Journal of Lipid Research最新文献_第4页

The Drosophila estrogen-related receptor promotes triglyceride storage within the larval fat body. 果蝇雌激素相关受体促进甘油三酯在幼虫脂肪体内的储存。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2025-06-01 Epub Date: 2025-04-25 DOI: 10.1016/j.jlr.2025.100815

Tess D Fasteen, Melody R Hernandez, Robert A Policastro, Maria C Sterrett, Gabriel E Zenter, Jason M Tennessen

{"title":"The Drosophila estrogen-related receptor promotes triglyceride storage within the larval fat body.","authors":"Tess D Fasteen, Melody R Hernandez, Robert A Policastro, Maria C Sterrett, Gabriel E Zenter, Jason M Tennessen","doi":"10.1016/j.jlr.2025.100815","DOIUrl":"10.1016/j.jlr.2025.100815","url":null,"abstract":"The estrogen-related receptor (ERR) family of nuclear receptors serves key roles in coordinating triglyceride (TAG) accumulation with juvenile growth and development. In both insects and mammals, ERR activity promotes TAG storage during the postembryonic growth phase, with loss-of-function mutations in mouse Esrra and Drosophila melanogaster dERR inducing a lean phenotype. However, the role of insect ERRs in controlling TAG accumulation within adipose tissue remains poorly understood, as nearly all transcriptomic and metabolomic studies have relied on whole animal analyses. Here, we address this shortcoming by using tissue-specific approaches to examine the role of dERR in regulating lipid metabolism within the Drosophila larval fat body. We find that dERR autonomously promotes TAG accumulation within fat body cells and regulates expression of genes involved in glycolysis, β-oxidation, and isoprenoid metabolism. As an extension of these results, we not only discovered that dERR mutant fat bodies exhibit decreased expression of known dHNF4 target genes but also found that dHNF4 activity is decreased in dERR mutants. Overall, our findings indicate that dERR plays a multifaceted role in the larval fat body to coordinate lipid storage with carbohydrate metabolism and developmental growth.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100815"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12155637/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144006785","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

Peroxisomal ether-glycerophospholipid synthesis is dysregulated after TBI. 脑外伤后过氧化物酶体醚-甘油磷脂合成失调。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2025-06-01 Epub Date: 2025-05-07 DOI: 10.1016/j.jlr.2025.100821

Amir A Mehrabani-Tabari, Nivedita Hegdekar, Sabrina Bustos, Yulemni Morel, Yuanyuan Ji, Sazia Arefin Kachi, Olivia Pettyjohn-Robin, Sagarina Thapa, Maya Bhattiprolu, Marta M Lipinski, Jace W Jones, Chinmoy Sarkar

{"title":"Peroxisomal ether-glycerophospholipid synthesis is dysregulated after TBI.","authors":"Amir A Mehrabani-Tabari, Nivedita Hegdekar, Sabrina Bustos, Yulemni Morel, Yuanyuan Ji, Sazia Arefin Kachi, Olivia Pettyjohn-Robin, Sagarina Thapa, Maya Bhattiprolu, Marta M Lipinski, Jace W Jones, Chinmoy Sarkar","doi":"10.1016/j.jlr.2025.100821","DOIUrl":"10.1016/j.jlr.2025.100821","url":null,"abstract":"Ether-glycerophospholipids (ether-GPs), the ether bond- (- O -) containing glycerophospholipids, are major components of the brain lipidome. Ether-GPs play a crucial role in regulating neuronal function, and their deficiency has been implicated in many neurodegenerative diseases. However, how they are affected after traumatic brain injury (TBI) is not known. Our data demonstrate a significant decrease in ether-GPs abundance in the mouse cortex following controlled cortical impact (CCI)-induced TBI. This is at least in part due to the impairment of peroxisomal ether-GP synthesis in the mouse brain after TBI. We detected dysregulation of peroxisomal ether-GPs synthesizing enzymes - glyceronephosphate-O-acyltransferase (GNPAT) and alkylglycerone phosphate synthase (AGPS) in the injured mouse brains. Our data demonstrate a significant decline in GNPAT level in the peroxisomal fraction and a marked accumulation of AGPS in the cytosol of mouse cortices after TBI. To restore the ether-GP level in the injured brain, we treated TBI mice with an ether-GP precursor, 1-O-octadecylglycerol (OAG), to bypass the peroxisomal ether-GPs synthesizing steps. OAG partially restored the levels of several ether-GPs, attenuated inflammatory cytokine expression, and improved their functional recovery after TBI. Taken together, our data demonstrate that the decline in ether-GPs abundance after TBI is at least in part due to the impairment in peroxisomal ether-GPs synthesis and that restoration of ether-GPs by OAG treatment can improve TBI outcomes.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100821"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12255425/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143999908","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

