Publications

Analytical challenges of shotgun lipidomics at different resolution of measurements.
Wang J, Han X
TrAC Trends in Analytical Chemistry. 2019 Oct 17. doi: 10.1016/j.trac.2019.115697. [In press]

Abstract:

The essence of shotgun lipidomics is to maintain consistency of the chemical environment of lipid samples during mass spectrometry acquisition. This strategy is suitable for large-scale quantitative analysis. This strategy also allows sufficient time to collect data to improve the signal-to-noise ratio. The initial approach of shotgun lipidomics was the electrospray ionization (ESI)-based direct infusion mass spectrometry strategy. With development of mass spectrometry for small molecules, shotgun lipidomics methods have been extended to matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) and ambient mass spectrometry, including MS imaging methods. Furthermore, the object of analysis has extended from organ and body fluid levels to tissue and cell levels with technological developments. In this article, we summarize the status and technical challenges of shotgun lipidomics at different resolution of measurements from the mass spectrometry perspective.


Can Oral Health and Oral-derived Biospecimens Predict Progression of Dementia?
Orr ME, Reveles KR, Yeh CK, Young EH, Han X
Oral Diseases. 2019 Sep 21. doi: 10.1111/odi.13201. [Epub ahead of print]

Abstract:

Growing evidence indicates that oral health and brain health are interconnected. Declining cognition and dementia coincide with lack of self-preservation, including oral hygiene. The oral microbiota plays an important role in maintaining oral health. Emerging evidence suggests a link between oral dysbiosis and cognitive decline in patients with Alzheimer’s disease. This review showcases the recent advances connecting oral health and cognitive function during aging and the potential utility of oral-derived biospecimens to inform on brain health. Collectively, experimental findings indicate that the connection between oral health and cognition cannot be underestimated; moreover, oral biospecimens are abundant and readily obtainable without invasive procedures, which may help inform on cognitive health.


Neuronal microtubules impact lifespan.
Apple E, Chen L
Aging (Albany NY). 2019 Sep 6;11(17):6616-6617. doi: 10.18632/aging.102224. Epub 2019 Sep 6.


Loss of mitochondrial energetics is associated with poor recovery of muscle function but not mass following disuse atrophy.
Trevino MB, Zhang X, Standley RA, Wang M, Han X, Reis FCG, Periasamy M, Yu G, Kelly DP, Goodpaster BH, Vega RB, Coen PM
American Journal of Physiology. Endocrinology and Metabolism. 2019 Sep 3. doi: 10.1152/ajpendo.00161.2019. [Epub ahead of print]

Abstract:

Skeletal muscle atrophy is a clinically important outcome of disuse due to injury, immobilization and bed rest. Disuse atrophy is accompanied by mitochondrial dysfunction which likely contributes to activation of the muscle atrophy program. However, the linkage of muscle mass and mitochondrial energetics, during disuse atrophy and its recovery is incompletely understood. Transcriptomic analysis of muscle biopsies from healthy older adults subject to complete bed rest revealed marked inhibition of mitochondrial energy metabolic pathways. To determine the temporal sequence of muscle atrophy, and changes in intramyocellular lipid and mitochondrial energetics, we conducted a time course of hind limb unloading induced atrophy in adult mice. Mitochondrial respiration and calcium retention capacity were diminished while H2O2emission was increased in as soon as 3 days of unloading, prior to significant muscle atrophy. These changes were associated with a decrease in total cardiolipin and profound changes in remodeled cardiolipin species. Hindlimb unloading performed in muscle-specific PGC-1a/bknockout mice, a model of mitochondrial dysfunction, did not affect muscle atrophy but impacted muscle function. These data suggest early mitochondrial remodeling affects muscle function but not mass during disuse atrophy. Early alterations in mitochondrial energetics and lipid remodeling may represent novel targets to prevent muscle functional impairment caused by disuse and to enhance recovery from periods of muscle atrophy.


A Non-canonical Role of YAP/TEAD Is Required for Activation of Estrogen-Regulated Enhancers in Breast Cancer.
Zhu C, Li L, Zhang Z1 Bi M, Wang H, Su W, Hernandez K, Liu P, Chen J, Chen M, Huang TH, Chen L*, Liu Z*
Molecular Cell. 2019 Aug 22;75(4):791-806.e8. doi: 10.1016/j.molcel.2019.06.010. Epub 2019 Jul 11. *co-corresponding authors

Abstract:

YAP/TEAD are nuclear effectors of the Hippo pathway, regulating organ size and tumorigenesis largely through promoter-associated function. However, their function as enhancer regulators remains poorly understood. Through an in vivo proximity-dependent labeling (BioID) technique, we identified YAP1 and TEAD4 protein as co-regulators of ERα on enhancers. The binding of YAP1/TEAD4 to ERα-bound enhancers is augmented upon E2 stimulation and is required for the induction of E2/ERα target genes and E2-induced oncogenic cell growth. Furthermore, their enhancer binding is a prerequisite for enhancer activation marked by eRNA transcription and for the recruitment of the enhancer activation machinery component MED1. The binding of TEAD4 on active ERE-containing enhancers is independent of its DNA-binding behavior, and instead, occurs through protein-tethering trans-binding. Our data reveal a non-canonical function of YAP1 and TEAD4 as ERα cofactors in regulating cancer growth, highlighting the potential of YAP/TEAD as possible actionable drug targets for ERα+ breast cancer.


