Publications by authors named "Sin-Man Lam"

92 Publications

AGPAT2 interaction with CDP-diacylglycerol synthases promotes the flux of fatty acids through the CDP-diacylglycerol pathway.

Nat Commun 2021 Nov 25;12(1):6877. Epub 2021 Nov 25.

School of Biotechnology and Biomolecular Sciences, the University of New South Wales, Sydney, NSW, 2052, Australia.

AGPATs (1-acylglycerol-3-phosphate O-acyltransferases) catalyze the acylation of lysophosphatidic acid to form phosphatidic acid (PA), a key step in the glycerol-3-phosphate pathway for the synthesis of phospholipids and triacylglycerols. AGPAT2 is the only AGPAT isoform whose loss-of-function mutations cause a severe form of human congenital generalized lipodystrophy. Paradoxically, AGPAT2 deficiency is known to dramatically increase the level of its product, PA. Here, we find that AGPAT2 deficiency impairs the biogenesis and growth of lipid droplets. We show that AGPAT2 deficiency compromises the stability of CDP-diacylglycerol (DAG) synthases (CDSs) and decreases CDS activity in both cell lines and mouse liver. Moreover, AGPAT2 and CDS1/2 can directly interact and form functional complexes, which promote the metabolism of PA along the CDP-DAG pathway of phospholipid synthesis. Our results provide key insights into the regulation of metabolic flux during lipid synthesis and suggest substrate channelling at a major branch point of the glycerol-3-phosphate pathway.
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http://dx.doi.org/10.1038/s41467-021-27279-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8616899PMC
November 2021

Effect of the underlying malignancy on critically ill septic patient's outcome.

Asia Pac J Clin Oncol 2021 Nov 24. Epub 2021 Nov 24.

Department of Clinical Oncology, Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong.

Background: Sepsis is an important cause of mortality and morbidity among critically ill patients with underlying malignancy.

Methods: Patients with sepsis admitted to the intensive care unit (ICU) of the Pamela Youde Nethersole Eastern Hospital from January 1, 2010 to April 30, 2019 were recruited. Demographics, laboratory parameter, and outcome were analyzed. Those with underlying malignancy were matched with those without malignancy based on their severity of organ failure (defined by the sequential organ failure assessment [SOFA] score) and septic source.

Results: Two hundred sixty-three patients with underlying active malignancy were matched with 259 patients without malignancy. Those with malignancy had higher APACHE IV score (89 vs. 83), lower albumin (22.1 vs. 24.4), neutrophil count (6.0 vs. 9.3), hemoglobin (8.0 vs. 9.8), platelet count (113 vs. 133), less use of mechanical ventilation (35.7% vs. 45.9%), renal replacement therapy (22.1% vs. 28.2%) and vasopressor (66.2% vs. 74.9%), higher 30-day (34.2% vs. 24.3%) ICU (22.4% vs. 18.9%), and 1-year (62.4% vs. 36.7%) mortality compared with those without malignancy. A higher APACHE IV score and pulmonary sepsis were predictors of 30-day mortality by Cox regression analysis.

Conclusion: Disease severity and pulmonary sepsis, but not underlying malignancy, predicted short-term mortality among critically ill septic patients.
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http://dx.doi.org/10.1111/ajco.13638DOI Listing
November 2021

Targeted lipidomics reveals plasmalogen phosphatidylethanolamines and storage triacylglcyerols as the major systemic lipid aberrations in Bietti crystalline corneoretinal dystrophy.

J Genet Genomics 2021 Oct 25. Epub 2021 Oct 25.

Department of Ophthalmology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China. Electronic address:

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http://dx.doi.org/10.1016/j.jgg.2021.10.003DOI Listing
October 2021

Dogs lacking Apolipoprotein E show advanced atherosclerosis leading to apparent clinical complications.

Sci China Life Sci 2021 Oct 21. Epub 2021 Oct 21.

Key Laboratory of Molecular Developmental Biology, and CAS Center for Excellence in Brain Science and Intelligence Technology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China.

Atherosclerotic cardiovascular disease resulting from dysregulated lipid metabolism is the leading cause of morbidity and mortality worldwide. Apolipoprotein E (ApoE) plays a critical role in cholesterol metabolism. Knockouts in lipid-metabolizing proteins including ApoE in multiple model organisms such as mice and rats exhibiting elevated levels of cholesterol have been widely used for dissecting the pathology of atherosclerosis, but few of these animal models exhibit advanced atherosclerotic plaques leading to ischemia-induced clinical symptoms, limiting their use for translational studies. Here we report hypercholesterolemia and severe atherosclerosis characterized by stenosis and occlusion of arteries, together with clinical manifestations of stroke and gangrene, in ApoE knockout dogs generated by CRISPR/Cas9 and cloned by somatic cell nuclear transfer technologies. Importantly, the hypercholesterolemia and atherosclerotic complications in F0 mutants are recapitulated in their offspring. As the ApoE-associated atherosclerosis and clinical manifestations in mutant dogs are more similar to that in human patients compared with those in other animal models, these mutant dogs will be invaluable in developing and evaluating new therapies, including endovascular procedures, against atherosclerosis and related disorders.
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http://dx.doi.org/10.1007/s11427-021-2006-yDOI Listing
October 2021

The role of glutathione-mediated triacylglycerol synthesis in the response to ultra-high cadmium stress in Auxenochlorella protothecoides.

J Environ Sci (China) 2021 Oct 28;108:58-69. Epub 2021 Feb 28.

