Journal of Lipid Research最新文献_第7页

HBV-miR-3 induces hepatic cholesterol accumulation by targeting ABCA1: Evidence for potential benefits of statin usage. HBV-miR-3通过靶向ABCA1诱导肝脏胆固醇积累：他汀类药物使用潜在益处的证据。

IF 4.1 2区医学

Journal of Lipid Research Pub Date : 2025-08-01 Epub Date: 2025-07-21 DOI: 10.1016/j.jlr.2025.100866

Shruti Chowdhari, Auroni Deep, Belal Ahmad, Jasmine Samal, Ekta Gupta, Perumal Vivekanandan

{"title":"HBV-miR-3 induces hepatic cholesterol accumulation by targeting ABCA1: Evidence for potential benefits of statin usage.","authors":"Shruti Chowdhari, Auroni Deep, Belal Ahmad, Jasmine Samal, Ekta Gupta, Perumal Vivekanandan","doi":"10.1016/j.jlr.2025.100866","DOIUrl":"10.1016/j.jlr.2025.100866","url":null,"abstract":"The cellular targets of hepatitis B virus (HBV)-encoded miRNAs remain poorly understood. The evolutionary conservation of HBV-miR-3 across HBV genotypes suggests its potential functional importance. Transcriptome profiling of HBV-miR-3 expressing hepatocytes demonstrates differential expression of several genes associated with lipid metabolic processes. The cholesterol efflux regulator gene ABCA1 was found to be downregulated in our microarray data and GEO datasets from HBV-infected liver. We validated ABCA1 as a bona fide target of HBV-miR-3. HBV-miR-3-mediated suppression of ABCA1 led to increased cholesterol and lipid droplet accumulation in addition to increased proliferation and colony formation in hepatocyte cell lines. Interestingly, widely prescribed cholesterol-lowering drugs (simvastatin, atorvastatin, and fluvastatin) could inhibit the pro-oncogenic effects of HBV-miR-3. HBV-miR-3 expression was detectable in all liver biopsies (n = 20) from patients with chronic HBV (CHBV). Patients with high intrahepatic HBV loads had higher levels of HBV-miR-3, suggesting that the virus-encoded miRNA levels correlate with virus replication. Patients with high HBV-miR-3 expression had significantly lower ABCA1 transcript levels in the liver. Hepatic steatosis was more frequently observed in biopsies of patients with high intrahepatic HBV-miR-3 levels compared to those with low HBV-miR-3 levels (71% vs. 53%), although this was not statistically significant. Taken together, our findings support the notion that HBV-miR-3-mediated suppression of ABCA1 contributes to dysregulation of lipid metabolism in CHBV infection. In sum, HBV-miR-3 may represent the \"missing link\" between CHBV and altered lipid metabolism in hepatocytes. Statin-mediated inhibition of HBV-miR-3-induced intrahepatic lipid accumulation and cell proliferation has potential clinical utility and merits further investigation.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100866"},"PeriodicalIF":4.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12391803/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144698831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Optogenetic perturbation of lipid droplet localization affects lipid metabolism and development in Drosophila. 脂滴定位的光遗传扰动影响果蝇脂质代谢和发育。

IF 4.1 2区医学

Journal of Lipid Research Pub Date : 2025-08-01 Epub Date: 2025-06-20 DOI: 10.1016/j.jlr.2025.100848

Xin Deng, Wei Wang, Dandan Peng, Luhao Zhang, Zhihao Ma, Junfen Fu, Chao Tong, Yingke Xu