Circulating lipidome underpins gender differences in the pathogenesis of type 2 diabetes. 循环脂质组支持2型糖尿病发病机制的性别差异。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2025-06-01 Epub Date: 2025-04-26 DOI: 10.1016/j.jlr.2025.100816

Madhusmita Rout, Oliver Fiehn, Dharambir K Sanghera

{"title":"Circulating lipidome underpins gender differences in the pathogenesis of type 2 diabetes.","authors":"Madhusmita Rout, Oliver Fiehn, Dharambir K Sanghera","doi":"10.1016/j.jlr.2025.100816","DOIUrl":"10.1016/j.jlr.2025.100816","url":null,"abstract":"Metabolic alterations in human lipidome significantly impact various chronic diseases including type 2 diabetes (T2D). However, epidemiology and clinical studies have yet to identify clinically meaningful lipid markers for T2D. Fatty acids (FAs) are the backbone of lipid species. However, conflicting results on the essential FAs including omega 3 and omega 6 in the development of metabolic diseases urge deeper evaluations of diverse clinical cohorts including underrepresented populations. This study investigated the lipidomics profiles of 3,000 individuals from a well-characterized cohort of Asian Indians. Untargeted lipidomic profiles were created using blood samples applying reversed-phase liquid chromatography-accurate mass tandem mass spectrometry. Free FAs and lysophosphatidylcholines (LPCs) were upregulated, while sphingomyelin and phosphatidylcholines were decreased in T2D. We observed a significant increase of essential FAs-FA20:4 (AA), FA20:5 (EPA), and FA22:6 (DHA) in T2D after adjusting for age, gender, and body mass index. However, most ω-3 and ω-6 FAs were reduced by 2 to 6-fold in obesity in both genders. We also observed gender differences in age-associated lipid patterns in which cholesterol sulfate and LPC 22:6 were elevated in all age groups in men, but LPC 22:6 rapidly increased after menopause in women, and sphingomyelins increased in men after 40 years. Machine learning analysis identified long-chain FAs, ether-based LPCs, and clinical risk scores among the most informative features associated with T2D. Our study identified lipidomic markers that could be potential mediators of T2D and obesity. Their patterns may underpin gender differences in the pathogenesis of metabolic and cardiovascular diseases.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100816"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12155659/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143999704","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

Exosome-derived miR-548ag drives hepatic lipid accumulation via upregulating FASN through inhibition of DNMT3B. 外泌体来源的miR-548ag通过抑制DNMT3B上调FASN来驱动肝脏脂质积累。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2025-06-01 Epub Date: 2025-05-06 DOI: 10.1016/j.jlr.2025.100818

Xiaolong Chu, Yanting Hou, Chaoling Peng, Wei Li, Maodi Liang, Jin Mei, Meiyu Qian, Juan Wang, Shibo Xu, Yidan Jiang, Xin Wen, Yao Chen, Fangyuan Yuan, Jianxin Xie, Cuizhe Wang, Jun Zhang

{"title":"Exosome-derived miR-548ag drives hepatic lipid accumulation via upregulating FASN through inhibition of DNMT3B.","authors":"Xiaolong Chu, Yanting Hou, Chaoling Peng, Wei Li, Maodi Liang, Jin Mei, Meiyu Qian, Juan Wang, Shibo Xu, Yidan Jiang, Xin Wen, Yao Chen, Fangyuan Yuan, Jianxin Xie, Cuizhe Wang, Jun Zhang","doi":"10.1016/j.jlr.2025.100818","DOIUrl":"10.1016/j.jlr.2025.100818","url":null,"abstract":"Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease worldwide. This study investigates the role of serum miR-548ag in regulating lipid metabolism and its contribution to MASLD in obesity. We found that miR-548ag levels were significantly elevated in the serum of both obese and MASLD patients and positively correlated with body mass index, fasting plasma glucose, triglycerides, total cholesterol, LDL, HDL, aspartate aminotransferase, and alanine aminotransferase levels. Additionally, miR-548ag expression was significantly higher in the liver and abdominal adipose tissue of obese individuals than those of normal weight. In vitro studies in HepG2 and L02 cells, along with previous findings, demonstrated that miR-548ag promotes fatty acid synthase (FASN) expression by inhibiting DNA methyltransferase 3B (DNMT3B), thereby enhancing lipid synthesis. This was confirmed in two mouse models: one with tail vein injections of miR-548ag mimic/inhibitor adeno-associated viruses and another with tail vein injections of exosomes from serum of normal-weight and obese individuals. Both models showed that miR-548ag upregulated FASN through DNMT3B inhibition, leading to increased lipid synthesis and larger hepatic lipid droplets, effects that were reversed by miR-548ag inhibition. Together, this study revealed a significant increase in the levels of exosome miR-548ag in the serum of obese patients, which reaches the liver through blood circulation. In the liver, miR-548ag can target and inhibit DNMT3B, upregulate FASN expression, and increase hepatic lipid synthesis, thereby promoting the development of MASLD.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100818"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12164036/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143986013","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