Tutorial on lipidomics.
Wang J, Wang C, Han X
Analytica Chimica Acta. 2019 Jul 11;1061:28-41. doi: 10.1016/j.aca.2019.01.043. Epub 2019 Feb 1.

Abstract:

The mainstream of lipidomics involves mass spectrometry-based, systematic, and large-scale studies of the structure, composition, and quantity of lipids in biological systems such as organs, cells, and body fluids. As increasingly more researchers in broad fields are beginning to pay attention to and actively learn about the lipidomic technology, some introduction on the topic is needed to help the newcomers to better understand the field. This tutorial seeks to introduce the basic knowledge about lipidomics and to provide readers with some core ideas and the most important approaches for studying the field.


Strategies to Improve/Eliminate the Limitations in Shotgun Lipidomics.
Hu C, Duan Q, Han X
Proteomics. 2019 Jul 10:e1900070. doi: 10.1002/pmic.201900070. [Epub ahead of print]

Abstract:

Direct infusion-based shotgun lipidomics is one of the most powerful and useful tools in comprehensive analysis of lipid species from lipid extracts of various biological samples with high accuracy/precision. However, despite many advantages, the classical shotgun lipidomics suffers some general dogmas of limitations, such as ion suppression, ambiguous identification of isobaric/isomeric lipid species, and ion source-generated artifacts, restraining the applications in analysis of low-abundance lipid species, particularly those less ionizable or isomers that yield almost identical fragmentation patterns. This article reviews the strategies (such as modifier addition, prefractionation, chemical derivatization, charge feature utilization) that have been employed to improve/eliminate these limitations in modern shotgun lipidomics approaches (e.g., high mass resolution mass spectrometry-based and multidimensional mass spectrometry-based shotgun lipidomics). Therefore, with the enhancement of these strategies for shotgun lipidomics, comprehensive analysis of lipid species including isomeric/isobaric species is achieved in a more accurate and effective manner, greatly substantiating the aberrant lipid metabolism, signaling trafficking, and homeostasis under pathological conditions.


MondoA drives muscle lipid accumulation and insulin resistance.
Ahn B, Wan S, Jaiswal N, Vega RB, Ayer DE, Titchenell PM, Han X, Won KJ, Kelly DP
JCI Insight. 2019 Jul 9;5. pii: 129119. doi: 10.1172/jci.insight.129119.

Abstract:

Obesity-related insulin resistance is associated with intramyocellular lipid accumulation in skeletal muscle. We hypothesized that in contrast to current dogma, this linkage is related to an upstream mechanism that coordinately regulates both processes. We demonstrate that the muscle-enriched transcription factor MondoA is glucose/fructose responsive in human skeletal myotubes and directs the transcription of genes in cellular metabolic pathways involved in diversion of energy substrate from a catabolic fate into nutrient storage pathways including fatty acid desaturation and elongation, triacylglyeride (TAG) biosynthesis, glycogen storage, and hexosamine biosynthesis. MondoA also reduces myocyte glucose uptake by suppressing insulin signaling. Mice with muscle-specific MondoA deficiency were partially protected from insulin resistance and muscle TAG accumulation in the context of diet-induced obesity. These results identify MondoA as a nutrient-regulated transcription factor that under normal physiological conditions serves a dynamic checkpoint function to prevent excess energy substrate flux into muscle catabolic pathways when myocyte nutrient balance is positive. However, in conditions of chronic caloric excess, this mechanism becomes persistently activated leading to progressive myocyte lipid storage and insulin resistance.


Association of Altered Liver Enzymes With Alzheimer Disease Diagnosis, Cognition, Neuroimaging Measures, and Cerebrospinal Fluid Biomarkers.
Nho K, Kueider-Paisley A, Ahmad S, MahmoudianDehkordi S, Arnold M, Risacher SL, Louie G, Blach C, Baillie R, Han X, Kastenmüller G, Trojanowski JQ, Shaw LM, Weiner MW, Doraiswamy PM, van Duijn C, Saykin AJ, Kaddurah-Daouk R; Alzheimer’s Disease Neuroimaging Initiative and the Alzheimer Disease Metabolomics Consortium.
JAMA Network Open. 2019 Jul 3;2(7):e197978. doi: 10.1001/jamanetworkopen.2019.7978.