State Key Laboratory of Agrobiotechnology and Key Laboratory of Soil Microbiology, Ministry of Agriculture, College of Biological Sciences, China Agricultural University, Beijing 100193, China. Electronic address:

Under ultra-high cadmium (Cd) stress, large amounts of glutathione are produced in Auxenochlorella protothecoides UTEX 2341, and the lipid content increases significantly. Glutathione is the best reductant that can effectively remove Cd, but the relationship between lipid accumulation and the cellular response to Cd stress has not been ascertained. Integrating analyses of the transcriptomes and lipidomes, the mechanism of lipid accumulation to Cd tolerance were studied from the perspectives of metabolism, transcriptional regulation and protein glutathionylation. Under Cd stress, basic metabolic pathways, such as purine metabolism, translation and pre-mRNA splicing process, were inhibited, while the lipid accumulation pathway was significantly activated. Further analysis revealed that the transcription factors (TFs) and genes related to lipid accumulation were also activated. Analysis of the TF interaction sites showed that ABI5, MYB_rel and NF-YB could further regulate the expression of diacylglycerol acyltransferase through glutathionylation/deglutathionylation, which led to increase of the triacylglycerol (TAG) content. Lipidomes analysis showed that TAG could help maintain lipid homeostasis by adjusting its saturation/unsaturation levels. This study for the first time indicated that glutathione could activate TAG synthesis in microalga A. protothecoides, leading to TAG accumulation and glutathione accumulation under Cd stress. Therefore, the accumulation of TAG and glutathione can confer resistance to high Cd stress. This study provided insights into a new operation mode of TAG accumulation under heavy metal stress.
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http://dx.doi.org/10.1016/j.jes.2021.02.018DOI Listing
October 2021

Prokineticin-2 prevents neuronal cell deaths in a model of traumatic brain injury.

Nat Commun 2021 07 9;12(1):4220. Epub 2021 Jul 9.

Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

Prokineticin-2 (Prok2) is an important secreted protein likely involved in the pathogenesis of several acute and chronic neurological diseases through currently unidentified regulatory mechanisms. The initial mechanical injury of neurons by traumatic brain injury triggers multiple secondary responses including various cell death programs. One of these is ferroptosis, which is associated with dysregulation of iron and thiols and culminates in fatal lipid peroxidation. Here, we explore the regulatory role of Prok2 in neuronal ferroptosis in vitro and in vivo. We show that Prok2 prevents neuronal cell death by suppressing the biosynthesis of lipid peroxidation substrates, arachidonic acid-phospholipids, via accelerated F-box only protein 10 (Fbxo10)-driven ubiquitination, degradation of long-chain-fatty-acid-CoA ligase 4 (Acsl4), and inhibition of lipid peroxidation. Mice injected with adeno-associated virus-Prok2 before controlled cortical impact injury show reduced neuronal degeneration and improved motor and cognitive functions, which could be inhibited by Fbxo10 knockdown. Our study shows that Prok2 mediates neuronal cell deaths in traumatic brain injury via ferroptosis.
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http://dx.doi.org/10.1038/s41467-021-24469-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270965PMC
July 2021

A multi-omics investigation of the composition and function of extracellular vesicles along the temporal trajectory of COVID-19.

Nat Metab 2021 07 22;3(7):909-922. Epub 2021 Jun 22.

State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.

Exosomes represent a subtype of extracellular vesicle that is released through retrograde transport and fusion of multivesicular bodies with the plasma membrane. Although no perfect methodologies currently exist for the high-throughput, unbiased isolation of pure plasma exosomes, investigation of exosome-enriched plasma fractions of extracellular vesicles can confer a glimpse into the endocytic pathway on a systems level. Here we conduct high-coverage lipidomics with an emphasis on sterols and oxysterols, and proteomic analyses of exosome-enriched extracellular vesicles (EVs hereafter) from patients at different temporal stages of COVID-19, including the presymptomatic, hyperinflammatory, resolution and convalescent phases. Our study highlights dysregulated raft lipid metabolism that underlies changes in EV lipid membrane anisotropy that alter the exosomal localization of presenilin-1 (PS-1) in the hyperinflammatory phase. We also show in vitro that EVs from different temporal phases trigger distinct metabolic and transcriptional responses in recipient cells, including in alveolar epithelial cells, which denote the primary site of infection, and liver hepatocytes, which represent a distal secondary site. In comparison to the hyperinflammatory phase, EVs from the resolution phase induce opposing effects on eukaryotic translation and Notch signalling. Our results provide insights into cellular lipid metabolism and inter-tissue crosstalk at different stages of COVID-19 and are a resource to increase our understanding of metabolic dysregulation in COVID-19.
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http://dx.doi.org/10.1038/s42255-021-00425-4DOI Listing
July 2021

The Attenuation of Diabetic Nephropathy by Annexin A1 via Regulation of Lipid Metabolism Through the AMPK/PPARα/CPT1b Pathway.

Diabetes 2021 10 8;70(10):2192-2203. Epub 2021 Jun 8.

Renal Division, Department of Medicine, Peking University First Hospital; Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China

Inflammation and abnormal metabolism play important roles in the pathogenesis of diabetic nephropathy (DN). Annexin A1 (ANXA1) contributes to inflammation resolution and improves metabolism. In this study, we assess the effects of ANXA1 in diabetic mice and proximal tubular epithelial cells (PTECs) treated with high glucose plus palmitate acid (HGPA) and explore the association of ANXA1 with lipid accumulation in patients with DN. It is found that ANXA1 deletion aggravates renal injuries, including albuminuria, mesangial matrix expansion, and tubulointerstitial lesions in high-fat diet/streptozotocin-induced diabetic mice. ANXA1 deficiency promotes intrarenal lipid accumulation and drives mitochondrial alterations in kidneys. In addition, Ac2-26, an ANXA1 mimetic peptide, has a therapeutic effect against lipid toxicity in diabetic mice. In HGPA-treated human PTECs, ANXA1 silencing causes FPR2/ALX-driven deleterious effects, which suppress phosphorylated Thr AMPK, resulting in decreased peroxisome proliferator-activated receptor α and carnitine palmitoyltransferase 1b expression and increased HGPA-induced lipid accumulation, apoptosis, and elevated expression of proinflammatory and profibrotic genes. Last but not least, the extent of lipid accumulation correlates with renal function, and the level of tubulointerstitial ANXA1 expression correlates with ectopic lipid deposition in kidneys of patients with DN. These data demonstrate that ANXA1 regulates lipid metabolism of PTECs to ameliorate disease progression; hence, it holds great potential as a therapeutic target for DN.
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http://dx.doi.org/10.2337/db21-0050DOI Listing
October 2021

Architecture of the mycobacterial succinate dehydrogenase with a membrane-embedded Rieske FeS cluster.

