterol metabolism under hyperuricemia by inhibiting A2AR-SREBP-2/CREB/HMGCR axis.
IF 5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-21 DOI: 10.1016/j.jlr.2025.100746
Beibei Chen, Ruixia Bao, Jujie Pan, Zicheng Zhu, Qian Chen, Dan Wang, Yuzheng Wu, Haiyang Yu, Yi Zhang, Tao Wang

Dysfunctional cholesterol metabolism is highly prevalent in patients with hyperuricemia. Both uric acid and cholesterol are independent risk factors for atherosclerosis, contributing to an increased incidence of cardiovascular disease in hyperuricemia. Investigating the pathological mechanisms underlying cholesterol metabolism dysfunction in hyperuricemia is essential. This study identified adenosine and inosine, two major purine metabolites, as key regulators of cholesterol biosynthesis. These metabolites up-regulate 3-hydroxy-3-methylglutaryl-CoA (HMGCR). Further mechanistic studies revealed that adenosine/inosine up-regulated the expression of HMGCR by activating adenosine A2A receptor (A2AR) via the sterol-regulatory element binding protein 2 (SREBP-2)/CREB axis in hyperuricemia. Additionally, we found that taurine deficiency contributes to cholesterol metabolism dysfunction in hyperuricemia. Taurine administration in hyperuricemia mice significantly reduced cholesterol elevation by inhibiting A2AR. This study provides a promising strategy for treating comorbid hypercholesterolemia and hyperuricemia.

{"title":"Taurine alleviates dysfunction of cholesterol metabolism under hyperuricemia by inhibiting A2AR-SREBP-2/CREB/HMGCR axis.","authors":"Beibei Chen, Ruixia Bao, Jujie Pan, Zicheng Zhu, Qian Chen, Dan Wang, Yuzheng Wu, Haiyang Yu, Yi Zhang, Tao Wang","doi":"10.1016/j.jlr.2025.100746","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100746","url":null,"abstract":"<p><p>Dysfunctional cholesterol metabolism is highly prevalent in patients with hyperuricemia. Both uric acid and cholesterol are independent risk factors for atherosclerosis, contributing to an increased incidence of cardiovascular disease in hyperuricemia. Investigating the pathological mechanisms underlying cholesterol metabolism dysfunction in hyperuricemia is essential. This study identified adenosine and inosine, two major purine metabolites, as key regulators of cholesterol biosynthesis. These metabolites up-regulate 3-hydroxy-3-methylglutaryl-CoA (HMGCR). Further mechanistic studies revealed that adenosine/inosine up-regulated the expression of HMGCR by activating adenosine A2A receptor (A2AR) via the sterol-regulatory element binding protein 2 (SREBP-2)/CREB axis in hyperuricemia. Additionally, we found that taurine deficiency contributes to cholesterol metabolism dysfunction in hyperuricemia. Taurine administration in hyperuricemia mice significantly reduced cholesterol elevation by inhibiting A2AR. This study provides a promising strategy for treating comorbid hypercholesterolemia and hyperuricemia.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100746"},"PeriodicalIF":5.0,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Physiological accumulation of lipid droplets in newborn liver during breastfeeding is driven by TLR4 ligands. 母乳喂养期间新生儿肝脏脂滴的生理性积累是由TLR4配体驱动的。
IF 5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-13 DOI: 10.1016/j.jlr.2025.100744
Wanderson Ferreira da Silva Júnior, Karen Marques de Oliveira Costa, Hortência Maciel Castro Oliveira, Maísa Mota Antunes, Kassiana Mafra, Brenda Naemi Nakagaki, Pedro Sérgio Corradi da Silva, Júlia Duarte Megale, Sarah Campos de Sales, Douglas Carvalho Caixeta, Mário Machado Martins, Robinson Sabino-Silva, Cristina Maria Pinto de Paula, Luiz Ricardo Goulart, Rafael Machado Rezende, Gustavo Batista Menezes

Background: The liver plays a central role in fat storage, but little is known about physiological fat accumulation during early development. Here we investigated a transient surge in hepatic lipid droplets observed in newborn mice immediately after birth.

Methods: We developed a novel model to quantify liver fat content without tissue processing. Using high-resolution microscopy assessed spatial distribution of lipid droplets within hepatocytes. Lugol's iodine staining determined the timing weaning period, and milk deprivation experiments investigated the relationship between milk intake and fat accumulation. Lipidomic analysis revealed changes in the metabolic profile of the developing liver. Finally, we investigated the role of Toll-like receptor 4 (TLR4) signaling in fat storage using knockout mice and cell-specific deletion strategies.