Plasmalogen. Quo vadis?

IF 5 2区医学

Journal of Lipid Research Pub Date : 2025-06-01 Epub Date: 2025-04-23 DOI: 10.1016/j.jlr.2025.100814

Katrin Watschinger

引用次数: 0

Global deletion of COX-2 attenuates hepatic inflammation but impairs metabolic homeostasis in diet-induced obesity. COX-2的整体缺失减轻了肝脏炎症，但损害了饮食性肥胖的代谢稳态。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2025-06-01 Epub Date: 2025-05-08 DOI: 10.1016/j.jlr.2025.100823

Jeyakumar Balakrishnan, Cyrus Desouza, Rishikesh Thakare, Yazen Alnouti, Viswanathan Saraswathi

{"title":"Global deletion of COX-2 attenuates hepatic inflammation but impairs metabolic homeostasis in diet-induced obesity.","authors":"Jeyakumar Balakrishnan, Cyrus Desouza, Rishikesh Thakare, Yazen Alnouti, Viswanathan Saraswathi","doi":"10.1016/j.jlr.2025.100823","DOIUrl":"10.1016/j.jlr.2025.100823","url":null,"abstract":"The role of cyclooxygenase-2 (COX-2), a well-known pharmacological target for attenuating inflammation, in regulating obesity and its comorbidities remains unclear. We sought to determine the role of COX-2 in modulating metabolic inflammation and systemic metabolic homeostasis in obesity. Male WT and COX-2 KO mice were fed a chow diet or a high fat diet (HF, 45% fat) for 13 weeks. While the body weight gain did not alter, the visceral adipose tissue mass was significantly higher in KO-HF mice than in WT-HF mice. Plasma triglycerides and total cholesterol levels were higher in KO-HF mice than in WT-HF mice. Total body fat mass was higher with a concomitant reduction in lean mass in KO-HF mice than in WT-HF mice. Paradoxically, hepatic steatosis was reduced in KO-HF mice. While liver triglycerides were reduced, the liver cholesterol was increased in KO-HF mice. Bile acids and markers of cholesterol biosynthesis were unaltered between WT-HF and KO-HF groups. The mRNA and/or protein levels of autophagy markers were significantly decreased in KO-HF mice compared to WT-HF mice, indicating that a reduction in autophagy may increase cholesterol levels in these mice. The liver inflammatory markers were significantly increased only in WT mice fed a HF diet but not in KO-HF fed mice compared to their respective controls. Visceral adipose tissue showed a reduction in inflammatory markers in spite of an increase in adiposity. These data suggest that despite being effective in attenuating the inflammatory processes, inhibition of COX-2 exerts undesirable consequences on metabolic homeostasis.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100823"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12197966/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144022803","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

Stearoyl-CoA desaturase 1 deficiency drives saturated lipid accumulation and increases liver and plasma acylcarnitines. 硬脂酰辅酶a去饱和酶1缺乏驱动饱和脂质积累，增加肝脏和血浆酰基肉碱。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2025-06-01 Epub Date: 2025-05-09 DOI: 10.1016/j.jlr.2025.100824

Mugagga Kalyesubula, Helaina Von Bank, Jessica W Davidson, Maggie S Burhans, Madelaine M Becker, Ahmed Aljohani, Judith Simcox, James M Ntambi