Proc Natl Acad Sci U S A 2021 04;118(15)

State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin 300353, China;

Complex II, also known as succinate dehydrogenase (SQR) or fumarate reductase (QFR), is an enzyme involved in both the Krebs cycle and oxidative phosphorylation. Mycobacterial Sdh1 has recently been identified as a new class of respiratory complex II (type F) but with an unknown electron transfer mechanism. Here, using cryoelectron microscopy, we have determined the structure of Sdh1 in the presence and absence of the substrate, ubiquinone-1, at 2.53-Å and 2.88-Å resolution, respectively. Sdh1 comprises three subunits, two that are water soluble, SdhA and SdhB, and one that is membrane spanning, SdhC. Within these subunits we identified a quinone-binding site and a rarely observed Rieske-type [2Fe-2S] cluster, the latter being embedded in the transmembrane region. A mutant, where two His ligands of the Rieske-type [2Fe-2S] were changed to alanine, abolished the quinone reduction activity of the Sdh1. Our structures allow the proposal of an electron transfer pathway that connects the substrate-binding and quinone-binding sites. Given the unique features of Sdh1 and its essential role in , these structures will facilitate antituberculosis drug discovery efforts that specifically target this complex.
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http://dx.doi.org/10.1073/pnas.2022308118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054011PMC
April 2021

GM130 regulates pulmonary surfactant protein secretion in alveolar type II cells.

Sci China Life Sci 2021 Mar 16. Epub 2021 Mar 16.

Department of Health Sciences, Institute of Physical Science and Information Technology, Anhui University, Hefei, 230601, China.

Pulmonary surfactant is a lipid-protein complex secreted by alveolar type II epithelial cells and is essential for the maintenance of the delicate structure of mammalian alveoli to promote efficient gas exchange across the air-liquid barrier. The Golgi apparatus plays an important role in pulmonary surfactant modification and secretory trafficking. However, the physiological function of the Golgi apparatus in the transport of pulmonary surfactants is unclear. In the present study, deletion of GM130, which encodes for a matrix protein of the cis-Golgi cisternae, was shown to induce the disruption of the Golgi structure leading to impaired secretion of lung surfactant proteins and lipids. Specifically, the results of in vitro and in vivo analysis indicated that the loss of GM130 resulted in trapping of Sftpa in the endoplasmic reticulum, Sftpb and Sftpc accumulation in the Golgi apparatus, and an increase in the compensatory secretion of Sftpd. Moreover, global and epithelial-specific GM130 knockout in mice resulted in an enlargement of alveolar airspace and an increase in alveolar epithelial autophagy; however, surfactant repletion partially rescued the enlarged airspace defects in GM130-deficient mice. Therefore, our results demonstrate that GM130 and the mammalian Golgi apparatus play a critical role in the control of surfactant protein secretion in pulmonary epithelial cells.
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http://dx.doi.org/10.1007/s11427-020-1875-xDOI Listing
March 2021

The Unusual Homodimer of a Heme-Copper Terminal Oxidase Allows Itself to Utilize Two Electron Donors.

Angew Chem Int Ed Engl 2021 06 6;60(24):13323-13330. Epub 2021 May 6.

National Key Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing, 100101, China.

The heme-copper oxidase superfamily comprises cytochrome c and ubiquinol oxidases. These enzymes catalyze the transfer of electrons from different electron donors onto molecular oxygen. A B-family cytochrome c oxidase from the hyperthermophilic bacterium Aquifex aeolicus was discovered previously to be able to use both cytochrome c and naphthoquinol as electron donors. Its molecular mechanism as well as the evolutionary significance are yet unknown. Here we solved its 3.4 Å resolution electron cryo-microscopic structure and discovered a novel dimeric structure mediated by subunit I (CoxA2) that would be essential for naphthoquinol binding and oxidation. The unique structural features in both proton and oxygen pathways suggest an evolutionary adaptation of this oxidase to its hyperthermophilic environment. Our results add a new conceptual understanding of structural variation of cytochrome c oxidases in different species.
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http://dx.doi.org/10.1002/anie.202016785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251803PMC
June 2021

Author Correction: Cryo-EM structure of trimeric Mycobacterium smegmatis succinate dehydrogenase with a membrane-anchor SdhF.

Nat Commun 2021 Feb 23;12(1):1370. Epub 2021 Feb 23.

State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, 300353, Tianjin, China.

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http://dx.doi.org/10.1038/s41467-021-21616-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902622PMC
February 2021

Targeted lipidomics reveals associations between serum sphingolipids and insulin sensitivity measured by the hyperinsulinemic-euglycemic clamp.

Diabetes Res Clin Pract 2021 Mar 14;173:108699. Epub 2021 Feb 14.

Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University (Jiangsu Province Hospital), Nanjing, Jiangsu, China. Electronic address:

Aims: Sphingolipids(SPs) and their substrates and constituents, fatty acids (FAs), are implicated in the pathogenesis of various metabolic diseases associated. This study aimed to systematically investigate the associations between serum sphingolipids and insulin sensitivity as well as insulin secretion.