Results: Newborn mice displayed a dramatic accumulation of hepatic lipid droplets within the first 12 hours after birth, persisting for the initial two weeks of life. This pattern coincided with exclusive milk feeding and completely abated by the 3rd week, aligning with weaning. Importantly, the observed fat accumulation shared characteristics with established models of pathological steatosis, suggesting potential biological relevance. Lipid droplets were primarily localized within the cytoplasm of hepatocytes. Milk deprivation experiments demonstrated that milk intake is the primary driver of this transient fat accumulation. Lipidomic analysis revealed significant changes in the metabolic profile of newborn livers compared to adults. Interestingly, several highly abundant lipids in newborns were identified as putative ligands for TLR4. Subsequent studies using TLR4-deficient mice and cell-specific deletion revealed that TLR4 signaling, particularly within hepatocytes, plays a critical role in driving fat storage within the newborn liver. Additionally, a potential collaboration between metabolic and immune systems was suggested by the observed effects of myeloid cell-specific TLR4 ablation.

Conclusions: This study demonstrates a unique phenomenon of transient hepatic fat accumulation in newborn mice driven by milk intake and potentially regulated by TLR4 signaling, particularly within hepatocytes.

背景:肝脏在脂肪储存中起着核心作用,但对发育早期的生理性脂肪积累知之甚少。在这里,我们研究了在新生小鼠出生后立即观察到的肝脂滴的短暂激增。方法:我们建立了一种新的模型来量化肝脏脂肪含量,而不需要组织处理。使用高分辨率显微镜评估肝细胞内脂滴的空间分布。卢戈尔碘染色法测定断奶时间,缺乳实验研究摄乳量与脂肪积累的关系。脂质组学分析揭示了发育中的肝脏代谢谱的变化。最后,我们利用敲除小鼠和细胞特异性缺失策略研究了toll样受体4 (TLR4)信号在脂肪储存中的作用。结果:新生小鼠在出生后的最初12小时内表现出肝脏脂滴的急剧积累,并持续到生命的最初两周。这种模式与纯奶喂养一致,并在第三周完全减弱,与断奶一致。重要的是,观察到的脂肪堆积与已建立的病理性脂肪变性模型具有共同的特征,表明潜在的生物学相关性。脂滴主要定位于肝细胞的细胞质内。牛奶剥夺实验表明,牛奶摄入是这种短暂脂肪积累的主要驱动因素。脂质组学分析显示,与成年人相比,新生儿肝脏代谢谱发生了显著变化。有趣的是,新生儿中几种高度丰富的脂质被认为是TLR4的配体。随后对TLR4缺陷小鼠和细胞特异性缺失的研究表明,TLR4信号,特别是肝细胞内的TLR4信号,在驱动新生儿肝脏内脂肪储存方面起着关键作用。此外,观察到骨髓细胞特异性TLR4消融的作用,表明代谢系统和免疫系统之间存在潜在的合作。结论:本研究证明了一种独特的现象,即新生小鼠肝脏脂肪的短暂积累是由牛奶摄入驱动的,并可能受到TLR4信号的调节,特别是在肝细胞内。
{"title":"Physiological accumulation of lipid droplets in newborn liver during breastfeeding is driven by TLR4 ligands.","authors":"Wanderson Ferreira da Silva Júnior, Karen Marques de Oliveira Costa, Hortência Maciel Castro Oliveira, Maísa Mota Antunes, Kassiana Mafra, Brenda Naemi Nakagaki, Pedro Sérgio Corradi da Silva, Júlia Duarte Megale, Sarah Campos de Sales, Douglas Carvalho Caixeta, Mário Machado Martins, Robinson Sabino-Silva, Cristina Maria Pinto de Paula, Luiz Ricardo Goulart, Rafael Machado Rezende, Gustavo Batista Menezes","doi":"10.1016/j.jlr.2025.100744","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100744","url":null,"abstract":"<p><strong>Background: </strong>The liver plays a central role in fat storage, but little is known about physiological fat accumulation during early development. Here we investigated a transient surge in hepatic lipid droplets observed in newborn mice immediately after birth.</p><p><strong>Methods: </strong>We developed a novel model to quantify liver fat content without tissue processing. Using high-resolution microscopy assessed spatial distribution of lipid droplets within hepatocytes. Lugol's iodine staining determined the timing weaning period, and milk deprivation experiments investigated the relationship between milk intake and fat accumulation. Lipidomic analysis revealed changes in the metabolic profile of the developing liver. Finally, we investigated the role of Toll-like receptor 4 (TLR4) signaling in fat storage using knockout mice and cell-specific deletion strategies.</p><p><strong>Results: </strong>Newborn mice displayed a dramatic accumulation of hepatic lipid droplets within the first 12 hours after birth, persisting for the initial two weeks of life. This pattern coincided with exclusive milk feeding and completely abated by the 3rd week, aligning with weaning. Importantly, the observed fat accumulation shared characteristics with established models of pathological steatosis, suggesting potential biological relevance. Lipid droplets were primarily localized within the cytoplasm of hepatocytes. Milk deprivation experiments demonstrated that milk intake is the primary driver of this transient fat accumulation. Lipidomic analysis revealed significant changes in the metabolic profile of newborn livers compared to adults. Interestingly, several highly abundant lipids in newborns were identified as putative ligands for TLR4. Subsequent studies using TLR4-deficient mice and cell-specific deletion revealed that TLR4 signaling, particularly within hepatocytes, plays a critical role in driving fat storage within the newborn liver. Additionally, a potential collaboration between metabolic and immune systems was suggested by the observed effects of myeloid cell-specific TLR4 ablation.</p><p><strong>Conclusions: </strong>This study demonstrates a unique phenomenon of transient hepatic fat accumulation in newborn mice driven by milk intake and potentially regulated by TLR4 signaling, particularly within hepatocytes.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100744"},"PeriodicalIF":5.0,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143006809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Competitive displacement of lipoprotein lipase from heparan sulfate is orchestrated by a disordered acidic cluster in GPIHBP1. 在GPIHBP1中,脂蛋白脂肪酶从硫酸肝素中竞争性置换是由一个无序的酸性簇组织的。
IF 5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-13 DOI: 10.1016/j.jlr.2025.100745
Anamika Biswas, Samina Arshid, Kristian Kølby Kristensen, Thomas J D Jørgensen, Michael Ploug