{"title":"Optogenetic perturbation of lipid droplet localization affects lipid metabolism and development in Drosophila.","authors":"Xin Deng, Wei Wang, Dandan Peng, Luhao Zhang, Zhihao Ma, Junfen Fu, Chao Tong, Yingke Xu","doi":"10.1016/j.jlr.2025.100848","DOIUrl":"10.1016/j.jlr.2025.100848","url":null,"abstract":"Lipid droplets (LDs) are dynamic organelles crucial for lipid storage and homeostasis. Despite extensive documentation of their importance, the causal relationship between LD localization and function in health and disease remains inadequately understood. Here, we developed optogenetics-based tools, termed \"Opto-LDs,\" which facilitate the interaction between LDs and motor proteins in a light-dependent manner, enabling precise control of LD localization within cells. Utilizing these optogenetic modules, we demonstrated that light-induced relocation of LDs to the periphery of hepatocytes results in elevated very-low-density lipoprotein (VLDL) secretion, recapturing the beneficial effect of insulin in vitro. Furthermore, our studies in transgenic Drosophila revealed that proper LD localization is critical for embryonic development, with mistargeting of LDs significantly affecting egg hatching success. In summary, our work underscores the great importance of LD localization in lipid metabolism and development, and our developed tools offer valuable insights into the functions of LDs in health and disease.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100848"},"PeriodicalIF":4.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12302289/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144368984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Human hepatoma Huh-7 cell culture models deficient in apolipoprotein B secretion. 人肝癌Huh-7细胞培养模型缺乏载脂蛋白B分泌。

IF 4.1 2区医学

Journal of Lipid Research Pub Date : 2025-08-01 Epub Date: 2025-07-23 DOI: 10.1016/j.jlr.2025.100867

Swati Valmiki, Sara Rosario, Ashley Mooring, Chandana Prakashmurthy, Florencia Schlamp, Binu Prakash, Atrayee Chattopadhyay, Abulaish Ansari, José O Alemán, Nathalie Pamir, M Mahmood Hussain

{"title":"Human hepatoma Huh-7 cell culture models deficient in apolipoprotein B secretion.","authors":"Swati Valmiki, Sara Rosario, Ashley Mooring, Chandana Prakashmurthy, Florencia Schlamp, Binu Prakash, Atrayee Chattopadhyay, Abulaish Ansari, José O Alemán, Nathalie Pamir, M Mahmood Hussain","doi":"10.1016/j.jlr.2025.100867","DOIUrl":"10.1016/j.jlr.2025.100867","url":null,"abstract":"ApoB is an essential structural protein for the assembly and secretion of triglyceride-rich lipoproteins and therefore remains a potential target to lower plasma cholesterol levels in hypercholesterolemia patients. To understand the global consequences of APOB gene deficiency, we employed CRISPR-Cas9 system to generate apoB-deficient human hepatoma Huh-7 cells (Ako cells). ApoB was not detectable in the cells and media of the Ako cells. ApoB deficiency had no effect on microsomal triglyceride transfer protein expression and activity. These cells supported apoB48 secretion when transfected with plasmids for the expression of apoB48 suggesting that these cells retain all the lipoprotein assembly and secretion machinery except for apoB expression. APOB gene deficiency had no significant effect on cellular lipid levels, cell growth, and ER stress markers. Proteome analysis of secreted proteins revealed that the most upregulated protein was the vitamin D binding protein, while the most downregulated protein was apoB in Ako cells compared to control cells. This analysis also identified coagulation as an upregulated pathway. Total RNA transcriptome analysis identified DNA replication and complement and coagulation pathways as the most upregulated pathways in Ako cells. Further detailed studies are needed to establish how apoB regulates these pathways. These Ako cells may be useful in studying structure-function analysis of apoB peptides and to address the cellular consequences of disruptions in lipoprotein assembly and secretion.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100867"},"PeriodicalIF":4.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12396022/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

In Memoriam: Scott M. Grundy (1933-2025). 纪念：斯科特·格伦迪（1933-2025）。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2025-07-16 DOI: 10.1016/j.jlr.2025.100852

Gloria Lena Vega, Jay D Horton, Henry N Ginsberg, Paul Nestel

引用次数: 0

The origin of hydroxy-cyclohexenone fatty acids from skin barrier protein and relevance to covalent binding of ceramides. 皮肤屏障蛋白中羟基环己酮脂肪酸的来源及其与神经酰胺共价结合的关系。

IF 4.1 2区医学

Journal of Lipid Research Pub Date : 2025-07-01 Epub Date: 2025-06-14 DOI: 10.1016/j.jlr.2025.100843