Methods: We conducted a lipidomics evaluation of molecularly distinct SPs in the serum of 86 consecutive Chinese adults using LC/MS. The glucose infusion rate over 30 min (GIR) was measured under steady conditions to assess insulin sensitivity by the gold standard hyperinsulinemic-euglycemic clamp. We created the ROC curves to detect the serum SMs diagnostic value.

Results: Total and subspecies of serum SMs and globotriaosyl ceramides (Gb3s) were positively related to GIR, free FAs (FFA 16:1, FFA20:4), some long chain GM3 and complex ceramide GluCers showed strong negative correlations with GIR. Notably, ROC curves showed that SM/Cer and SM d18:0/26:0 may be good serum lipid predictors of diagnostic indicators of insulin sensitivity close to conventional clinical indexes such as 1/HOMA-IR (areas under the curve > 0.80) based on GIR as standard diagnostic criteria, and (SM/Cer)/(BMI*LDLc) areas under the curve = 0.93) is the best.

Conclusions: These results provide novel associations between serum sphingolipid between insulin sensitivity measured by the hyperinsulinemic-euglycemic clamp and identify two specific SPs that may represent prognostic biomarkers for insulin sensitivity.
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http://dx.doi.org/10.1016/j.diabres.2021.108699DOI Listing
March 2021

Rebaudioside A Enhances Resistance to Oxidative Stress and Extends Lifespan and Healthspan in .

Antioxidants (Basel) 2021 Feb 8;10(2). Epub 2021 Feb 8.

State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.

Non-nutritive sweeteners are widely used in food and medicines to reduce energy content without compromising flavor. Herein, we report that Rebaudioside A (Reb A), a natural, non-nutritive sweetener, can extend both the lifespan and healthspan of . The beneficial effects of Reb A were principally mediated via reducing the level of cellular reactive oxygen species (ROS) in response to oxidative stress and attenuating neutral lipid accumulation with aging. Transcriptomics analysis presented maximum differential expression of genes along the target of rapamycin (TOR) signaling pathway, which was further confirmed by quantitative real-time PCR (qPCR); while lipidomics uncovered concomitant reductions in the levels of phosphatidic acids (PAs), phosphatidylinositols (PIs) and lysophosphatidylcholines (LPCs) in worms treated with Reb A. Our results suggest that Reb A attenuates aging by acting as effective cellular antioxidants and also in lowering the ectopic accumulation of neutral lipids.
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http://dx.doi.org/10.3390/antiox10020262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915623PMC
February 2021

High-coverage lipidomics for functional lipid and pathway analyses.

Anal Chim Acta 2021 Feb 25;1147:199-210. Epub 2020 Nov 25.

State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, People's Republic of China; University of Chinese Academy of Sciences, Beijing, People's Republic of China. Electronic address:

Rapid advances in front-end separation approaches and analytical technologies have accelerated the development of lipidomics, particularly in terms of increasing analytical coverage to encompass an expanding repertoire of lipids within a single analytical approach. Developments in lipid pathway analysis, however, have somewhat lingered behind, primarily due to (1) the lack of coherent alignment between lipid identifiers in common databases versus that generated from experiments, owing to the differing structural resolution of lipids at molecular level that is specific to the analytical approaches adopted by various laboratories; (2) the immense complexity of lipid metabolic relationships that may entail head group changes, fatty acyls modifications of various forms (e.g. elongation, desaturation, oxidation), as well as active remodeling that demands a multidimensional, panoramic view to take into account all possibilities in lipid pathway analyses. Herein, we discuss current efforts undertaken to address these challenges, as well as alternative form of "pathway analyses" that may be particularly useful for uncovering functional lipid interactions under different biological contexts. Consolidating lipid pathway analyses will be indispensable in facilitating the transition of lipidomics from its prior role of phenotype validation to a hypothesis-generating tool that uncovers novel molecular targets to drive downstream mechanistic pursuits under biomedical settings.
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http://dx.doi.org/10.1016/j.aca.2020.11.024DOI Listing
February 2021

AP2/ERF and R2R3-MYB family transcription factors: potential associations between temperature stress and lipid metabolism in Auxenochlorella protothecoides.

Biotechnol Biofuels 2021 Jan 15;14(1):22. Epub 2021 Jan 15.

State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China.

Background: Both APETALA2/Ethylene Responsive Factor (AP2/ERF) superfamily and R2R3-MYB family were from one of the largest diverse families of transcription factors (TFs) in plants, and played important roles in plant development and responses to various stresses. However, no systematic analysis of these TFs had been conducted in the green algae A. protothecoides heretofore. Temperature was a critical factor affecting growth and lipid metabolism of A. protothecoides. It also remained largely unknown whether these TFs would respond to temperature stress and be involved in controlling lipid metabolism process.

Results: Hereby, a total of six AP2 TFs, six ERF TFs and six R2R3-MYB TFs were identified and their expression profiles were also analyzed under low-temperature (LT) and high-temperature (HT) stresses. Meanwhile, differential adjustments of lipid pathways were triggered, with enhanced triacylglycerol accumulation. A co-expression network was built between these 18 TFs and 32 lipid-metabolism-related genes, suggesting intrinsic associations between TFs and the regulatory mechanism of lipid metabolism.

Conclusions: This study represented an important first step towards identifying functions and roles of AP2 superfamily and R2R3-MYB family in lipid adjustments and response to temperature stress. These findings would facilitate the biotechnological development in microalgae-based biofuel production and the better understanding of photosynthetic organisms' adaptive mechanism to temperature stress.
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http://dx.doi.org/10.1186/s13068-021-01881-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811268PMC
January 2021

Localized increases in CEPT1 and ATGL elevate plasmalogen phosphatidylcholines in HDLs contributing to atheroprotective lipid profiles in hyperglycemic GCK-MODY.