Movement of lipoprotein lipase (LPL) from myocytes or adipocytes to the capillary lumen is essential for intravascular lipolysis and plasma triglyceride homeostasis-low LPL activity in the capillary lumen causes hypertriglyceridemia. The trans-endothelial transport of LPL depends on ionic interactions with GPIHBP1's intrinsically disordered N-terminal tail, which harbors two acidic clusters at positions 5-12 and 19-30. This polyanionic tail provides a molecular switch that controls LPL detachment from heparan sulfate proteoglycans (HSPGs) by competitive displacement. When the acidic tail was neutralized in gene-edited mice, LPL remained trapped in the sub-endothelial spaces triggering hypertriglyceridemia. Due to its disordered state, the crystal structure of LPL•GPIHBP1 provided no information on these electrostatic interactions between LPL and GPIHBP1s acidic tail. In the current study, we positioned the acidic tail on LPL using zero-length crosslinking. Acidic residues at positions 19-30 in GPIHBP1 mapped to Lys445, Lys441, Lys414 and Lys407 close to the interface between the C- and N-terminal domains in LPL. Modeling this interface revealed widespread polyelectrolyte interactions spanning both LPL domains, which explains why the acidic tail stabilizes LPL activity and protein conformation. In functional assays, we showed that the acidic cluster at 19-30 also had the greatest impact on preserving LPL activity, mitigating ANGPTL4-catalyzed LPL inactivation, preventing PSCK3-mediated LPL cleavage, and, importantly, displacing LPL from HSPGs. Our current study provides key insights into the biophysical mechanism(s) orchestrating intravascular compartmentalization of LPL activity-an intriguing pathway entailing competitive displacement of HSPG-bound LPL by a disordered acidic tail in GPIHBP1.