Saori Noguchi, William E Boeglin, Fumie Nakashima, Donald F Stec, M Wade Calcutt, Takuya Takeichi, Masashi Akiyama, Alan R Brash

{"title":"The origin of hydroxy-cyclohexenone fatty acids from skin barrier protein and relevance to covalent binding of ceramides.","authors":"Saori Noguchi, William E Boeglin, Fumie Nakashima, Donald F Stec, M Wade Calcutt, Takuya Takeichi, Masashi Akiyama, Alan R Brash","doi":"10.1016/j.jlr.2025.100843","DOIUrl":"10.1016/j.jlr.2025.100843","url":null,"abstract":"Lipid constituents of the skin permeability barrier include a portion of ceramides and fatty acids covalently bound to the barrier protein. The covalent binding requires enzymatic oxidation of linoleate (C18:2) esterified to skin-specific acylceramides, forming a reactive 9,10-epoxy-11E-13-keto derivative. Barrier proteins treated with alkali release the bound lipids and as described recently, including two prominent cyclic linoleate derivatives, C18 hydroxy-cyclohexenone fatty acids. Herein we addressed the origin of these cyclic products by alkali treatment of potential precursors. A UV-based assay indicated the rates of Michael adduction of 9,10-epoxy-11E-13-keto to cysteine are two orders of magnitude faster than for a typical unsaturated keto fatty acid, and 10-fold faster for the dihydroxy analog, rationalizing their biosynthesis for protein adduction. Alkali treatment degraded the epoxy-ketone and its cysteinyl (glutathione) adduct to multiple UV-absorbing products, although not including the hydroxy-cyclohexenones. By contrast, these derivatives were prominently produced from KOH treatment of the 9,10-dihydroxy-13-ketone or its glutathione adduct. As further evidence of the origin of the hydroxy-cyclohexenones, LC-MS quantitation showed a 90% reduction following KOH treatment of epidermis from mice deficient in Srd9c7, the dehydrogenase in the linoleate oxidation pathway. Taken together, the results confirm the hydroxy-cyclohexenones as derivatives of the linoleate oxidations in the skin barrier pathway and identify the dihydroxy-ketone as a component of the covalently-bonded lipids, and critical to integrity of the epidermal barrier.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100843"},"PeriodicalIF":4.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12274931/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144310024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Creb3l3 deficiency promotes intestinal lipid accumulation and alters ApoB-containing lipoprotein kinetics. Creb3l3缺乏促进肠道脂质积累并改变载脂蛋白动力学。

IF 4.1 2区医学

Journal of Lipid Research Pub Date : 2025-07-01 Epub Date: 2025-05-29 DOI: 10.1016/j.jlr.2025.100833

Darby W Sweeney, Meng-Chieh Shen, Steven A Farber

{"title":"Creb3l3 deficiency promotes intestinal lipid accumulation and alters ApoB-containing lipoprotein kinetics.","authors":"Darby W Sweeney, Meng-Chieh Shen, Steven A Farber","doi":"10.1016/j.jlr.2025.100833","DOIUrl":"10.1016/j.jlr.2025.100833","url":null,"abstract":"Elevated levels of triglycerides in the bloodstream, a condition known as hypertriglyceridemia, represent a significant risk factor for the development of metabolic disorders and cardiovascular diseases. One key regulator of lipid metabolism is the transcription factor cAMP-responsive element-binding protein 3-like 3 (CREB3L3), which is expressed in the liver, intestine, and adipose tissue. CREB3L3 is localized to the endoplasmic reticulum membrane, and in vertebrates plays a crucial role in plasma lipid homeostasis. However, the precise molecular mechanisms underlying Creb3l3's influence on cellular lipid metabolism remains undefined. To address this knowledge gap, we generated zebrafish mutants lacking both creb3l3 orthologs (creb3l3a and creb3l3b). Gene expression analysis revealed that key creb3l3 target genes, such as apoC2 and apoA4, were significantly downregulated in the intestines of these double mutants. Using two zebrafish lipoprotein reporter lines, we assessed lipoprotein dynamics in creb3l3 mutants. Despite producing similar total levels of lipoproteins, creb3l3 mutants exhibited impaired lipoprotein turnover, suggesting a disruption in circulating lipid clearance. Additionally, histological analysis showed an accumulation of intestinal lipids, characterized by an increased number and size of enterocyte lipid droplets. These findings indicate that creb3l3 is essential for regulating postprandial lipid flux in enterocytes through altering the balance between lipid storage and secretion. Our study highlights a critical, unappreciated role of Creb3l3 in maintaining intestinal lipid homeostasis.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100833"},"PeriodicalIF":4.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12271627/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