Redox Biol 2021 04 6;40:101855. Epub 2021 Jan 6.

State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, People's Republic of China; University of Chinese Academy of Sciences, Beijing, People's Republic of China. Electronic address:

Glucokinase-maturity onset diabetes of the young (GCK-MODY) represents a rare genetic disorder due to mutation in the glucokinase (GCK) gene. The low incidence of vascular complications in GCK-MODY makes it a natural paradigm for interrogating molecular mechanisms promoting vascular health under prolonged hyperglycemia. Clinical rate of misdiagnosis has remained high, and a reliable serum lipid biomarker that precedes genetic screening can facilitate correct diagnosis and treatment. Herein, we comprehensively quantitated 565 serum lipids from 25 classes in 105 subjects (42 nondiabetic controls, 30 GC K-MODY patients, 33 drug-naïve, and newly-onset T2D patients). At false-discovery rate (FDR) < 0.05, several phosphatidylcholines (PCs) and plasmalogen PCs were specifically increased in GCK-MODY, while triacylglycerols (TAGs) and diacylglycerols (DAGs) were reduced. Correlation matrices between lipids uncovered coregulation between plasmalogen PCs (PCps) and glycerolipid precursors was distinctly enhanced in GCK-MODY compared to T2D. Strengthened positive correlations between serum PCps and circulating HDLs was specifically observed in hyperglycemic subjects (i.e. T2D and GCK-MODY) compared to normglycemic controls, suggesting that HDL-PCps may elicit distinct physiological effects under hyperglycemia. Amongst GCK-MODY patients, individuals harboring variants of GCK mutations with elevated PCps also exhibited higher HDLs. Isolated HDLs displayed localized increases (p < 0.05) in very-long-chain PUFA-PCs and PCps in GCK-MODY. Protein analyses revealed elevated levels of HDL-resident ATGL (P = 0.003) and CEPT1 (P < 0.0001), which mediate critical steps of PCps production along the TAG-DAG-PC axis, in GCK-MODY relative to T2D. A panel of four lipids differentiated GCK-MODY from T2D with AUC of 0.950 (95% CI 0.903-9.997). This study provides the first evidence that enhanced recruitment of CEPT1 and ATGL onto HDLs essentially underlie the atheroprotective profiles associated with GCK-MODY. Resultant increases in the production of HDL-PCps and PUFA-PCs provides an active, circulating form of protection towards the vasculature of GCK-MODY, thereby lowering the incidence of vascular complications despite chronic exposure to hyperglycemia since birth.
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http://dx.doi.org/10.1016/j.redox.2021.101855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810764PMC
April 2021

Role of VAMP7-Dependent Secretion of Reticulon 3 in Neurite Growth.

Cell Rep 2020 12;33(12):108536

Université de Paris, Institute of Psychiatry and Neuroscience of Paris, INSERM U1266, Membrane Traffic in Healthy & Diseased Brain, 75014 Paris, France; GHU PARIS Psychiatrie & Neurosciences, 75014 Paris, France. Electronic address:

VAMP7 is involved in autophagy and in exocytosis-mediated neurite growth, two yet unconnected cellular pathways. Here, we find that nutrient restriction and activation of autophagy stimulate axonal growth, while autophagy inhibition leads to loss of neuronal polarity. VAMP7 knockout (KO) neuronal cells show impaired neurite growth, whereas this process is increased in autophagy-null ATG5 KO cells. We find that endoplasmic reticulum (ER)-phagy-related LC3-interacting-region-containing proteins Atlastin 3 and Reticulon 3 (RTN3) are more abundant in autophagy-related protein ATG5 KO and less abundant in VAMP7 KO secretomes. Treatment of neuronal cells with ATG5 or VAMP7 KO conditioned medium does not recapitulate the effect of these KOs on neurite growth. A nanobody directed against VAMP7 inhibits axonal overgrowth induced by nutrient restriction. Furthermore, expression of the inhibitory Longin domain of VAMP7 impairs the subcellular localization of RTN3 in neurons. We propose that VAMP7-dependent secretion of RTN3 regulates neurite growth.
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http://dx.doi.org/10.1016/j.celrep.2020.108536DOI Listing
December 2020

Comprehensive lipidomics in apoM mice reveals an overall state of metabolic distress and attenuated hepatic lipid secretion into the circulation.

J Genet Genomics 2020 09 3;47(9):523-534. Epub 2020 Oct 3.

Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China. Electronic address:

Apolipoprotein M (apoM) participates in both high-density lipoprotein and cholesterol metabolism. Little is known about how apoM affects lipid composition of the liver and serum. In this study, we systemically investigated the effects of apoM on liver and plasma lipidomes and how apoM participates in lipid cycling, via apoM knockout in mice and the human SMMC-7721 cell line. We used integrated mass spectrometry-based lipidomics approaches to semiquantify more than 600 lipid species from various lipid classes, which include free fatty acids, glycerolipids, phospholipids, sphingolipids, glycosphingolipids, cholesterol, and cholesteryl esters (CEs), in apoM mouse. Hepatic accumulation of neutral lipids, including CEs, triacylglycerols, and diacylglycerols, was observed in apoM mice; while serum lipidomic analyses showed that, in contrast to the liver, the overall levels of CEs and saturated/monounsaturated fatty acids were markedly diminished. Furthermore, the level of ApoB-100 was dramatically increased in the liver, whereas significant reductions in both ApoB-100 and low-density lipoprotein (LDL) cholesterol were observed in the serum of apoM mice, which indicated attenuated hepatic LDL secretion into the circulation. Lipid profiles and proinflammatory cytokine levels indicated that apoM leads to hepatic steatosis and an overall state of metabolic distress. Taken together, these results revealed that apoM knockout leads to hepatic steatosis, impaired lipid secretion, and an overall state of metabolic distress.
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http://dx.doi.org/10.1016/j.jgg.2020.08.003DOI Listing
September 2020

RICE ACYL-COA-BINDING PROTEIN6 Affects Acyl-CoA Homeostasis and Growth in Rice.