Abstract:

Importance: Increasing evidence suggests an important role of liver function in the pathophysiology of Alzheimer disease (AD). The liver is a major metabolic hub; therefore, investigating the association of liver function with AD, cognition, neuroimaging, and CSF biomarkers would improve the understanding of the role of metabolic dysfunction in AD.

Objective: To examine whether liver function markers are associated with cognitive dysfunction and the “A/T/N” (amyloid, tau, and neurodegeneration) biomarkers for AD.

Design, Setting, and Participants: In this cohort study, serum-based liver function markers were measured from September 1, 2005, to August 31, 2013, in 1581 AD Neuroimaging Initiative participants along with cognitive measures, cerebrospinal fluid (CSF) biomarkers, brain atrophy, brain glucose metabolism, and amyloid-β accumulation. Associations of liver function markers with AD-associated clinical and A/T/N biomarkers were assessed using generalized linear models adjusted for confounding variables and multiple comparisons. Statistical analysis was performed from November 1, 2017, to February 28, 2019.

Exposures: Five serum-based liver function markers (total bilirubin, albumin, alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase) from AD Neuroimaging Initiative participants were used as exposure variables.

Main Outcomes and Measures: Primary outcomes included diagnosis of AD, composite scores for executive functioning and memory, CSF biomarkers, atrophy measured by magnetic resonance imaging, brain glucose metabolism measured by fludeoxyglucose F 18 (18F) positron emission tomography, and amyloid-β accumulation measured by [18F]florbetapir positron emission tomography.

Results: Participants in the AD Neuroimaging Initiative (n = 1581; 697 women and 884 men; mean [SD] age, 73.4 [7.2] years) included 407 cognitively normal older adults, 20 with significant memory concern, 298 with early mild cognitive impairment, 544 with late mild cognitive impairment, and 312 with AD. An elevated aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio and lower levels of ALT were associated with AD diagnosis (AST to ALT ratio: odds ratio, 7.932 [95% CI, 1.673-37.617]; P = .03; ALT: odds ratio, 0.133 [95% CI, 0.042-0.422]; P = .004) and poor cognitive performance (AST to ALT ratio: β [SE], -0.465 [0.180]; P = .02 for memory composite score; β [SE], -0.679 [0.215]; P = .006 for executive function composite score; ALT: β [SE], 0.397 [0.128]; P = .006 for memory composite score; β [SE], 0.637 [0.152]; P < .001 for executive function composite score). Increased AST to ALT ratio values were associated with lower CSF amyloid-β 1-42 levels (β [SE], -0.170 [0.061]; P = .04) and increased amyloid-β deposition (amyloid biomarkers), higher CSF phosphorylated tau181 (β [SE], 0.175 [0.055]; P = .02) (tau biomarkers) and higher CSF total tau levels (β [SE], 0.160 [0.049]; P = .02) and reduced brain glucose metabolism (β [SE], -0.123 [0.042]; P = .03) (neurodegeneration biomarkers). Lower levels of ALT were associated with increased amyloid-β deposition (amyloid biomarkers), and reduced brain glucose metabolism (β [SE], 0.096 [0.030]; P = .02) and greater atrophy (neurodegeneration biomarkers).

Conclusions and Relevance: Consistent associations of serum-based liver function markers with cognitive performance and A/T/N biomarkers for AD highlight the involvement of metabolic disturbances in the pathophysiology of AD. Further studies are needed to determine if these associations represent a causative or secondary role. Liver enzyme involvement in AD opens avenues for novel diagnostics and therapeutics.


Dynamic changes to lipid mediators support transitions among macrophage subtypes during muscle regeneration.
Giannakis N, Sansbury BE, Patsalos A, Hays TT, Riley CO, Han X, Spite M, Nagy L
Nature Immunology. 2019 May;20(5):626-636. doi: 10.1038/s41590-019-0356-7. Epub 2019 Apr 1.

Abstract:

Muscle damage elicits a sterile immune response that facilitates complete regeneration. Here, we used mass spectrometry-based lipidomics to map the mediator lipidome during the transition from inflammation to resolution and regeneration in skeletal muscle injury. We observed temporal regulation of glycerophospholipids and production of pro-inflammatory lipid mediators (for example, leukotrienes and prostaglandins) and specialized pro-resolving lipid mediators (for example, resolvins and lipoxins) that were modulated by ibuprofen. These time-dependent profiles were recapitulated in sorted neutrophils and Ly6Chi and Ly6Clo muscle-infiltrating macrophages, with a distinct pro-resolving signature observed in Ly6Clo macrophages. RNA sequencing of macrophages stimulated with resolvin D2 showed similarities to transcriptional changes found during the temporal transition from Ly6Chi macrophage to Ly6Clo macrophage. In vivo, resolvin D2 increased Ly6Clo macrophages and functional improvement of the regenerating muscle. These results reveal dynamic lipid mediator signatures of innate immune cells and provide a proof of concept for their exploitable effector roles in muscle regeneration.


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