An ABCB11 variant registry and novel knockin mouse model of PFIC2 based on the clinically relevant ABCB11 E297G variant. 基于临床相关ABCB11 E297G变异的ABCB11变异登记和新型PFIC2敲入小鼠模型

IF 4.1 2区医学

Journal of Lipid Research Pub Date : 2025-07-01 Epub Date: 2025-06-11 DOI: 10.1016/j.jlr.2025.100840

Eric L Bell, Jennifer K Truong, Youhwa Jo, Adrianne Kolpak, Lauren Chunn, Natalie Syverud, Melida Mahinic, Jessica R Durrant, Eitan Hoch, Bharat Reddy, Patrick Stoiber, John P Miller, Yong Ren, Jonathan Moore, Robert O Hughes, Alastair S Garfield

{"title":"An ABCB11 variant registry and novel knockin mouse model of PFIC2 based on the clinically relevant ABCB11 E297G variant.","authors":"Eric L Bell, Jennifer K Truong, Youhwa Jo, Adrianne Kolpak, Lauren Chunn, Natalie Syverud, Melida Mahinic, Jessica R Durrant, Eitan Hoch, Bharat Reddy, Patrick Stoiber, John P Miller, Yong Ren, Jonathan Moore, Robert O Hughes, Alastair S Garfield","doi":"10.1016/j.jlr.2025.100840","DOIUrl":"10.1016/j.jlr.2025.100840","url":null,"abstract":"Progressive familial intrahepatic cholestasis type 2 (PFIC2) is a rare pediatric cholestatic liver disease caused by genetic deficiency in the bile salt export pump (BSEP, ABCB11). BSEP is an ATP-binding cassette transporter and the primary regulator of hepatic bile acid efflux. Loss of BSEP function in PFIC2 leads to cholestasis and intrahepatic accumulation of bile acids, the native toxicity of which drives progressive liver injury, in a manner that correlates with ABCB11 genotype. Here, to support ongoing PFIC2 research, we present two novel translational tools, 1) a codified evidence-based catalog of published disease relevant ABCB11 mutations and 2) a knockin mouse model of the PFIC2-associated missense variant E297G. Using a combination of AI-based indexing of the literature and manual review, we identified 476 nonbenign ABCB11 variants in published patients with cholestatic disease, of which 240 were associated with PFIC2. Additionally, we present phenotypic validation of a novel knockin mouse model of the cholestasis-associated ABCB11 E297G variant. BsepE297G homozygous mice recapitulate the core molecular and pathophysiological aspects of PFIC2, including perturbed Bsep processing and membrane trafficking, cholestasis, and hepatotoxicity. Moreover, and consistent with clinical data, pharmacological ileal bile acid transporter inhibition improved the cholestatic phenotype of BsepE297G mice through increased fecal bile acid excretion. Together, these tools can support clinical and translational efforts to advance understanding and treatment of PFIC2.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100840"},"PeriodicalIF":4.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12273561/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Fentanyl-induced transformations in composition of lipid droplets in central nervous system cells revealed by ramanomics. 芬太尼诱导中枢神经系统细胞脂滴组成的转变

IF 4.1 2区医学

Journal of Lipid Research Pub Date : 2025-07-01 Epub Date: 2025-05-19 DOI: 10.1016/j.jlr.2025.100827

Rahul K Das, Andrey N Kuzmin, Artem Pliss, Supriya D Mahajan, Shobha Shukla, Paras N Prasad