Rice (N Y) 2020 Nov 6;13(1):75. Epub 2020 Nov 6.

School of Biological Sciences, The University of Hong Kong, Pokfulam, Hong Kong.

Backgrounds: Acyl-coenzyme A (CoA) esters are important intermediates in lipid metabolism with regulatory properties. Acyl-CoA-binding proteins bind and transport acyl-CoAs to fulfill these functions. RICE ACYL-COA-BINDING PROTEIN6 (OsACBP6) is currently the only one peroxisome-localized plant ACBP that has been proposed to be involved in β-oxidation in transgenic Arabidopsis. The role of the peroxisomal ACBP (OsACBP6) in rice (Oryza sativa) was investigated.

Results: Here, we report on the function of OsACBP6 in rice. The osacbp6 mutant showed diminished growth with reduction in root meristem activity and leaf growth. Acyl-CoA profiling and lipidomic analysis revealed an increase in acyl-CoA content and a slight triacylglycerol accumulation caused by the loss of OsACBP6. Comparative transcriptomic analysis discerned the biological processes arising from the loss of OsACBP6. Reduced response to oxidative stress was represented by a decline in gene expression of a group of peroxidases and peroxidase activities. An elevation in hydrogen peroxide was observed in both roots and shoots/leaves of osacbp6. Taken together, loss of OsACBP6 not only resulted in a disruption of the acyl-CoA homeostasis but also peroxidase-dependent reactive oxygen species (ROS) homeostasis. In contrast, osacbp6-complemented transgenic rice displayed similar phenotype to the wild type rice, supporting a role for OsACBP6 in the maintenance of the acyl-CoA pool and ROS homeostasis. Furthermore, quantification of plant hormones supported the findings observed in the transcriptome and an increase in jasmonic acid level occurred in osacbp6.

Conclusions: In summary, OsACBP6 appears to be required for the efficient utilization of acyl-CoAs. Disruption of OsACBP6 compromises growth and led to provoked defense response, suggesting a correlation of enhanced acyl-CoAs content with defense responses.
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http://dx.doi.org/10.1186/s12284-020-00435-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7647982PMC
November 2020

Neuronal lipolysis participates in PUFA-mediated neural function and neurodegeneration.

EMBO Rep 2020 11 9;21(11):e50214. Epub 2020 Oct 9.

State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.

Lipid droplets (LDs) are dynamic cytoplasmic organelles present in most eukaryotic cells. The appearance of LDs in neurons is not usually observed under physiological conditions, but is associated with neural diseases. It remains unclear how LD dynamics is regulated in neurons and how the appearance of LDs affects neuronal functions. We discovered that mutations of two key lipolysis genes atgl-1 and lid-1 lead to LD appearance in neurons of Caenorhabditis elegans. This neuronal lipid accumulation protects neurons from hyperactivation-triggered neurodegeneration, with a mild decrease in touch sensation. We also discovered that reduced biosynthesis of polyunsaturated fatty acids (PUFAs) causes similar effects and synergizes with decreased lipolysis. Furthermore, we demonstrated that these changes in lipolysis and PUFA biosynthesis increase PUFA partitioning toward triacylglycerol, and reduced incorporation of PUFAs into phospholipids increases neuronal protection. Together, these results suggest the crucial role of neuronal lipolysis in cell-autonomous regulation of neural functions and neurodegeneration.
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http://dx.doi.org/10.15252/embr.202050214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645260PMC
November 2020

Constant Light Exposure Alters Gut Microbiota and Promotes the Progression of Steatohepatitis in High Fat Diet Rats.

Front Microbiol 2020 21;11:1975. Epub 2020 Aug 21.

Department of Endocrinology, Xiangya Hospital, Central South University, Changsha, China.

Background: Non-alcoholic fatty liver disease (NAFLD) poses a significant health concern worldwide. With the progression of urbanization, light pollution may be a previously unrecognized risk factor for NAFLD/NASH development. However, the role of light pollution on NAFLD is insufficiently understood, and the underlying mechanism remains unclear. Interestingly, recent studies indicate the gut microbiota affects NAFLD/NASH development. Therefore, the present study explored effects of constant light exposure on NAFLD and its related microbiotic mechanisms.

Materials And Methods: Twenty-eight SD male rats were divided into four groups ( = 7 each): rats fed a normal chow diet, and exposed to standard light-dark cycle (ND-LD); rats fed a normal chow diet, and exposed to constant light (ND-LL); rats fed a high fat diet, and exposed to standard light-dark cycle (HFD-LD); and rats on a high fat diet, and exposed to constant light (HFD-LL). Body weight, hepatic pathophysiology, gut microbiota, and short/medium chain fatty acids in colon contents, serum lipopolysaccharide (LPS), and liver LPS-binding protein (LBP) mRNA expression were documented post intervention and compared among groups.

Result: In normal chow fed groups, rats exposed to constant light displayed glucose abnormalities and dyslipidemia. In HFD-fed rats, constant light exposure exacerbated glucose abnormalities, insulin resistance, inflammation, and liver steatohepatitis. Constant light exposure altered composition of gut microbiota in both normal chow and HFD fed rats. Compared with HFD-LD group, HFD-LL rats displayed less , and , butyrate levels in colon contents, decreased colon expression of occludin-1 and zonula occluden-1 (ZO-1), and increased serum LPS and liver LBP mRNA expression.