脂蛋白脂肪酶(LPL)从肌细胞或脂肪细胞向毛细血管管腔的运动对于血管内脂解和血浆甘油三酯稳态至关重要——毛细血管管腔中LPL活性低会导致高甘油三酯血症。LPL的跨内皮转运依赖于与GPIHBP1内在无序的n端尾部的离子相互作用,其在5-12和19-30位置上包含两个酸性簇。这种聚阴离子尾部提供了一种分子开关,通过竞争位移控制LPL从硫酸肝素蛋白聚糖(HSPGs)中脱离。当酸性尾在基因编辑小鼠中被中和时,LPL仍然被困在内皮下空间中,引发高甘油三酯血症。由于无序状态,LPL•GPIHBP1的晶体结构无法提供LPL与GPIHBP1酸尾之间静电相互作用的信息。在目前的研究中,我们使用零长度交联将酸性尾定位在LPL上。GPIHBP1中19-30位的酸性残基定位于Lys445、Lys441、Lys414和Lys407,靠近LPL中C端和n端结构域之间的界面。对该界面的建模揭示了广泛的跨LPL结构域的多电解质相互作用,这解释了为什么酸性尾部稳定LPL活性和蛋白质构象。在功能分析中,我们发现19-30的酸性簇对保持LPL活性,减轻angptl4催化的LPL失活,防止psck3介导的LPL切割,以及重要的是,从HSPGs中取代LPL也有最大的影响。我们目前的研究为协调LPL活性的血管内区隔化的生物物理机制提供了关键的见解,这是一种有趣的途径,通过GPIHBP1中无序的酸性尾部导致hspg结合的LPL竞争性位移。
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引用次数: 0
A facile assay for zDHHC palmitoyl transferase activation elucidates effects of mutation and modification. 对zDHHC棕榈酰转移酶激活的一种简易试验阐明了突变和修饰的影响。
IF 5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-10 DOI: 10.1016/j.jlr.2025.100743
Naoko Adachi, Douglas T Hess, Takehiko Ueyama

At least 10% of proteins constituting the human proteome are subject to S-acylation by a long-chain fatty acid, thioesterified to a Cys thiol side chain. Fatty S-acylation (prototypically, S-palmitoylation) operates across eukaryotic phylogeny and cell type. S-palmitoylation is carried out in mammalian cells by a family of 23-24 dedicated zDHHC palmitoyl transferase enzymes, and mutation of zDHHCs is associated with a number of human pathophysiologies. Activation of the zDHHCs by auto-S-palmitoylation, the transthioesterification of the active site Cys by fatty acyl-CoA, is the necessary first step in zDHHC-mediated protein S-palmitoylation. Most prior in vitro assessments of zDHHC activation have utilized purified zDHHCs, a time- and effort-intensive approach, which removes zDHHCs from their native membrane environment. We describe here a facile assay for zDHHC activation in native membranes. We overexpressed HA-tagged wild-type or mutant zDHHCs in cultured HEK293 cells and prepared a whole membrane fraction, which was incubated with fluorescent palmitoyl CoA (NBD-palmitoyl-CoA) followed by SDS-PAGE, fluorescence imaging and western blotting for HA. We show by mutational analysis that, as assayed, zDHHC auto-S-palmitoylation by NBD-palmitoyl-CoA is limited to the active site Cys. Application of the assay revealed differential effects on zDHHC activation of posttranslational zDHHC modification, and of zDHHC mutations associated with human disease, in particular cancer. Our assay provides a facile means of assessing zDHHC activation and thus of differentiating the effects of zDHHC mutation and post-translational modification on zDHHC activation versus secondary effects on zDHHC functionality resulting from altered zDHHC interaction with substrate palmitoyl-proteins.

在构成人类蛋白质组的蛋白质中,至少有 10%的蛋白质受到长链脂肪酸的 S-酰化作用,硫酯化为 Cys 硫醇侧链。脂肪 S-酰化(原型为 S-棕榈酰化)跨越真核生物系统发育和细胞类型。在哺乳动物细胞中,S-棕榈酰化是由 23-24 种专用的 zDHHC 棕榈酰转移酶家族完成的,zDHHC 的突变与多种人类病理生理相关。通过自身-S-棕榈酰化(脂肪酰-CoA 对活性位点 Cys 的转硫酯化)激活 zDHHC 是 zDHHC 介导的蛋白质 S-棕榈酰化的必要第一步。之前对zDHHC活化的体外评估大多使用纯化的zDHHC,这种方法费时费力,而且会使zDHHC脱离原生膜环境。我们在此描述了一种在原生膜中活化zDHHC的简便检测方法。我们在培养的 HEK293 细胞中过表达了 HA 标记的野生型或突变型 zDHHCs,并制备了全膜部分,将其与荧光棕榈酰 CoA(NBD-棕榈酰-CoA)孵育,然后进行 SDS-PAGE、荧光成像和 HA 的 Western 印迹。我们通过突变分析表明,NBD-棕榈酰-CoA 的 zDHHC 自身-S-棕榈酰化作用仅限于活性位点 Cys。该检测方法的应用揭示了翻译后zDHHC修饰和与人类疾病(尤其是癌症)相关的zDHHC突变对zDHHC活化的不同影响。我们的试验提供了一种简便的方法来评估zDHHC的活化,从而区分zDHHC突变和翻译后修饰对zDHHC活化的影响,以及zDHHC与底物棕榈酰蛋白相互作用的改变对zDHHC功能的次要影响。
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引用次数: 0
Contribution of individual phospholipase A2 enzymes to the cleavage of oxidized phospholipids in human blood plasma. 单个磷脂酶A2酶对人血浆中氧化磷脂裂解的贡献
IF 5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-06 DOI: 10.1016/j.jlr.2025.100742
Philipp Jokesch, Olga Oskolkova, Maria Fedorova, Bernd Gesslbauer, Valery Bochkov