{"title":"Fentanyl-induced transformations in composition of lipid droplets in central nervous system cells revealed by ramanomics.","authors":"Rahul K Das, Andrey N Kuzmin, Artem Pliss, Supriya D Mahajan, Shobha Shukla, Paras N Prasad","doi":"10.1016/j.jlr.2025.100827","DOIUrl":"10.1016/j.jlr.2025.100827","url":null,"abstract":"Quantitative characterization of the transformations of subcellular molecular environment in response to fentanyl exposure in human microglia and astrocytes is warranted to provide insight into the regulation of neuroinflammatory responses and neural survival in the scenario of opiate drug addiction. Cytoplasmic lipid droplets (LD) act as depot for exogeneous hydrophobic molecules, such as fentanyl, which can lead to increased drug accumulation and alteration of their metabolism. In the present work, we have used an emerging Ramanomics technique that combines quantitative microlipid droplets -Raman spectrometry with biomolecular component analysis to unravel fentanyl induced changes in concentrations of phospholipids, sterols, glycogen, sphingomyelin, phosphocholine as well as RNA and proteins, in the LDs of microglia and astrocytes. The clinical relevance of these findings includes the potential to advance understanding of fentanyl's impact on the central nervous system at a molecular level. The observed alterations in lipid droplet composition, including changes in phospholipids, cholesterol esters, and glycogen accumulation, suggest that fentanyl overdose disrupts cellular homeostasis in microglia and astrocytes. This disruption could contribute to neuroinflammatory responses and impaired neural function, which are critical factors in opioid addiction and withdrawal. By utilizing Ramanomics as a noninvasive, real-time analytical tool, we can better assess fentanyl-induced cellular changes, paving the way for improved diagnostic assays and therapeutic strategies for opioid addiction and overdose treatment.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100827"},"PeriodicalIF":4.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12221884/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

N-aldehyde-modified phosphatidylethanolamines generated by lipid peroxidation are robust substrates of N-acyl phosphatidylethanolamine phospholipase D. 脂质过氧化生成的n -醛修饰磷脂酰乙醇胺是n -酰基磷脂酰乙醇胺磷脂酶D的强大底物。

IF 4.1 2区医学

Journal of Lipid Research Pub Date : 2025-07-01 Epub Date: 2025-05-21 DOI: 10.1016/j.jlr.2025.100831

Reza Fadaei, Annie C Bernstein, Andrew N Jenkins, Allison G Pickens, Jonah E Zarrow, Abdul-Musawwir Alli-Oluwafuyi, Keri A Tallman, Sean S Davies

{"title":"N-aldehyde-modified phosphatidylethanolamines generated by lipid peroxidation are robust substrates of N-acyl phosphatidylethanolamine phospholipase D.","authors":"Reza Fadaei, Annie C Bernstein, Andrew N Jenkins, Allison G Pickens, Jonah E Zarrow, Abdul-Musawwir Alli-Oluwafuyi, Keri A Tallman, Sean S Davies","doi":"10.1016/j.jlr.2025.100831","DOIUrl":"10.1016/j.jlr.2025.100831","url":null,"abstract":"N-acyl phosphatidylethanolamine-hydrolyzing phospholipase D (NAPE-PLD) hydrolyzes phosphatidylethanolamines (PEs) where the headgroup nitrogen has been enzymatically modified with acyl chains of four carbons or longer (N-acyl-PEs or NAPEs). The nitrogen headgroup of PE can also be nonenzymatically modified by reactive lipid aldehydes, thus forming N-aldehyde-modified PEs (NALPEs). Some NALPEs such as N-carboxyacyl-PEs are linked to PE via amide bonds similar to NAPEs, but others are linked by imine, pyrrole, or lactam moieties. Whether NAPE-PLD can hydrolyze NALPEs was unknown. We therefore characterized the major NALPE species formed during lipid peroxidation of arachidonic acid and linoleic acid and generated various NALPEs for characterization of their sensitivity to NAPE-PLD hydrolysis by reacting synthesized aldehydes with PE. We found that NAPE-PLD could act on NALPEs of various lengths and linkage types including those derived from PE modified by N-malondialdehyde, N-4-hydroxynonenal, N-4-oxo-nonenal, N-9-keto-12-oxo-dodecenoic acid, and N-15-E2-isolevuglandin. To assess the relative preference of NAPE-PLD for various NALPEs versus its canonical NAPE substrates, we generated a substrate mixture containing roughly equimolar concentrations of seven NALPEs as well as two NAPEs (N-palmitoyl-PE and N-linoleoyl-PE) and measured their rate of hydrolysis. Several NALPE species, including the N-4-hydroxynonenal-PE pyrrole species, were hydrolyzed at a similar rate as N-linoleoyl-PE, and many of the other NALPEs showed intermediate rates of hydrolysis. These results significantly expand the substrate repertoire of NAPE-PLD and suggest that it may play an important role in clearing products of lipid peroxidation in addition to its established role in the biosynthesis of N-acyl-ethanolamines.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100831"},"PeriodicalIF":4.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12214272/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144131996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Hepatoprotective drug screening identifies daclatasvir, a promising therapeutic candidate for MASLD by targeting PLIN2. 肝保护药物筛选通过靶向PLIN2确定daclatasvir是一种有希望的MASLD治疗候选者。