Conclusion: Constant light exposure impacts gut microbiota and its metabolic products, impairs gut barrier function and gut-liver axis, promotes NAFLD/NASH progression in HFD rats.
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http://dx.doi.org/10.3389/fmicb.2020.01975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472380PMC
August 2020

Discovery of broad-spectrum fungicides that block septin-dependent infection processes of pathogenic fungi.

Nat Microbiol 2020 12 21;5(12):1565-1575. Epub 2020 Sep 21.

State Key Laboratory of Crop Gene Exploration and Utilization in Southwest China, Key Laboratory of Major Crop Diseases & Collaborative Innovation Center for Hybrid Rice in Yangtze River Basin, Rice Research Institute, Sichuan Agricultural University, Chengdu, China.

Many pathogenic fungi depend on the development of specialized infection structures called appressoria to invade their hosts and cause disease. Impairing the function of fungal infection structures therefore provides a potential means by which diseases could be prevented. In spite of this extraordinary potential, however, relatively few anti-penetrant drugs have been developed to control fungal diseases, of either plants or animals. In the present study, we report the identification of compounds that act specifically to prevent fungal infection. We found that the organization of septin GTPases, which are essential for appressorium-mediated infection in the rice blast fungus Magnaporthe oryzae, requires very-long-chain fatty acids (VLCFAs), which act as mediators of septin organization at membrane interfaces. VLCFAs promote septin recruitment to curved plasma membranes and depletion of VLCFAs prevents septin assembly and host penetration by M. oryzae. We observed that VLCFA biosynthesis inhibitors not only prevent rice blast disease, but also show effective, broad-spectrum fungicidal activity against a wide range of fungal pathogens of maize, wheat and locusts, without affecting their respective hosts. Our findings reveal a mechanism underlying septin-mediated infection structure formation in fungi and provide a class of fungicides to control diverse diseases of plants and animals.
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http://dx.doi.org/10.1038/s41564-020-00790-yDOI Listing
December 2020

Cryo-EM structure of trimeric Mycobacterium smegmatis succinate dehydrogenase with a membrane-anchor SdhF.

Nat Commun 2020 08 25;11(1):4245. Epub 2020 Aug 25.

State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, 300353, Tianjin, China.

Diheme-containing succinate:menaquinone oxidoreductases (Sdh) are widespread in Gram-positive bacteria but little is known about the catalytic mechanisms they employ for succinate oxidation by menaquinone. Here, we present the 2.8 Å cryo-electron microscopy structure of a Mycobacterium smegmatis Sdh, which forms a trimer. We identified the membrane-anchored SdhF as a subunit of the complex. The 3 kDa SdhF forms a single transmembrane helix and this helix plays a role in blocking the canonically proximal quinone-binding site. We also identified two distal quinone-binding sites with bound quinones. One distal binding site is formed by neighboring subunits of the complex. Our structure further reveals the electron/proton transfer pathway for succinate oxidation by menaquinone. Moreover, this study provides further structural insights into the physiological significance of a trimeric respiratory complex II. The structure of the menaquinone binding site could provide a framework for the development of Sdh-selective anti-mycobacterial drugs.
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http://dx.doi.org/10.1038/s41467-020-18011-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447783PMC
August 2020

Rnf20 deficiency in adipocyte impairs adipose tissue development and thermogenesis.

Protein Cell 2021 06 14;12(6):475-492. Epub 2020 Aug 14.

State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, 100193, China.

RNF20, an E3 ligase critical for monoubiquitination of histone H2B at lysine 120 (H2Bub), has been implicated in the regulation of various cellar processes; however, its physiological roles in adipocytes remain poorly characterized. Here, we report that the adipocyte-specific knockout of Rnf20 (ASKO) in mice led to progressive fat loss, organomegaly and hyperinsulinemia. Despite signs of hyperinsulinemia, normal insulin sensitivity and improved glucose tolerance were observed in the young and aged CD-fed ASKO mice. In addition, high-fat diet-fed ASKO mice developed severe liver steatosis. Moreover, we observed that the ASKO mice were extremely sensitive to a cold environment due to decreased expression levels of brown adipose tissue (BAT) selective genes, including uncoupling protein 1 (Ucp1), and impaired mitochondrial functions. Significantly decreased levels of peroxisome proliferator-activated receptor gamma (Pparγ) were observed in the gonadal white adipose tissues (gWAT) from the ASKO mice, suggesting that Rnf20 regulates adipogenesis, at least in part, through Pparγ. Rosiglitazone-treated ASKO mice exhibited increased fat mass compared to that of the non-treated ASKO mice. Collectively, our results illustrate the critical role of RNF20 in control of white and brown adipose tissue development and physiological function.
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http://dx.doi.org/10.1007/s13238-020-00770-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160045PMC
June 2021

Comprehensive Lipidome Profiling of the Kidney in Early-Stage Diabetic Nephropathy.

Front Endocrinol (Lausanne) 2020 19;11:359. Epub 2020 Jun 19.

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Peking Union Medical College, Beijing Key Laboratory of Drug Target, Screening Research, Chinese Academy of Medical Sciences, Beijing, China.