Phospholipids containing oxidized esterified PUFA residues (OxPLs) are increasingly recognized for multiple biological activities and causative involvement in disease pathogenesis. Pharmacokinetics of these compounds in blood plasma is essentially not studied. Human plasma contains both genuine phospholipases A2 [platelet activating factor acetyl hydrolase (PAF-AH) (also called Lp-PLA2) and secretory phospholipase A2] and multifunctional enzymes capable of removing sn-2 residues in native and oxidized PLs (lecithin-cholesterol acyltransferase, peroxiredoxin-6). The goal of this study was to compare relative activities of different PLA2 enzymes by analyzing cleavage of oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-phosphatidylcholine (OxPAPC) and oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-phosphatidylethanolamine (OxPAPE) by diluted plasma in the presence of enzyme inhibitors. We have found that human plasma demonstrated high total PLA2 activity against oxidized PCs and PEs. PAF-AH/Lp-PLA2 played a dominant role in LysoPC and LysoPE production as compared to other enzymes. Molecular species of oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-phosphatidylcholine and oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-phosphatidylethanolamine could be divided into three groups according to their degradation rate and sensitivity to PAF-AH/Lp-PLA2 inhibitor darapladib. Oxidatively truncated species were most rapidly metabolized in the presence of plasma; this process was strongly inhibited by darapladib. The rate of degradation of full-length OxPLs depended on the degree of oxygenation. Species containing 1 to 3 oxygen atoms were relatively stable to degradation in plasma, while OxPLs containing > 3 extra oxygens were degraded but at significantly slower rate than truncated species. In contrast to truncated species, degradation of full-length OxPLs with > 3 extra oxygens were only minimally inhibited by darapladib. These data provide further insights into the mechanisms regulating circulating levels of OxPLs and lipid mediators generated by PLA2 cleavage of OxPLs, namely oxylipins and LysoPC.

磷脂含有氧化酯化多聚脂肪酸残基(OxPLs)越来越多的认识到多种生物活性和致病参与疾病的发病机制。这些化合物在血浆中的药代动力学基本上没有研究。人血浆中含有真正的磷脂酶A2 (PAF-AH(也称为Lp-PLA2)和sPLA2)和能够去除天然和氧化PLs中sn-2残基的多功能酶(LCAT, PRDX6)。本研究的目的是通过分析在酶抑制剂存在下稀释血浆中OxPAPC和OxPAPE的裂解情况,比较不同PLA2酶的相对活性。我们发现人血浆对氧化的pc和pe表现出较高的PLA2总活性。与其他酶相比,PAF-AH/Lp-PLA2在LysoPC和LysoPE的产生中起主导作用。根据降解速率和对PAF-AH/Lp-PLA2抑制剂darapladib的敏感性,OxPAPC和OxPAPE分子种可分为3组。氧化截断种在血浆存在下代谢最快;该过程被darapladib强烈抑制。全长OxPLs的降解速率取决于氧化程度。含有1 ~ 3个氧原子的OxPLs在等离子体中降解相对稳定,而含有b> 3个额外氧原子的OxPLs降解速度明显慢于截断的OxPLs。与截断的物种相比,darapladib仅能最低限度地抑制含有bbb30额外氧的全长OxPLs的降解。这些数据进一步揭示了PLA2切割OxPLs产生的循环中OxPLs水平的调节机制和脂质介质,即氧磷脂和LysoPC。
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引用次数: 0
期刊
Journal of Lipid Research
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