IF 4.1 2区医学

Journal of Lipid Research Pub Date : 2025-07-01 Epub Date: 2025-05-29 DOI: 10.1016/j.jlr.2025.100835

Rui Shu, Song Tian, Weiyi Qu, Jinjie Yang, Wei Shi, Xinyan Li, Toujun Zou, Changjin Jiang, Yuxuan Zhang, Zifeng Yang, Han Tian, Hailong Yang, Jiajun Fu, Zhi-Gang She, Hongliang Li, Xiao-Jing Zhang

{"title":"Hepatoprotective drug screening identifies daclatasvir, a promising therapeutic candidate for MASLD by targeting PLIN2.","authors":"Rui Shu, Song Tian, Weiyi Qu, Jinjie Yang, Wei Shi, Xinyan Li, Toujun Zou, Changjin Jiang, Yuxuan Zhang, Zifeng Yang, Han Tian, Hailong Yang, Jiajun Fu, Zhi-Gang She, Hongliang Li, Xiao-Jing Zhang","doi":"10.1016/j.jlr.2025.100835","DOIUrl":"10.1016/j.jlr.2025.100835","url":null,"abstract":"Metabolic dysfunction-associated steatohepatitis (MASH) has become a global health challenge with limited therapeutic strategy. Here, this study aims to identify promising drug candidates for MASH and clarify its pharmacological mechanism. By extensive screening of FDA-approved hepatoprotective medicines using a PA/OA-stimulated hepatocytes model, we identified daclatasvir showing potent anti-MASH capacity against hepatic steatosis deposition and inflammatory response. The hepatoprotective benefits of daclatasvir were further validated in MASH mouse models, induced by a high-fat high-cholesterol (HFHC) diet for 16 weeks or a methionine-choline-deficient (MCD) diet for 4 weeks, as supported by markedly improved histopathological characteristics, serum biochemical level, and transcriptomic analyses. Using the molecular docking assay followed by isothermal titration calorimetry confirmation, we identified that daclatasvir functions as a new perilipin-2 (PLIN2) inhibitor by interrupting its stability. In specific, PLIN2 subjected to MARCH6-mediated protein degradation in a K11-type ubiquitination. Daclatasvir can directly bind to PLIN2 and enhance its interaction with MARCH6, leading to markedly strengthened PLIN2 ubiquitinational degradation and the subsequent decline in lipid droplet disintegration and lipotoxicity. The specific mutation at the binding amino acid sites of PLIN2 with daclatasvir largely abolished the anti-MASH benefit of daclatasvir. In conclusion, the findings of our study for the first time identified the anti-HCV drug daclatasvir as a novel and potent PLIN2 protein degradant for protection against MASH.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100835"},"PeriodicalIF":4.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12268039/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0