Metabolic changes associated with diabetes are reported to lead to the onset of early-stage diabetic nephropathy (DN). Furthermore, lipotoxicity is implicated in renal dysfunction. Most studies of DN have focused on a single or limited number of lipids, and the lipidome of the kidney during early-stage DN remains to be elucidated. In the present study, we aimed to comprehensively identify lipid abnormalities during early-stage DN; to this end, we established an early-stage DN rat model by feeding a high-sucrose and high-fat diet combined with administration of low-dose streptozotocin. Using a high-coverage, targeted lipidomic approach, we established the lipid profile, comprising 437 lipid species and 25 lipid classes, of the kidney cortex in normal rats and the DN rat model. Our findings additionally confirmed that the DN rat model had been successfully established. We observed distinct lipidomic signatures in the DN kidney, with characteristic alterations in side chain composition and degree of unsaturation. Glyceride lipids, especially cholesteryl esters, showed a significant increase in the DN kidney cortex. The levels of most phospholipids exhibited a decline, except those of phospholipids with side chain of 36:1. Furthermore, the levels of lyso-phospholipids and sphingolipids, including ceramide and its derivatives, were dramatically elevated in the present DN rat model. Our findings, which provide a comprehensive lipidome of the kidney cortex in rats with DN, are expected to be useful for the identification of pathologically relevant lipid species in DN. Furthermore, the results represent novel insights into the mechanistic basis of DN.
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http://dx.doi.org/10.3389/fendo.2020.00359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325916PMC
May 2021

Omics-Driven Systems Interrogation of Metabolic Dysregulation in COVID-19 Pathogenesis.

Cell Metab 2020 08 24;32(2):188-202.e5. Epub 2020 Jun 24.

State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China. Electronic address:

The coronavirus disease 2019 (COVID-19) pandemic presents an unprecedented threat to global public health. Herein, we utilized a combination of targeted and untargeted tandem mass spectrometry to analyze the plasma lipidome and metabolome in mild, moderate, and severe COVID-19 patients and healthy controls. A panel of 10 plasma metabolites effectively distinguished COVID-19 patients from healthy controls (AUC = 0.975). Plasma lipidome of COVID-19 resembled that of monosialodihexosyl ganglioside (GM3)-enriched exosomes, with enhanced levels of sphingomyelins (SMs) and GM3s, and reduced diacylglycerols (DAGs). Systems evaluation of metabolic dysregulation in COVID-19 was performed using multiscale embedded differential correlation network analyses. Using exosomes isolated from the same cohort, we demonstrated that exosomes of COVID-19 patients with elevating disease severity were increasingly enriched in GM3s. Our work suggests that GM3-enriched exosomes may partake in pathological processes related to COVID-19 pathogenesis and presents the largest repository on the plasma lipidome and metabolome distinct to COVID-19.
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http://dx.doi.org/10.1016/j.cmet.2020.06.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311890PMC
August 2020

Lipidomics insight into chronic exposure to ambient air pollution in mice.

Environ Pollut 2020 Jul 24;262:114668. Epub 2020 Apr 24.

School of Basic Medical Sciences and Public Health, Joint China-US Research Center for Environment and Pulmonary Diseases, Zhejiang Chinese Medical University, Hangzhou, China. Electronic address:

More recent evidences are supportive of air pollution exposure on diabetes risk, including worsening of whole-body insulin sensitivity, enhancement of hepatic lipogenesis and nonalcoholic fatty liver disease after fine particulate matter (PM) exposure. Therefore, we aimed to explore the lipidomics to get a comprehensive insight about ambient real-world PM exposure on lipid metabolism in blood and liver. After ambient PM exposure for 6 months, excess triglyceride accumulation in the liver was observed. Remarkable metabolic alterations including neutral lipids, glycerophospholipids and sphingolipids were noticed. Lipidomic signatures in liver is different from plasma in response to PM exposure. Lipids including species of ceramide, sphingomyeline and triglyceride may become potential biomarkers of lipotoxicity contributing to PM-induced metabolic dysfunction, and the present study may serve as a reference lipid bank for further studies.
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http://dx.doi.org/10.1016/j.envpol.2020.114668DOI Listing
July 2020

Sex-dependent effects of ambient PM pollution on insulin sensitivity and hepatic lipid metabolism in mice.

Part Fibre Toxicol 2020 04 22;17(1):14. Epub 2020 Apr 22.

School of Basic Medical Sciences and Public Health, Zhejiang Chinese Medical University, 548 Binwen Rd, Building 15#, Room 215, Hangzhou, 310053, China.

Background & Aims: Emerging evidence supports ambient fine particulate matter (PM) exposure is associated with insulin resistance (IR) and hepatic lipid accumulation. In this study, we aimed to evaluate the sex-dependent vulnerability in response to PM exposure and investigate the underlying mechanism by which PM modulates hepatic lipid metabolism.

Methods: Both male and female C57BL/6 mice were randomly assigned to ambient PM or filtered air for 24 weeks via a whole body exposure system. High-coverage quantitative lipidomics approaches and liquid chromatography-mass spectrometry techniques were performed to measure hepatic metabolites and hormones in plasma. Metabolic studies, histological analyses, as well as gene expression levels and molecular signal transduction analysis were applied to examine the effects and mechanisms by which PM exposure-induced metabolic disorder.

Results: Female mice were more susceptible than their male counterparts to ambient PM exposure-induced IR and hepatic lipid accumulation. The hepatic lipid profile was changed in response to ambient PM exposure. Levels of hepatic triacylglycerols (TAGs), free fatty acids (FFAs) and cholesterol were only increased in female mice from PM group compared to control group. Plasmalogens were dysregulated in the liver from PM-exposed mice as well. In addition, exposure to PM led to enhanced hepatic ApoB and microsomal triglyceride transport protein expression in female mice. Finally, PM exposure inhibited hypothalamus-pituitary-adrenal (HPA) axis and decreased glucocorticoids levels, which may contribute to the vulnerability in PM-induced metabolic dysfunction.

Conclusions: Ambient PM exposure inhibited HPA axis and demonstrated sex-associated differences in its effects on IR and disorder of hepatic lipid metabolism. These findings provide new mechanistic evidence of hormone regulation in air pollution-mediated metabolic abnormalities of lipids and more personalized care should be considered in terms of sex-specific risk factors.
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http://dx.doi.org/10.1186/s12989-020-00343-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178763PMC
April 2020
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