{"title":"Stearoyl-CoA desaturase 1 deficiency drives saturated lipid accumulation and increases liver and plasma acylcarnitines.","authors":"Mugagga Kalyesubula, Helaina Von Bank, Jessica W Davidson, Maggie S Burhans, Madelaine M Becker, Ahmed Aljohani, Judith Simcox, James M Ntambi","doi":"10.1016/j.jlr.2025.100824","DOIUrl":"10.1016/j.jlr.2025.100824","url":null,"abstract":"Stearoyl-CoA desaturase-1 (SCD1) is a critical regulator of lipogenesis that catalyzes the synthesis of MUFAs, mainly oleate (18:1n-9) and palmitoleate (16:1n-7) from saturated fatty acids, stearoyl-CoA (18:0) and palmitoyl-CoA (16:0), respectively. Elevated SCD1 expression and its products are associated with obesity, metabolic dysfunction-associated steatotic liver disease, insulin resistance, and cancer. Conversely, Scd1 deficiency diminishes de novo lipogenesis and protects mice against adiposity, hepatic steatosis, and hyperglycemia. Yet, the comprehensive impact of Scd1 deficiency on hepatic and circulating lipids remains incompletely understood. To further delineate the effects of SCD1 on lipid metabolism, we employed lipidomics on the liver from mice under a lipogenic high carbohydrate, very low-fat diet. We found that Scd1 deficiency leads to an accumulation of saturated lipids and an increase in hepatic and plasma acylcarnitines. Remarkably, transgenic replenishment of de novo oleate synthesis by human SCD5 in the liver of Scd1-deficient mice not only restored hepatic lipid desaturation levels but also attenuated acylcarnitine accumulation, highlighting the distinct role of SCD1 and oleate in regulating intracellular lipid homeostasis.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100824"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12173144/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144004896","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

Plaat1 deficiency reduces cardiac cardiolipin content and impairs exercise tolerance. Plaat1缺乏会降低心磷脂含量，损害运动耐受性。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2025-06-01 Epub Date: 2025-05-08 DOI: 10.1016/j.jlr.2025.100822

Ashkan Hashemi, Ming Rong Liu, John Z Chan, Antonia N Berdeklis, Alex D Cocco, Michelle V Tomczewski, Douglas Strathdee, Ken D Stark, Robin E Duncan

{"title":"Plaat1 deficiency reduces cardiac cardiolipin content and impairs exercise tolerance.","authors":"Ashkan Hashemi, Ming Rong Liu, John Z Chan, Antonia N Berdeklis, Alex D Cocco, Michelle V Tomczewski, Douglas Strathdee, Ken D Stark, Robin E Duncan","doi":"10.1016/j.jlr.2025.100822","DOIUrl":"10.1016/j.jlr.2025.100822","url":null,"abstract":"Phospholipase A and acyltransferase 1 (PLAAT1) catalyzes O-transacylase, N-transacylase, and phospholipase A1/2 reactions. We have demonstrated that PLAAT1 has O-transacylase activity in vitro using phosphatidylcholine as an acyl donor and monolysocardiolipin (MLCL) as an acyl acceptor, generating cardiolipin. However, a role for PLAAT1 in cardiolipin regulation in vivo has not yet been reported. We generated Plaat1-deficient (Plaat1-/-) mice and studied males and females for gross morphological differences, food intakes, respiratory gas exchange, total energy expenditure, and voluntary activity. We also evaluated cardiac cardiolipin contents, levels of mitochondrial proteins, and exercise capacity. Sex-matched Plaat1-/- mice had highly similar body weights to their wild-type (Wt) littermates, although male Plaat1-/- mice ate less. Male and female Plaat1-/- hearts were 14.2% and 10.6% smaller, respectively. Cardiac cardiolipin levels were ∼one-third lower in male and female Plaat1-/- mice compared to their sex-matched Wt littermates, largely due to lower cardiolipin linoleate. Levels of the mitochondrial protein succinate dehydrogenase complex flavoprotein subunit A were 13.8% and 16.3% lower in male and female Plaat1-/- mice, respectively. Both male and female Plaat1-/- mice had significantly lower oxygen consumption, carbon dioxide production, and total energy expenditure, and male Plaat1-/- mice had lower rearing activity than their sex-matched Wt littermates. While other measures of voluntary activity, including locomotion and ambulation did not differ significantly between genotypes, both males and females had reduced exercise tolerance. This work demonstrates a critical role for PLAAT1 in cardiac cardiolipin content and the regulation of energy metabolism and exercise tolerance in vivo.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100822"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12169743/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144014608","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 5 2区医学

Journal of Lipid Research Pub 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":5.0,"publicationDate":"2025-05-29","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

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 5 2区医学

Journal of Lipid Research Pub 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":5.0,"publicationDate":"2025-05-29","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